Urinary disorder improvement agent

Abstract

To provide a dysuria-alleviating agent useful for treating or alleviating (or mitigating) dysuria regardless of the presence or degree of prostatomegaly.SOLUTION: A dysuria-alleviating agent includes, as an active ingredient, a 2-oxapregnane compound represented by formula (1) (where, R1 to R3 represent an alkyl group such as a methyl group, R4 represents an alkylcarbonyl group such as an acetyl group, X represents a halogen atom such as a chlorine atom, and Y represents a hydroxyl group or an oxo group bonded at the position 11, 15, or 16 of a steroid skeleton).SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to an agent for improving dysuria, which comprises a pregnane compound or a pharma- ceutical acceptable salt thereof as an active ingredient and is useful for improving dysuria such as residual urine sensation. [Background technology]

[0002] As the aging society progresses, it is becoming important to improve or alleviate diseases or symptoms of urinary disorders in the elderly, such as difficulty in urination, residual urine sensation, frequent urination, and urinary incontinence. As an improving agent for improving such urinary disorders, JP-A-5-155773 (Patent Document 1) describes a xanthine derivative that is effective in treating and preventing urinary disorders such as frequent urination or urinary incontinence, and JP-A-8-3045 (Patent Document 2) describes a urinary disorder improving drug containing an N-substituted indole derivative as an active ingredient. WO2012 / 020749 (Patent Document 3) describes a triazine derivative and a pharmaceutical composition containing the same that has an analgesic effect or an urinary disorder improving effect.

[0003] In addition, alpha-1 blockers, 5α-reductase inhibitors, and other drugs are available on the market to improve urinary disorders. 5α-reductase inhibitors suppress the production of dihydrotestosterone from testosterone, shrinking an enlarged prostate and improving urinary disorders.

[0004] Japanese Patent Application Laid-Open No. 61-204198 (Patent Document 4) and Endocrine Journal 1994, 41(4), 445-452 (Non-Patent Document 1) describe TZP-4238 (17α-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione) as an anti-androgenic agent, and also describe that TZP-4238 is useful for treating diseases such as prostatic hyperplasia and prostatic cancer.

[0005] In addition, Japanese Patent No. 2591640 (Patent Document 5) describes 2-oxapregnane compounds such as 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione as compounds having antiandrogenic activity. This document describes that the compounds are useful as therapeutic agents for androgen-dependent diseases such as prostatic hyperplasia, prostatic cancer, and alopecia.

[0006] In addition, with regard to plant preparations, JP 2011-20972 A (Patent Document 6) describes an agent for improving dysuria that contains a saw palmetto fruit extract and contains oleic acid and myristic acid in a ratio of 1:0 to 2:3. This Patent Document 6 describes that with aging, the prostate gland in men becomes enlarged, and the part close to the urethra (periurethral gland) proliferates and becomes larger (mechanical obstruction), and dihydrotestosterone accumulates in the prostate, causing benign prostate hyperplasia (BPH), and describes that symptoms of benign prostate hyperplasia include lower urinary tract symptoms such as difficulty in urination and frequent urination.

[0007] However, prostate hypertrophy does not necessarily lead to dysuria.For example, World Journal of Urology, 13, 9-13 (1995) (Non-Patent Document 2) reports that there is a statistically significant relationship between prostate size and urethral obstruction, but there is no correlation between symptoms of dysuria and the degree of urethral obstruction or prostate size.

[0008] The Journal of Urology, 150, 351-358 August 1993 (Non-Patent Document 3) reports that there is no correlation between prostate size and residual urine volume, and that there is no correlation between residual urine volume, prostate size and various symptoms.Specifically, a correlation matrix is ​​described for patients with benign prostatic hyperplasia (BPH), and it is described that, despite a relatively large sample size, there is no statistically significant relationship between the severity of symptoms and residual urine volume, prostate size or prostate specific antigen (PSA) level, and it is described that prostate hyperplasia, which is also a characteristic of BPH, is not a decisive factor in the generation of either symptoms or physiological lower obstruction, and that in some patients (individuals), even a small degree of hyperplasia around the urethra can cause physiological disorders, while in other patients (individuals), significant hyperplasia can occur without causing disorders.

[0009] Therefore, there is a need for an effective treatment or improvement of dysuria regardless of the degree or presence of prostatic hyperplasia. Furthermore, in the treatment of dysuria, drugs are administered for a long period of time to elderly patients and other such patients, and therefore high safety is required in addition to high therapeutic efficacy. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] JP 5-155773 A (Claims) [Patent Document 2] JP 8-3045 A (Claims) [Patent Document 3] WO2012 / 020749(Claims) [Patent Document 4] JP 61-204198 A (Claims, page 1, right column) [Patent Document 5] Patent No. 2591640 (Claims, column 11, line 49 to column 12, line 49) [Patent Document 6] JP 2011-20972 A (Claims,

[0002] ) [Non-patent literature]

[0011] [Non-Patent Document 1] Endocrine Journal 1994, 41(4), 445-452 [Non-Patent Document 2] World Journal of Urology, 13, 9-13 (1995) (Summary) [Non-Patent Document 3] The Journal of Urology, 150, 351-358 August 1993 (Page 354, right column, lines 5 to 10, page 355, left column, lines 9 from the bottom to right column, lines 6, Table 3, Table 5) Summary of the Invention [Problem to be solved by the invention]

[0012] Accordingly, an object of the present invention is to provide an agent for improving dysuria that is useful for treating or improving (or alleviating) dysuria.

[0013] Another object of the present invention is to provide an agent for improving dysuria which is highly safe and useful for treating or improving dysuria with a high therapeutic or improving effect even when administered over a long period of time.

[0014] A further object of the present invention is to provide an agent for improving dysuria which is useful for treating or alleviating dysuria, regardless of the degree or presence of prostatic hyperplasia. [Means for solving the problem]

[0015] In order to achieve the above object, the present inventors have intensively studied the relationship between 2-oxapregnan compounds having high antiandrogenic activity and dysuria, and have found that even 2-oxapregnan compounds having high antiandrogenic activity have a large difference in the improvement of dysuria depending on the presence or absence of a hydroxyl group or an oxo group at a specific site of the steroid skeleton. That is, a compound that does not have a hydroxyl group substituted at a specific site of the steroid skeleton has high antiandrogenic activity, but does not show any therapeutic effect on dysuria in subjects without prostatic hyperplasia, whereas a compound that has a hydroxyl group or an oxo group substituted at a specific site of the steroid skeleton shows a high therapeutic or ameliorative effect on dysuria regardless of the presence or absence of prostatic hyperplasia. The present invention has been completed based on these findings.

[0016] That is, the agent for improving dysuria of the present invention contains, as an active ingredient, a 2-oxapregnane compound represented by the following formula (1) or a pharma- ceutically acceptable salt thereof, in which the steroid skeleton in the following formula (1) is numbered by position.

[0017] [ka]

[0018] (wherein R1 to R3 are the same or different and each represents an alkyl group; R4 represents a hydrogen atom or an alkylcarbonyl group; X represents a halogen atom; and Y represents a hydroxyl group or an oxo group bonded to the 11th, 15th, or 16th position of the steroid skeleton).

[0019] R1 to R3 are the same or different and are C 1-4 R4 may be an alkyl group (e.g., a methyl group), and R4 may be a lower alkanoyl group or an acyl group (C 1-4The halogen atom represented by X may be a chlorine atom, and Y may be a hydroxyl group or an oxo group bonded to the 15-position of the steroid skeleton. The representative 2-oxapregnane compound represented by formula (1) may be 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione.

[0020] The compound or a pharma- ceutically acceptable salt thereof is useful for preventing, treating, or improving or alleviating urination disorders or symptoms. The urination disorder may be, for example, at least one urination disorder (or disease) or symptom selected from residual urine, weak urine flow, hesitancy, straining urination, terminal dribbling, post-void dribbling, urinary incontinence (including urgency, stress, mixed, and overflow), frequent urination (including daytime, nocturnal, and psychogenic), urgency, bladder pain or bladder pain syndrome, pain during urination, bladder atrophy, neurogenic bladder, detrusor overactivity or overactive bladder (including essential, neurogenic, and refractory), chronic cystitis, interstitial cystitis, chronic prostatitis, pelvic pain syndrome, underactive bladder, detrusor hyperreflexia and detrusor contraction dysfunction, etc. The agent for improving urination disorder of the present invention is useful for improving at least one urination disorder or symptom selected from residual urine volume, urination efficiency, bladder capacity, bladder wet weight, and kidney wet weight. Specifically, the compound or a pharma- ceutically acceptable salt thereof shows a high therapeutic or improving effect on urination disorder, regardless of the presence or absence of prostatic hyperplasia. That is, the urination disorder may be either urination disorder without prostatic hyperplasia or urination disorder associated with prostatic hyperplasia. Therefore, the subject having urination disorder may be either male or female (male and female). In addition, the urination disorder may be urination disorder associated with a disorder of smooth muscle contraction. Furthermore, the urination disorder may be urination disorder associated with at least one disease selected from diseases causing neurogenic bladder, diabetes, and neuropathy associated with diabetes. The agent for improving urination disorder may improve or promote urination. Therefore, the agent for improving urination disorder may be called an agent for improving urination or an agent for promoting urination.

[0021] The present invention also includes a method for treating, improving, or alleviating dysuria (as well as a method for improving or promoting urination) by administering a 2-oxapregnan compound represented by the formula (1) or a pharma- ceutically acceptable salt thereof as an active ingredient to a subject having dysuria. The present invention further includes the use of a 2-oxapregnan compound represented by the formula (1) or a pharma- ceutically acceptable salt thereof as an active ingredient for treating, improving, or alleviating dysuria (as well as improving or promoting urination); and the use of a 2-oxapregnan compound represented by the formula (1) or a pharma- ceutically acceptable salt thereof for producing an agent for improving dysuria, an agent for improving urination, or an agent for promoting urination. The dosage to a human subject (or patient) may be about 0.01 to 100 mg per day in terms of the compound represented by the formula (1).

[0022] The agent for improving dysuria of the present invention may be a solid preparation. The carrier of the solid preparation may contain at least one carrier selected from an excipient, a binder, and a disintegrant. Effect of the Invention

[0023] The agent for improving dysuria of the present invention contains a specific 2-oxapregnane compound or a pharma- ceutically acceptable salt thereof, and therefore can effectively treat or improve (or alleviate) dysuria. Furthermore, the compound or a pharma- ceutically acceptable salt thereof is highly safe, and can improve dysuria with a high therapeutic or alleviating effect even when administered for a long period of time. Furthermore, since the compound has a hydroxyl group or an oxo group at a specific site of the steroid skeleton, it can treat or alleviate dysuria regardless of the degree or presence of prostatic hyperplasia. [Brief description of the drawings]

[0024] [Figure 1] FIG. 1 is a graph showing the relationship between residual urine volume and test substance under non-anesthesia and anesthesia in Test Example 1. [Diagram 2] FIG. 2 is a graph showing the relationship between urination efficiency and the test substance under non-anesthesia and anesthesia in Test Example 1. [Diagram 3]FIG. 3 is a graph showing the relationship between bladder capacity and test substance in Test Example 1. [Figure 4] FIG. 4 is a graph showing the relationship between the bladder wet weight and the test substance in Test Example 1. [Diagram 5] FIG. 5 is a graph showing the relationship between kidney wet weight and test substance in Test Example 1. [Figure 6] FIG. 6 is a graph showing the relationship between the survival rate and the test substance in Test Example 1. [Figure 7] FIG. 7 is a graph showing the relationship between residual urine volume and test substance in Test Example 2. [Figure 8] FIG. 8 is a graph showing the relationship between urination efficiency and the test substance in Test Example 2. [Figure 9] FIG. 9 is a graph showing the relationship between bladder contraction tension induced by square wave transmural electrical stimulation and the test substance in Test Example 3. [Figure 10] FIG. 10 is a graph showing the relationship between bladder contraction tension induced by Carbachol (muscarinic receptor stimulation) and KCl (depolarization-dependent Ca 2+ stimulation) and the test substance in Test Example 3. [Figure 11] FIG. 11 is a graph showing the relationship between bladder capacity in awake cystometry (CMG) and the test substance in Test Example 4. [Figure 12] FIG. 12 is a graph showing the relationship between the residual urine volume in cystometry (CMG) under consciousness and the test substance in Test Example 4. [Figure 13] FIG. 13 is a graph showing the relationship between urination efficiency in cystometry (CMG) under wakefulness and the test substance in Test Example 4. [Figure 14] FIG. 14 is a graph showing the relationship between bladder capacity in cystometry (CMG) under anesthesia and the test substance in Test Example 4. [Figure 15] FIG. 15 is a graph showing the relationship between the residual urine volume in cystometry (CMG) under anesthesia and the test substance in Test Example 4. [Figure 16] FIG. 16 is a graph showing the relationship between urination efficiency in cystometry (CMG) under anesthesia and the test substance in Test Example 4. [Figure 17] FIG. 17 is a graph showing the nomogram analysis results in Test Example 4. [Figure 18] FIG. 18 is a graph showing the relationship between uterus weight and test substance in Test Example 5. [Figure 19] FIG. 19 is a graph showing the relationship between the residual urine volume in cystometry (CMG) under consciousness and the test substance in Test Example 6. [Figure 20] FIG. 20 is a graph showing the relationship between urination efficiency in awake cystometry (CMG) and the test substance in Test Example 6. [Figure 21] FIG. 21 is a graph showing the nomogram analysis results in Test Example 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] [2-Oxapregnane Compound or Pharmaceutically Acceptable Salt Thereof] The compound represented by the formula (1) is publicly known and described in the above Patent Document 5. As described above, this compound has high antiandrogenic activity and is useful as a therapeutic agent for prostatic hyperplasia, but is also characterized by its ability to effectively treat or improve dysuria regardless of prostatic hyperplasia.

[0026] In the formula (1), examples of the alkyl group represented by R1 to R3 include linear or branched C alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a s-butyl group, and a t-butyl group. 1-6 Examples of the alkyl group include a linear or branched C 1-4 Alkyl groups, preferably linear or branched C 1-3 It is preferably an alkyl group, more preferably a methyl group or an ethyl group, and is often a methyl group. Specifically, the alkyl groups represented by R1 to R3 may be the same or different, and are often all methyl groups.

[0027] R4 may be either a hydrogen atom or an alkylcarbonyl group, and is usually an alkylcarbonyl group (alkanoyl group or acyl group). Examples of the alkylcarbonyl group (or acyl group) represented by R4 include linear or branched C alkyl groups such as acetyl group, propionyl group, butyryl group, isobutyryl group, t-butyryl group, pentanoyl group (valeryl group), and hexanoyl group. 1-10 Examples of the alkylcarbonyl group include a linear or branched C 1-6 Alkyl-carbonyl groups, preferably C 1-4 Alkyl-carbonyl groups, more preferably C 1-3 It is an alkyl-carbonyl group, often an acetyl group. The alkylcarbonyl group represented by R4 may be hydrolyzed by a hydrolase to convert it to a hydrogen atom, and the hydrogen atom represented by R4 may be converted to an alkylcarbonyl group by an acylation enzyme.

[0028] The halogen atom represented by X includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The halogen atom is often a fluorine atom, a chlorine atom, or a bromine atom, and particularly often a chlorine atom.

[0029] The substitution position of the hydroxyl group or oxo group represented by Y may be any one of the 11-, 15-, or 16-positions of the steroid skeleton, and is usually bonded to the 15-position of the steroid skeleton in many cases.

[0030] The oxo group and the hydroxyl group of the steroid skeleton may be mutually convertible by an oxidoreductase in the living body. Therefore, Y may be either a hydroxyl group or an oxo group. Y is usually a hydroxyl group in many cases. When Y is a hydroxyl group, the hydroxyl group may have an α-position or β-position configuration as shown in the following formula. For example, the hydroxyl group bonded to the 15-position of the steroid skeleton may have a β-position configuration.

[0031] [ka]

[0032] The compound represented by formula (1) contains 17α-C 1-4 Alkyl-carbonyloxy-6-halo-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-diones, 17α-C 1-4 Alkyl-carbonyloxy-6-halo-2-oxa-4,6-pregnadiene-3,15,20-triones are included.

[0033] Preferred compounds have a hydroxyl group represented by Y at the 11th, 15th or 16th position of the steroid skeleton, and can be represented by the following formula (1a).

[0034] [ka]

[0035] Representative compounds represented by formula (1a) or pharma- ceutically acceptable salts thereof include 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione or pharma- ceutically acceptable salts thereof.

[0036] The 2-oxapregnan compound represented by the formula (1) or a pharma- ceutically acceptable salt thereof may be a racemate or an optically active substance (or an optical isomer).The 2-oxapregnan compound represented by the formula (1) or a pharma- ceutically acceptable salt thereof may be a metabolite.

[0037] Examples of salts include salts with inorganic acids (such as hydrochloric acid and sulfuric acid), salts with organic acids (such as acetic acid), salts with inorganic bases (such as alkali metals such as ammonia, sodium and potassium, and alkaline earth metals such as calcium), and salts with organic bases (such as amines such as triethylamine).

[0038] The 2-oxapregnane compound represented by the above formula (1) or a pharma- ceutically acceptable salt thereof can be prepared by a conventional method, for example, in accordance with the method described in the above Patent Document 5.

[0039] The 2-oxapregnane compound represented by formula (1) or a pharma- ceutically acceptable salt thereof may have antiandrogenic activity and may act as an androgen receptor modulator.Furthermore, the compound may have both antiandrogenic and antiprogesterone activity.

[0040] The urination disorder improving agent of the present invention may contain at least the 2-oxapregnan compound represented by the formula (1) or a pharma- ceutically acceptable salt thereof as an active ingredient, and may contain other physiologically active ingredients or pharmacologically active ingredients (other urination improving drugs, etc.) as necessary. Examples of other urination improving drugs (second urination improving drugs) include α1 receptor blockers (antihypertensive drugs) or prostatic hyperplasia treatment drugs (doxazosin mesilate, urapidil, prazosin hydrochloride, bunazosin hydrochloride, oxendron gestorone caproate, chlormadinone acetate, tamsulosin hydrochloride, naftopidil, silodosin, etc.), 5α-reductase inhibitors (dutasteride, etc.), antiandrogens (methyltestosterone, testosterone propionate, testosterone enanthate, bicalutamide, enzalutamide, etc.), PDE5 inhibitors (tadalafil, etc.), and herbal medicines. These second micturition improving agents may be used in a ratio of about 0.1 to 100 parts by mass (eg, 1 to 50 parts by mass) per 100 parts by mass of the 2-oxapregnane compound represented by the above formula (1).

[0041] The agent (or preparation) for improving urination disorder of the present invention is effective for treating and / or preventing various urination disorders and improves or alleviates urination disorders. Therefore, the agent for improving urination disorder can also be called a therapeutic agent and / or prophylactic agent for treating and / or preventing urination disorders, or a alleviating agent for alleviating urination disorders.

[0042] Examples of dysuria include diseases or symptoms such as difficulty in urination (dysuria), residual urine, weakened urinary flow, delayed urination, abdominal straining urination, terminal dribbling, post-urination dribbling, urinary incontinence (including urgency, abdominal strain, mixed, and overflow), frequent urination (including daytime, nocturnal, and psychogenic), urgency, bladder pain or bladder pain syndrome, pain during urination, bladder atrophy, neurogenic bladder, detrusor overactivity or overactive bladder (including essential, neurogenic, and refractory), chronic cystitis, interstitial cystitis, chronic prostatitis, pelvic pain syndrome, underactive bladder, and detrusor hyperreflexic contraction dysfunction. Furthermore, the symptom may be at least one symptom selected from an increase in residual urine volume, a decrease in urination efficiency, an increase in bladder capacity, an increase in bladder wet weight, and an increase in kidney wet weight, and such at least one symptom may be used as an index or criterion for dysuria. Dysuria may be a disorder caused by a combination of a plurality of these diseases or symptoms. For example, difficulty in urination may be accompanied by a feeling of residual urine and a weak urinary flow. Dysuria is usually manifested as symptoms such as a feeling of residual urine, a weak urinary flow, urinary incontinence, frequent urination, or a sense of urgency (e.g., lower urinary tract symptoms). Therefore, in the present invention, urination may be improved or promoted.

[0043] The above-mentioned dysuria may or may not be accompanied by prostatic hyperplasia. That is, the dysuria may be either dysuria without prostatic hyperplasia or dysuria associated with prostatic hyperplasia. The present invention can effectively treat or improve dysuria regardless of the degree and / or presence of prostatic hyperplasia.

[0044] The dysuria may be associated with a disorder of smooth muscle contraction (dysfunction of smooth muscle contraction of the bladder). Examples of the dysuria include diseases that cause neurogenic bladder, diabetes, neuropathy associated with diabetes (afferent or efferent neuropathy of the micturition reflex system), hyperglycemia, and neuropathy associated with hyperglycemia. These dysuria may or may not be associated with prostatic hyperplasia; in many cases, they are dysuria without prostatic hyperplasia. Diseases that cause neurogenic bladder may be, for example, cerebrovascular disease (stroke), Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebellar degeneration, myelomeningocele (spina bifida), tethered spinal cord syndrome, herniated disc, spinal canal stenosis, and peripheral nerve damage to the bladder due to surgery for rectal cancer or uterine cancer. Specifically, even if not accompanied by prostatic hyperplasia, for example, as in neurogenic bladder, the contraction of smooth muscle is inhibited by central or peripheral nerve damage, resulting in dysuria. It is also known that in diabetic patients and / or hyperglycemic patients, regardless of whether they are insulin-dependent or insulin-independent, central or peripheral nerve damage occurs, resulting in dysuria due to complication of neuropathy (e.g., sensory (afferent) or efferent neuropathy of the micturition reflex system). The diabetes may be either type I or type II diabetes. Thus, dysuria may be caused by inhibiting the contraction of bladder smooth muscle through the neuropathy. It is also known that dysuria (e.g., underactive bladder, diabetic dysuria) is associated with bladder smooth muscle contraction disorder both clinically and non-clinically. In the present invention, even such dysuria without prostatic hyperplasia can be effectively treated or improved. Therefore, a subject having urinary dysfunction may be either male or female, and the compound or a pharma- ceutically acceptable salt thereof and an agent (or preparation) for improving urinary dysfunction of the present invention are effective in treating or improving urinary dysfunction regardless of gender.

[0045] The dysuria improving agent of the present invention may be formed by the 2-oxapregnane compound represented by the formula (1) or a pharma- ceutically acceptable salt thereof alone, or may be used as a pharmaceutical composition or a physiologically active composition in combination with a carrier (e.g., a pharmacologically or physiologically acceptable carrier). The carrier of the dysuria improving agent (pharmaceutical composition, physiologically active composition) can be selected according to the form of the preparation (i.e., dosage form), the administration form, the application, and the like. The dosage form is not particularly limited, and may be a solid preparation [powders, powders, granules (granules, fine granules, etc.), pills, pills, tablets, capsules (soft capsules, hard capsules, etc.), dry syrup, suppositories, film or sheet preparations, etc.], semi-solid preparations (creams, ointments, gels, gummies, etc.), liquid preparations (injections, syrups, etc.), and the like. In a preferred embodiment, the dosage form of the dysuria improving agent of the present invention is a solid preparation, particularly a granule, tablet, or capsule.

[0046] The powder also includes sprays and aerosols. The capsule may be either a soft capsule or a hard capsule, may be a liquid-filled capsule, or may be a capsule filled with a solid agent such as granules. The preparation may be a freeze-dried preparation. Furthermore, the urination disorder improving agent (or preparation) of the present invention may be a preparation in which the release rate of the drug is controlled (sustained release preparation, immediate release preparation). The administration route of the urination disorder improving agent (or preparation) is not particularly limited, and may be an oral administration preparation (granules, powders, tablets (sublingual tablets, orally disintegrating tablets, etc.), capsules, film preparations, etc.), or a parenteral administration preparation (inhalation agents, transdermal administration preparations, nasal administration preparations, suppositories, injections, etc.). Furthermore, the preparation may be a topical administration preparation (ointment, patch, cataplasm, etc.). The urination disorder improving agent (or preparation) of the present invention is often a solid preparation (for example, an oral solid preparation). Therefore, the following explanation will focus on the components of the solid preparation.

[0047] The carrier can be selected from ingredients (e.g., excipients, binders, disintegrants, lubricants, coating agents, etc.) listed in, for example, the 17th Revised Japanese Pharmacopoeia (Pharmacopoeia), (1) Pharmaceutical Additives Handbook, Japan Pharmaceutical Additives Association, (2007), (2) "Dictionary of Pharmaceutical Additives 2016" (Yakuji Nipposha, February 2016), (3) Pharmaceutics, Revised 5th Edition, Nankodo Co., Ltd. (1997), and (4) Pharmaceutical Additives Standards 2018 (Yakuji Nipposha, July 2018) according to the administration route and formulation use. As a carrier for a solid formulation, at least one selected from excipients and disintegrants, or at least one selected from excipients, binders, and disintegrants is often used. In addition, the urinary disorder improving agent (or formulation) may contain lipids.

[0048] Examples of the excipient include sugars or sugar alcohols such as lactose (or lactose hydrate), glucose (glucose), sucrose, maltose (maltose or maltose hydrate), maltitol, mannitol, sorbitol, xylitol, and isomaltulose hydrate; starches such as corn starch and potato starch; soluble starches such as pregelatinized starch and partially pregelatinized starch; polysaccharides such as crystalline cellulose (including microcrystalline cellulose), dextrin, gum arabic, and sodium alginate; carboxymethylcellulose or metal salts thereof (or crosslinked products thereof) such as carmellose, carmellose sodium, carmellose calcium, and croscarmellose sodium; and low-substituted cellulose. Examples of such excipients include: highly hydroxypropyl cellulose; sodium carboxymethyl starch (sodium starch glycolate), low-substituted sodium carboxymethyl starch; synthetic polymers such as polyvinylpyrrolidone polymers (polyvinylpyrrolidone (PVP, povidone), copolymers such as vinylpyrrolidone-vinyl acetate copolymer (copolyvidone), crosslinked polyvinylpyrrolidone (crospovidone), etc.); silicon oxides or silicates such as kaolin, light anhydrous silicic acid, calcium silicate, magnesium silicate, magnesium aluminosilicate, silicon dioxide, and hydrous silicon dioxide; and phosphates such as calcium hydrogen phosphate, calcium dihydrogen phosphate, and anhydrous calcium hydrogen phosphate. These excipients can be used alone or in combination of two or more. Among these excipients, sugars or sugar alcohols, starches such as corn starch, polysaccharides such as crystalline cellulose, and phosphates such as anhydrous calcium hydrogen phosphate are preferred from the viewpoint of excellent stability of the formulation, and in particular, sugars or sugar alcohols such as lactose (or lactose hydrate), corn starch, crystalline cellulose, anhydrous calcium hydrogen phosphate, etc. are preferred.

[0049] The total amount of the excipients per unit preparation (for example, one tablet) may be about 60 to 99.5% by mass, preferably 65 to 99% by mass, more preferably 70 to 98.5% by mass, and even more preferably 75 to 98% by mass.

[0050] Examples of binders include soluble starches such as pregelatinized starch and partially pregelatinized starch; starches such as corn starch and potato starch; polysaccharides such as crystalline cellulose (including microcrystalline cellulose), gum arabic, dextrin, sodium alginate, pectin, agar, and gelatin; polyvinylpyrrolidone-based polymers (polyvinylpyrrolidone (PVP, povidone), copolymers such as vinylpyrrolidone-vinyl acetate copolymer (copolyvidone), etc.), polyvinyl alcohol (PVA), carboxyvinyl polymers, poly(meth)acrylic acid-based polymers (methacrylic acid copolymers such as Eudragit L, S, and L30D-55, aminoalkyl methacrylate copolymers such as Eudragit E and RS, etc.), and polyvinyl alcohol (PVA). Examples of binders include synthetic polymers such as polylactic acid copolymers, polylactic acid, and polyethylene glycol (polyethylene glycol 6000, etc.); cellulose ethers such as methylcellulose (MC), ethylcellulose (EC), carboxymethylcellulose (carmellose, CMC), sodium carboxymethylcellulose (carmellose sodium), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC); sugars or sugar alcohols such as lactose (or lactose hydrate), glucose, sucrose, maltose (maltose or maltose hydrate), maltitol, mannitol, and sorbitol; and waxes such as beeswax. These binders can be used alone or in combination of two or more.

[0051] The total amount of the binder may be, for example, about 0.1 to 100 parts by mass, preferably about 0.1 to 50 parts by mass, more preferably about 0.5 to 30 parts by mass, and more preferably about 1 to 15 parts by mass (e.g., 2 to 10 parts by mass) relative to 100 parts by mass of the excipient.

[0052] Examples of disintegrants include soluble starches such as pregelatinized starch and partially pregelatinized starch; starches such as corn starch and potato starch; carboxymethylcellulose or its metal salts (or crosslinked products) such as carmellose, carmellose sodium, carmellose calcium, and croscarmellose sodium; synthetic polymers such as polyvinylpyrrolidone-based polymers (crosslinked polyvinylpyrrolidone (crospovidone) and the like); low-substituted hydroxypropylcellulose; sodium carboxymethyl starch (sodium starch glycolate), low-substituted sodium carboxymethyl starch; sugars or sugar alcohols such as lactose (or lactose hydrate), glucose, sucrose, maltose (maltose or maltose hydrate), maltitol, mannitol, and sorbitol. These disintegrants can be used alone or in combination of two or more. Of the disintegrants, from the viewpoint of the stability of the formulation, soluble starches such as pregelatinized starch and partially pregelatinized starch, carboxymethylcellulose or metal salts thereof such as croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, and the like are preferably used.

[0053] The total amount of the disintegrant may be, for example, about 0.1 to 100 parts by mass, preferably about 0.1 to 50 parts by mass, more preferably about 0.5 to 30 parts by mass, and more preferably about 1 to 25 parts by mass (e.g., 1.5 to 20 parts by mass) relative to 100 parts by mass of the excipient.

[0054] Examples of the lubricant include minerals such as talc; higher fatty acids or metal salts thereof such as stearic acid, magnesium stearate, aluminum stearate, and calcium stearate; higher fatty acid esters such as glycerin fatty acid ester, sucrose fatty acid ester, glycerin monostearate, and hardened oil; waxes such as carnauba wax, beeswax, lunau wax, and Japan wax; paraffins such as liquid paraffin; and synthetic polymers such as polyethylene glycol (e.g., polyethylene glycol 6000). These lubricants can be used alone or in combination of two or more. A preferred lubricant is magnesium stearate.

[0055] The total amount of the lubricant may be, for example, about 0.01 to 20 parts by mass, preferably about 0.1 to 10 parts by mass, more preferably about 0.3 to 7 parts by mass, and even more preferably about 0.5 to 5 parts by mass, relative to 100 parts by mass of the excipient.

[0056] Examples of the coating agent include sugars, cellulose derivatives such as ethyl cellulose and hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methyl methacrylate-(meth)acrylic acid copolymer, and Eudragit (methacrylic acid-acrylic acid copolymer). The coating agent may be an enteric component such as cellulose phthalate, hydroxypropyl methylcellulose phthalate, or methyl methacrylate-(meth)acrylic acid copolymer, or a gastric component composed of a polymer (such as Eudragit) containing a basic component such as dialkylaminoalkyl (meth)acrylate. The preparation may be a capsule containing these enteric or gastric components in the shell.

[0057] These carriers can be used alone or in combination of two or more. Among these carriers, when a carrier in the form of a metal salt is used, the preparation may be colored, but in the present invention, they can be used to the extent that they do not impair the efficacy or stability of the preparation.

[0058] In the preparation, known additives can be appropriately used depending on the administration route, dosage form, etc. Examples of such additives include disintegration aids, antioxidants or antioxidants, stabilizers, preservatives or preservatives, bactericides or antibacterial agents, antistatic agents, flavorings or masking agents, colorants, odorants or fragrances, refreshing agents, antifoaming agents, etc. These additives can be used alone or in combination of two or more.

[0059] In a pharmaceutical composition or physiologically active composition combined with a carrier (such as a pharmacologically or physiologically acceptable carrier), the content of the 2-oxapregnane compound represented by the formula (1) or a pharma- ceutically acceptable salt thereof can be appropriately selected depending on the species, age, weight, and condition (general condition, pathology, presence or absence of complications, etc.) of the subject to be administered, the administration time, dosage form, administration method, etc., and may be, for example, about 0.1 to 20% by mass, preferably 0.5 to 15% by mass, and more preferably about 1 to 10% by mass per unit preparation (e.g., one tablet).

[0060] The agent for improving urinary disorders (pharmaceutical composition or formulation) of the present invention can be prepared using the active ingredient, as well as carrier components and, if necessary, additives, by a conventional formulation method, for example, the manufacturing method described in the 16th Edition of the Japanese Pharmacopoeia or a method similar to this manufacturing method.

[0061] The 2-oxapregnane compound or a pharma- ceutically acceptable salt thereof is a known compound as described above, has been used for many years, and is highly stable and safe.

[0062] The agent for improving dysuria (pharmaceutical composition or preparation) of the present invention can be safely administered to humans and non-human animals, usually mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.). The dosage can be selected according to the species, age, weight, and condition (general condition, pathology, presence or absence of complications, etc.) of the subject, administration time, dosage form, administration method, etc. For example, the dosage (daily dose) for humans may be, for example, about 0.01 to 100 mg / day, preferably 0.05 to 75 mg / day (e.g., 0.1 to 50 mg / day), particularly about 0.1 to 30 mg / day (e.g., 1 to 20 mg / day) in terms of the compound represented by formula (1).

[0063] The administration method may be oral administration, or may be local administration or parenteral administration (e.g., subcutaneous administration, intramuscular administration, rectal administration, vaginal administration, etc.). In a preferred embodiment, the agent for improving dysuria of the present invention (pharmaceutical composition or preparation) is orally administered. The number of administrations is not particularly limited, and may be, for example, once a day, or multiple times a day (e.g., 2 to 3 times) as necessary.

[0064] As described above, the present invention also includes a method for treating, improving, or alleviating urination disorder (as well as a method for improving or promoting urination) by administering the 2-oxapregnan compound or a pharma- ceutical acceptable salt thereof as an active ingredient or administering the urination disorder improving agent (pharmaceutical composition or preparation) to a subject having urination disorder. Furthermore, the present invention also includes the use of the 2-oxapregnan compound or a pharma- ceutical acceptable salt thereof as an active ingredient for treating, improving, or alleviating urination disorder (as well as improving or promoting urination), or the use of the urination disorder improving agent (pharmaceutical composition or preparation) for treating, improving, or alleviating urination disorder (as well as improving or promoting urination); and the use of the 2-oxapregnan compound or a pharma- ceutical acceptable salt thereof for producing the urination disorder improving agent, urination improving agent, or urination promoting agent. EXAMPLES

[0065] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples.

[0066] Test Example 1 A rat lower urinary tract obstruction model was used as a test system, and the test substance was repeatedly orally administered to this lower urinary tract obstruction model for 2 weeks to examine the effect on the voiding function of the lower urinary tract obstruction model.

[0067] More specifically, the rats (female, Crl:CD(SD), 8 weeks old; Charles River Japan) were subjected to lower urinary tract obstruction surgery, and the test substance was repeatedly orally administered once a day for 2 weeks. After the administration, a catheter was placed in the bladder under anesthesia, cystometry was performed without anesthesia, cystometry was performed under urethane anesthesia, and the rats were euthanized under deep anesthesia, and tissues (bladder, kidney) were removed. The rats were used as a normal group without lower urinary tract obstruction surgery.

[0068] The test system, test substance and dosage are as follows.

[0069] Normal group: 0.5v / v% polysorbate 80 solution, 10mL / kg (n=6) Solvent group (control group): 0.5 v / v% polysorbate 80 solution, 10 mL / kg (n=15) Group A: Compound A, 10mg / kg (n=15) Group B3: Compound B, 3mg / kg (n=7) Group B10: Compound B, 10mg / kg (n=7)

[0070] The compound names of Compound A and Compound B are as follows: Compound A: 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione Compound B: TZP-4238 (17α-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione)

[0071] Then, the residual urine volume, urination efficiency, and bladder capacity were measured as follows.

[0072] [Residual urine volume] After urination, the remaining urine was aspirated from the other end of the catheter placed in the bladder and the volume (mL) was measured.

[0073] [Urination efficiency] After urination, the weight of the urine was measured to determine the urination volume (g = mL), and then the urination efficiency was calculated using the following formula. Urinary efficiency (%) = [(urinary volume (mL)) / (urinary volume (mL) + residual urine volume (mL))] x 100

[0074] [Bladder capacity] Bladder capacity was calculated from the voided urine volume and residual urine volume using the following formula. Bladder capacity (mL) = urinary volume (mL) + residual urine volume (mL)

[0075] In addition, the wet weights of the excised bladders and kidneys were measured.

[0076] Figures 1 to 6 show the results of residual urine volume, urination efficiency, bladder capacity, wet weight of excised tissues (bladder, kidney) and survival rate in a female rat lower urinary tract obstruction model. Figure 1 shows the relationship between residual urine volume and test substance, and Figure 2 shows the relationship between urination efficiency and test substance. Figure 3 shows the relationship between bladder capacity and test substance, Figures 4 and 5 show the relationship between bladder and kidney wet weight and test substance, and Figure 6 shows the relationship between survival rate and test substance.

[0077] As is clear from Figures 1 to 3, Group B (Group B3 and Group B10) significantly increased the residual urine volume and bladder capacity and decreased the urination efficiency compared to the control group (solvent group), whereas Group A significantly reduced the residual urine volume and bladder capacity and increased the urination efficiency compared to the control group. Also, as is clear from Figures 4 and 5, Group A acted in the direction of significantly suppressing the increase in bladder and kidney wet weight associated with lower urinary tract obstruction, whereas Group B acted in the direction of increasing it. Thus, Group B did not improve or rather acted in the direction of worsening the urination function, whereas Group A significantly improved the urination function that had decreased with lower urinary tract obstruction. Furthermore, Group A significantly improved the urination function in the lower urinary tract obstruction model system of female rats without prostate, indicating that Compound A improves urination disorder regardless of the presence or absence of prostatic hyperplasia.

[0078] Furthermore, as is clear from Figure 6, the survival rate of rats with lower urinary tract obstruction was reduced in Group B, but no reduction in survival rate was observed in Group A. This confirmed that Compound A is highly safe.

[0079] Although the compound belongs to the same 2-oxapregnane compound (progesterone group), the reason why the above results were obtained in female rats is not clear, but it is thought to be as follows.

[0080] In clinical practice, it is generally believed that progesterone, which increases during pregnancy, relaxes the organs surrounding the uterus, including the bladder. It has also been reported that pregnancy and progesterone affect bladder muscarinic receptors in rats, increasing bladder capacity and inhibiting bladder contraction (Pharmacology. 50(3):192-200.1995). In addition to relaxation caused by progesterone, the bladder is also functionally hypotonic due to mechanical pressure from the posterior side of the pregnant uterus. This may lead to residual urine or vesicoureteral reflux.

[0081] Group B has a strong progesterone-like effect and is considered to suppress bladder contraction by the above-mentioned mechanism. However, in a pathological model in which bladder function is severely impaired, such as the female lower urinary tract obstruction model, it is possible that in group B, bladder contraction was excessively suppressed by compound B, causing the pathological condition to worsen.

[0082] On the other hand, compound A has a mild anti-progesterone effect. The sexual cycle of female rats is about 4 days, and it is possible that in group A, compound A antagonized endogenous progesterone, which increases with the sexual cycle, and acted protectively against further suppression of bladder function in the lower urinary tract obstruction model.

[0083] Test Example 2 A rat lower urinary tract obstruction model was used as a test system, and the test substance was repeatedly orally administered to this lower urinary tract obstruction model for 14 days to examine the effect on the urination function of the lower urinary tract obstruction model. Note that the lower urinary tract obstruction model is not a prostatic hyperplasia model in which the prostate is enlarged.

[0084] More specifically, the rats (male, Crl:CD (SD), 8 weeks old; Charles River Japan) were subjected to lower urinary tract obstruction surgery, and the test substance was repeatedly orally administered once a day for 14 days. After completion of administration, a catheter was placed in the bladder under anesthesia, and cystometry was performed without anesthesia to evaluate the residual urine volume and urination efficiency.

[0085] The test substances and the doses administered in the test system (male rats with lower urinary tract obstruction) are as follows.

[0086] Solvent group (control group): 0.5 v / v% polysorbate 80 solution, 10 mL / kg (n = 8) Group A: Compound A, 10mg / kg (n=12) Group C: Compound C (dutasteride), 0.5 mg / kg (n=11) Dutasteride is a 5α-reductase inhibitor.

[0087] The results are shown in Figures 7 and 8.

[0088] 7 and 8 suggest that in the male rat lower urinary tract obstruction model, Group A had a stronger effect of improving urinary function (residual urine volume, urination efficiency) than Group C (dutasteride).

[0089] Test Example 3 The relationship between the bladder and urethral contraction responses and the test substance was examined in aged male rats (22 weeks old; Charles River Japan). Note that the rats are a model in which the prostate is predicted to be enlarged due to their advanced age.

[0090] The test substance was orally administered to the above-mentioned male rats for 2 weeks once a day, and then the bladder specimens were removed.The bladder specimens were suspended in a constant temperature (37℃) Magnus tube filled with physiological saline solution aerated with 95% O2-5% CO2 gas at a resting tension of about 9.8mN, and isometric contraction experiments were performed by applying square wave transmural electrical stimulation (EFS, Amplitude; 0.3 ms, Frequency; 1, 2, 5, 10, 20 Hz, Duration; 5s), Carbachol (CCH, 100 nmol / L-100 μmol / L), and KCl (40, 80 mmol / L).

[0091] The test substances and doses administered in the test system (old male rats) are as follows.

[0092] Solvent group (control group): 0.5 v / v% polysorbate 80 solution, 10 mL / kg (n=6) Group A: Compound A, 10mg / kg (n=6) Group C: Compound C (dutasteride), 0.3 mg / kg (n=6)

[0093] The results are shown in Figures 9 and 10.

[0094] 9 and 10, the square-wave transmural electrical stimulation (bladder efferent nerve stimulation), Carbachol (muscarinic receptor stimulation), and KCl (depolarization-dependent Ca stimulation) in Group A were significantly greater than in Group C. 2+ The bladder contraction tension induced by the stimulation was significantly stronger or in a stronger direction.

[0095] Test Example 4 A diabetes mellitus-associated urination disorder model was prepared and evaluated for urination disorder as described below. Note that this model does not involve benign prostatic hyperplasia, but is a urination disorder model associated with neuropathy and smooth muscle contraction disorder.

[0096] The body weight of rats (male, Crl:CD(SD), 5 weeks old; Charles River Japan) was measured, and after overnight fasting, blood was collected from the tail vein and fasting blood glucose was measured. Based on the body weight and fasting blood glucose level, the rats were divided into two groups by multivariate block allocation. On the day after group division, the first group was intraperitoneally administered with 0.1 mmol / L citrate buffer (pH 4.5) (10 mL / kg), and the second group was intraperitoneally administered with streptozocin (STZ; Sigma-Aldrich) (50 mg / kg). Streptozocin (STZ) was administered as the above citrate buffer solution at a concentration of 5 mg / mL.

[0097] Approximately one week after the administration of streptozocin (STZ), body weight and fasting blood glucose were measured, and in the streptozocin (STZ) administration group (second group), individuals with fasting blood glucose levels of 300 mg / dL or more were selected as diabetic animals. These diabetic animals are models with no abnormalities in the prostate (no benign prostatic hyperplasia). The diabetic animals (models) were divided into three groups by multivariate block allocation based on body weight and fasting blood glucose levels.

[0098] To the grouped diabetes-induced models, 0.5v / v% polysorbate 80 solution (0.5%P) (10mL / kg) or compound A (3 or 10mg / kg) was orally administered once a day, only on weekdays, for 4 weeks. In addition, 0.5v / v% polysorbate 80 solution (0.5%P) (10mL / kg) was orally administered to the first group according to the same administration schedule as above (normal group). On the last day of administration, under isoflurane anesthesia, a cannula was inserted and fixed at the top of the bladder, and cystometry (CMG) was performed under awake and urethane anesthesia, and the intravesical pressure, urination volume, and residual urine volume were measured. After the measurement, blood was collected under deep isoflurane anesthesia, and the prostate (ventral lobe, dorsal lobe), seminal vesicle, bladder, and kidney were removed and their weights were measured. In addition, the blood glucose level in the collected blood was measured.

[0099] The test substances and doses administered in the test system (diabetic rats with urinary dysfunction) are as follows.

[0100] Normal group: citrate buffer 10mL / kg (intraperitoneal administration), 0.5% P 10mL / kg (oral administration) (n=10) Vehicle group (control group): STZ 50 mg / kg (intraperitoneal administration), 0.5% P 10 mL / kg (oral administration) (n=10) Group A3: STZ 50 mg / kg (intraperitoneal administration), Compound A 3 mg / kg (oral administration) (n=10) Group A10: STZ 50 mg / kg (intraperitoneal administration), Compound A 10 mg / kg (oral administration) (n=9)

[0101] Voiding parameters: The obtained data on bladder pressure, urination volume, and residual urine volume were analyzed, and the urination parameters, bladder capacity (mL), residual urine volume (mL), and urination efficiency (%) were calculated for each urination. The average of the two measurements for these urination parameters was calculated and used as the measurement value for each individual.

[0102] Tissue weight: The weight of the entire prostate was calculated from the weights of the ventral and dorsal lobes of the prostate. The weights of the prostate, seminal vesicles, bladder and kidneys were converted into tissue weights per 100g of body weight. In addition, for the A3 and A10 groups administered with compound A, the inhibition rates of the prostate and seminal vesicles weights were calculated relative to the weights of the prostate and seminal vesicles in the vehicle group (to the first decimal place).

[0103] In the statistical analysis, the average value and standard deviation of each group were calculated for the final body weight, tissue weight (prostate, seminal vesicle, bladder, and kidney) per 100 g body weight, blood glucose level, and various urination parameters. For the statistical analysis, a significant difference test was performed using the SAS statistical analysis system (SAS version 9.4; manufactured by SAS Institute Japan, Ltd.). A two-tailed Student's t-test was performed between the normal group and the vehicle group, and a statistically significant difference was determined to exist at a risk level of less than 5%. In addition, a Williams multiple comparison test was performed between the vehicle group and the A3 and A10 groups, and a statistically significant difference was determined to exist at a risk level of less than 2.5%.

[0104] In addition, an "*" indicates a 5% significant difference (P<0.05 (vs. normal group) (Student's t-test)), and a "#" indicates a 2.5% significant difference (P<0.025 (vs. vehicle group) (Williams multiple comparison test)).

[0105] Bladder contraction force by nomogram analysis: In cystometry (CMG) under anesthesia, the maximum urinary flow rate (mL / sec) and the intravesical pressure at maximum urinary flow (cmH2O) were obtained, and the bladder contraction force during urination in each group was evaluated. That is, the average values ​​of the maximum urinary flow rate Qmax (mL / sec), the intravesical pressure at maximum urinary flow PdetQmax (cmH2O), and the bladder capacity BC (mL) were obtained for each group, and the maximum urinary flow rate / bladder capacity was plotted on the Y axis against the intravesical pressure at maximum urinary flow / bladder capacity on the X axis. The closer the distance from the origin, the weaker the bladder contraction force, and the farther the distance from the origin, the stronger the bladder contraction force.

[0106] The results are shown in Table 1, Figures 11 to 13 (awake cystometry (CMG) data), Figures 14 to 16 (anesthetized cystometry (CMG) data), and Figure 17 (nomogram analysis results). Each column in the table shows the "mean value ± standard deviation."

[0107] [Table 1]

[0108] [Body weight, tissue weight and blood glucose level] In the vehicle group (control group), body weight was significantly decreased, and bladder and kidney weights were significantly increased compared to the normal group. Blood glucose level was also significantly increased. In contrast, in the A3 and A10 groups, prostate and seminal vesicle weights were significantly decreased, and body weight, blood glucose level, and bladder and kidney weights were not affected.

[0109] As is clear from the blood glucose levels of the A3 and A10 groups compared to the vehicle group, compound A has no therapeutic effect on diabetes. In addition, in the diabetes-induced model, the prostate does not enlarge, and urinary disorders develop.

[0110] [Cystometry (CMG): bladder capacity, residual urine volume and voiding efficiency] The analysis results of cystometry (CMG) measurement data under consciousness are shown in Figures 11 to 13. In the vehicle group (control group), bladder capacity and residual urine volume were significantly increased and urination efficiency was significantly decreased compared to the normal group. In the A3 group, bladder capacity and residual urine volume were significantly decreased and urination efficiency was improved compared to the vehicle group (control group). In the A10 group, bladder capacity and residual urine volume were also significantly decreased and urination efficiency was significantly improved (P = 0.0359, Williams' multiple comparison test).

[0111] The analysis results of cystometry (CMG) measurement data under anesthesia are shown in Figures 14 to 16. In the vehicle group (control group), bladder capacity and residual urine volume increased significantly and urination efficiency decreased significantly compared to the normal group. Residual urine volume decreased significantly in the A3 group compared to the vehicle group (control group). Residual urine volume and bladder capacity also decreased significantly in the A10 group (P = 0.0336, Williams' multiple comparison test). Furthermore, urination efficiency improved in the A3 and A10 groups.

[0112] Furthermore, in the nomogram analysis (FIG. 17), groups A3 and A10 are judged to have stronger bladder contraction force during urination, since they are farther from the origin than the vehicle group (control group).

[0113] As described above, compound A was not found to have a therapeutic effect on diabetes (A3 and A10 groups), and furthermore, even in a diabetes-induced model in which the prostate was not enlarged, compound A was able to significantly improve dysuria.

[0114] Test Example 5 The anti-progesterone activity of Compound A and Compound D (mifepristone) was measured. That is, the test substance was repeatedly administered together with sex hormones to ovariectomized rats as a test system, and the anti-progesterone effect (anti-progesterone activity) was examined using the change in uterine weight associated with the formation of rat deciduoma (inhibitory effect on weight increase) as an index.

[0115] More specifically, rats (female, Crl:CD (SD), 5 weeks old: Charles River Japan) were ovariectomized, and one week after the operation, a high dose of estrone (5μg / rat) was subcutaneously administered once a day for three days. After one day of drug withdrawal, a low dose of estrone (1μg / rat) was subcutaneously administered once a day for eight days from the next day, progesterone (6mg / kg) was intramuscularly administered, and the test substance was orally administered. During the course of the administration, a decidualization reaction stimulation treatment was performed on the right side of the uterus on the fourth day after the start of administration, and the weight of the uterus (right side body) was measured on the day after the final administration (n=6). Note that the E group was ovariectomized and decidualization reaction stimulation treatment was performed, but no hormone treatment was performed.

[0116] The test substances and doses administered in the test system (ovariectomized rats) are as follows.

[0117] Group E: ovariectomized, hormone-untreated rats 0.5v / v% polysorbate 80 solution, 10mL / kg (n=6) Solvent group (control group): 0.5 v / v% polysorbate 80 solution, 10 mL / kg (n=6) Group A3: Compound A, 3mg / kg (n=6) Group A10: Compound A, 10mg / kg (n=6) Group A30: Compound A, 30mg / kg (n=6) Group D: Compound D (mifepristone), 3 mg / kg (n=6)

[0118] The results are shown in Figure 18.

[0119] 18, a significant inhibitory effect (inhibitory rate 89.5%) was observed in group D compared to the vehicle group. Also, while no significant inhibitory effect was observed in group A3 compared to the vehicle group (inhibitory rate 15.0%), significant inhibitory effects (inhibitory rates 63.0% and 83.3%, respectively) were observed in groups A10 and A30, demonstrating that compound A has anti-progesterone activity.

[0120] Test Example 6 As described below, a urination disorder model associated with streptozocin-induced diabetes was prepared as a urination disorder model in accordance with Test Example 4, and the effects of Compound A and Compound C on urination disorder were evaluated. This model is not accompanied by benign prostatic hyperplasia, but is associated with neuropathy and smooth muscle contraction disorder.

[0121] The body weight of rats (male, Crl:CD(SD), 5 weeks old; Charles River Japan) was measured and divided into two groups based on the body weight. On the day after grouping, the first group was intraperitoneally administered with 0.1 mmol / L citrate buffer (pH 4.5) (10 mL / kg), and the second group was intraperitoneally administered with streptozocin (STZ; Sigma-Aldrich) (50 mg / kg). Streptozocin (STZ) was administered as the above citrate buffer solution with a concentration of 5 mg / mL.

[0122] Approximately one week after the administration of streptozocin (STZ), body weight and fasting blood glucose were measured, and in the streptozocin (STZ) administration group (second group), individuals with fasting blood glucose levels of 300 mg / dL or more were selected as diabetic animals. These diabetic animals are models with no abnormalities in the prostate (no benign prostatic hyperplasia). The diabetic animals (models) were divided into three groups by multivariate block allocation based on body weight and fasting blood glucose levels.

[0123] To the grouped diabetes-induced models, 0.5v / v% polysorbate 80 solution (0.5%P) (10mL / kg), compound A (3mg / kg) or compound C (dutasteride) (0.3mg / kg) was orally administered once a day, only on weekdays, for 4 weeks. In addition, 0.5v / v% polysorbate 80 solution (0.5%P) (10mL / kg) was orally administered to the first group according to the same administration schedule as above (normal group). On the last day of administration, under isoflurane anesthesia, a cannula was inserted and fixed at the top of the bladder, and cystometry (CMG) was performed under awake and urethane anesthesia, and the intravesical pressure, urination volume and residual urine volume were measured. After the measurement, blood was collected under deep isoflurane anesthesia, and the prostate (ventral lobe, dorsal lobe) was removed and the weight of each was measured. In addition, the blood glucose level in the collected blood was measured.

[0124] The test substances and doses administered in the test system (diabetic rats with urinary dysfunction) are as follows.

[0125] Normal group: citrate buffer 10mL / kg (intraperitoneal administration), 0.5% P 10mL / kg (oral administration) (n=10) Vehicle group (control group): STZ 50 mg / kg (intraperitoneal administration), 0.5% P 10 mL / kg (oral administration) (n=10) Group A3: STZ 50 mg / kg (intraperitoneal administration), Compound A 3 mg / kg (oral administration) (n=10) Group C0.3: STZ 50 mg / kg (intraperitoneal administration), Compound C (dutasteride) 0.3 mg / kg (oral administration) (n=10)

[0126] Urination parameters: As in Test Example 4, the residual urine volume (mL) and urination efficiency (%) were determined as urination parameters for each urination, and the average of two measurements was taken as the measurement value for each individual.

[0127] Prostate weight: The weight of the prostate (ventral lobe, dorsal lobe and whole prostate) was converted to tissue weight per 100 g body weight in the same manner as in Test Example 4. In addition, for the A3 group administered with compound A and the C0.3 group administered with compound C, the inhibition rate of the prostate weight was calculated relative to the prostate weight of the vehicle group (to the first decimal place).

[0128] In the statistical analysis, a significant difference test was performed in the same manner as in Test Example 4. A two-tailed Student's t-test was performed between the normal group and the vehicle group, and a statistically significant difference of less than 5% was determined, and 5% significance was indicated with "*". A Dunnett's multiple comparison test was performed between the vehicle group and the A3 and C0.3 groups, and a statistically significant difference of less than 5% was determined, and 5% significance was indicated with "#".

[0129] Bladder contraction force by nomogram analysis: Bladder contraction force during urination was evaluated for each group in the same manner as in Test Example 4. In addition, maximum urinary flow rate / bladder capacity was plotted on the Y axis against intravesical pressure at maximum urinary flow / bladder capacity on the X axis, and it was determined that the closer the distance from the origin, the weaker the bladder contraction force, and the farther the distance from the origin, the stronger the bladder contraction force.

[0130] The results are shown in Table 2, Figures 19 and 20 (awake cystometry (CMG) data), and Figure 21 (nomogram analysis results).

[0131] [Table 2]

[0132] [Prostate weight and blood glucose level] Compared with the solvent group, the weight of the ventral lobe of the prostate, the dorsal lobe of the prostate and the whole prostate are significantly atrophied in the A3 group and the C0.3 group to the same extent (P<0.05).In addition, since there is no significant difference in the weight of the prostate between the normal group and the solvent group, the diabetes induction model is a model in which the prostate is not enlarged.In this diabetes model, the A3 group and the C0.3 group do not statistically affect the blood glucose level of the solvent group, as in the above-mentioned test example 4, so it is confirmed that compound A and compound C have no therapeutic effect on diabetes.

[0133] [Cystometry (CMG): Residual urine volume and voiding efficiency] From the analysis results of the cystometry (CMG) measurement data under consciousness, as shown in FIG. 19 and FIG. 20, the residual urine volume of the vehicle group was significantly increased and the urination efficiency was significantly decreased (p<0.05) with STZ treatment (induction of diabetes) compared to the normal group. From these results, the diabetes induction model developed urination disorder. In contrast, the A3 group significantly decreased the residual urine volume compared to the vehicle group (p<0.05), but the C0.3 group did not have a statistical effect on the residual urine volume of the vehicle group. In addition, the A3 group significantly improved the urination efficiency compared to the vehicle group (p<0.05), but the C0.3 group did not have a statistical effect on the urination efficiency of the vehicle group. In addition, a statistically different tendency was observed between the A3 group and the C0.3 group in terms of urination efficiency (p=0.0757, Student's t-test).

[0134] In addition, in the nomographic analysis (Figure 21), the plot of the normal group was located farthest from the origin, and the C0.3 group was located almost at the same position as the vehicle group. In contrast, the plot of the A3 group was located farther from the origin than the vehicle group. From this, it is judged that the A3 group has a stronger bladder contraction force during urination than the vehicle group and the C0.3 group.

[0135] Thus, compound A (group A3) was not found to have a therapeutic effect on diabetes, and furthermore, it was able to significantly improve dysuria even in a diabetes-induced model in which the prostate was not enlarged.

[0136] Formulation Example 1 100 g of the active ingredient (17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione), 2810 g of excipients (anhydrous calcium hydrogen phosphate (Fuji Chemical Industry Co., Ltd., "Fujicalin"), 300 g of corn starch (Nihon Shokuhin Kako Co., Ltd., "Nisshoku Pharmacopoeia Corn Starch"), 60 g of pregelatinized starch (Asahi Kasei Co., Ltd., "Swelstar PD-1"), and 30 g of lubricant (magnesium stearate (Taihei Chemical Industry Co., Ltd., "Magnesium Stearate")) were mixed, and the resulting mixture was compressed into tablets (5 mg tablets) containing the ingredients shown in Table 3 per tablet.

[0137] [Table 3]

[0138] Formulation Example 2 75 g of the active ingredient (17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione) was mixed with 2790 g of excipients (lactose hydrate (Dilactose S, Freund Corp.), 1500 g of crystalline cellulose (Ceolas UF711, Asahi Kasei Corp.), 450 g of corn starch (Nisshoku Pharmacopoeia Corn Starch, Nippon Shokuhin Kako Co., Ltd.), 90 g of croscarmellose sodium (KICCOLATE, Asahi Kasei Corp.), and 45 g of lubricant (magnesium stearate (Magnesium stearate, Taihei Chemical Industry Co., Ltd.)), and the resulting mixture was compressed into tablets to produce tablets (2.5 mg tablets) containing the ingredients shown in Table 4 per tablet.

[0139] [Table 4] [Industrial Applicability]

[0140] The agent for improving urination disorder of the present invention contains the 2-oxapregnane compound represented by formula (1), and therefore can effectively improve urination disorders such as residual urine sensation, weak urinary force, urinary incontinence, frequent urination, etc. Therefore, it can improve and enhance the quality of life of people (especially the elderly) suffering from urination disorder.

Claims

1. An agent for improving dysuria, comprising 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione or a pharma- ceutical acceptable salt thereof as an active ingredient, The agent for improving dysuria, wherein the dysuria is not accompanied by benign prostatic hyperplasia.

2. The agent for improving urination disorders according to claim 1, which improves at least one urination disorder or symptom selected from the group consisting of residual urine sensation, weakened urinary force, delayed urination, strained urination, terminal dribbling, post-urination dribbling, urinary incontinence, frequent urination, urgency, bladder pain or bladder pain syndrome, pain during urination, bladder atrophy, neurogenic bladder, detrusor overactivity or overactive bladder, chronic cystitis, interstitial cystitis, chronic prostatitis, pelvic pain syndrome, underactive bladder, and detrusor hyperreflexia and contractile dysfunction.

3. 3. The agent for improving urination disorder according to claim 1, which improves at least one urination disorder or symptom selected from residual urine volume, urination efficiency, bladder capacity, bladder wet weight, and kidney wet weight.

4. The agent for improving dysuria according to any one of claims 1 to 3, wherein the dysuria is associated with a disorder of smooth muscle contraction.

5. The agent for improving dysuria according to any one of claims 1 to 4, wherein the dysuria is associated with at least one disease selected from diseases causing neurogenic bladder, diabetes, and neuropathy associated with diabetes.

6. The agent for improving urination disorders according to any one of claims 1 to 5, which improves or promotes urination.

7. 7. The agent for improving urination disorders according to claim 1, wherein the dosage is 0.01 to 100 mg per day calculated as 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione.

8. The agent for improving dysuria according to any one of claims 1 to 7, which is a solid preparation.

9. 9. The agent for improving dysuria according to claim 8, wherein the carrier of the solid preparation comprises at least one carrier selected from the group consisting of an excipient, a binder and a disintegrant.

10. A solid formulation for improving urinary disorders comprising 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione or a pharma- ceutically acceptable salt thereof as an active ingredient and a carrier, said solid formulation being orally administered 1 to 3 times a day.

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