JP2022096696A - Dysuria-alleviating agent - Google Patents

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

The present invention relates to a dysuria improving agent containing a pregnane compound or a pharmaceutically acceptable salt thereof as an active ingredient and useful for improving dysuria such as feeling of residual urine.

As the aging society progresses, it is important to improve or alleviate dysuria in the elderly, for example, diseases or symptoms such as difficulty in urination, feeling of residual urine, pollakiuria, and urinary incontinence. As an improving agent for improving such dysuria, Japanese Patent Application Laid-Open No. 5-155773 (Patent Document 1) describes a xanthin derivative effective for the treatment and prevention of urinary disorders such as pollakiuria or urinary incontinence. Japanese Patent Publication No. 8-3045 (Patent Document 2) describes a dysuria-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 triazine derivative and having an analgesic effect or a dysuria improving effect.

In addition, as an agent for improving dysuria, an α1 blocker, a 5α-reductase inhibitor, and the like are commercially available, and the 5α-reductase inhibitor suppresses the production of dihydrotestosterone from testosterone, shrinks the enlarged prostate, and causes dysuria. To improve.

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-) as an anti-androgen agent. Chloro-2-oxa-4,6-pregnadien-3,20-dione) has been described, and TZP-4238 has also been described to be useful in the treatment of diseases such as benign prostatic hyperplasia and prostate cancer.

Further, in Japanese Patent No. 2591640 (Patent Document 5), as a compound having anti-androgen activity, 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadien-3,20- 2-Oxapregnan compounds such as dione have been described. This document describes that the compound is useful as a therapeutic agent for androgen-dependent diseases such as benign prostatic hyperplasia, prostate cancer, and alopecia.

Further, regarding plant preparations, Japanese Patent Application Laid-Open No. 2011-20972 (Patent Document 6) describes an agent for improving dysuria, which contains a saw palmetto fruit extract and contains oleic acid and myristic acid in a ratio of 1: 0 to 2: 3. ing. According to Patent Document 6, in men, the prostate gland is enlarged with aging, and the part near the urinary tract (peri-urinary gland) proliferates and becomes larger (mechanical obstruction), and dihydrotestosterone is accumulated in the prostate gland. , Benign prostate hyperplasia (BPH) is described, and it is described that the symptoms of benign prostatic hyperplasia include lower urinary tract symptoms such as difficulty in urination and frequent urination.

However, enlargement of the prostate does not necessarily lead to dysuria. For example, in the World Journal of Urology, 13, 9-13 (1995) (Non-Patent Document 2), there is a statistically significant relationship between prostate size and urethral obstruction, but with symptoms of dysuria. It has been reported that there is no correlation with the degree of urethral obstruction or prostate size.

The Journal of Urology, 150, 351-358 August 1993 (Non-Patent Document 3) shows that there is no correlation between prostate size and residual urine volume, and that there is a correlation between residual urine volume, prostate size and various symptoms. Not reported. Specifically, a correlation matrix in patients with benign prostatic hyperplasia (BPH) is described, with the severity of symptoms and residual urine output, prostate size or prostate specificity, despite the relatively large sample size. Prostate enlargement, which was noted to have no statistically significant relationship to sex antigen (PSA) levels and is also a characteristic of BPH, is a decisive factor in the production of either symptoms or physiological lower obstruction. Not so, and in some patients (individuals), a small degree of hyperplasia around the urinary tract can cause physiological disorders, while in other patients (individuals), it does not. It has been stated that significant hyperplasia can occur.

Therefore, it is required to effectively treat or improve dysuria regardless of the degree or presence of enlargement of the prostate. Furthermore, in the treatment of dysuria, since it is administered to patients such as the elderly for a long period of time, high therapeutic effect and high safety are required.

Japanese Patent Application Laid-Open No. 5-155773 (Claims) JP-A-8-3045 (Claims) WO2012 / 020749 (Claims) Japanese Patent Application Laid-Open No. 61-204198 (Claims, right column, page 1) Japanese Patent No. 2591640 (Claims, column 11, line 49 to column 12, line 49) Japanese Unexamined Patent Publication No. 2011-20972 (Claims, [0002])

Endocrine Journal 1994, 41 (4), 445-452 World Journal of Urology, 13, 9-13 (1995) (Summary) The Journal of Urology, 150, 351-358 August 1993 (Page 354, right column, lines 5-10, page 355, left column, bottom 9 to right column, 6 lines, Table 3, Table 5)

Therefore, an object of the present invention is to provide a dysuria improving agent useful for treating or ameliorating (or alleviating) dysuria.

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

Yet another object of the present invention is to provide a dysuria ameliorating agent useful for treating or alleviating dysuria regardless of the degree or presence of benign prostatic hyperplasia.

In order to achieve the above-mentioned problems, the present inventors have diligently investigated the relationship between a 2-oxapregnan compound having an oxo group at the 2-position of the steroid skeleton and having high antiandrogen activity and urinary disorders, and as a result, high antiandrogen. It was found that even in the case of an active 2-oxapregnane compound, a large difference is observed in the improvement of urinary disorders depending on the presence or absence of a hydroxyl group or an oxo group at a predetermined site of the steroid skeleton. That is, a compound in which a hydroxyl group is not substituted at a predetermined site of the steroid skeleton has high anti-androgen activity, but does not show any therapeutic effect on dysuria in a subject who does not have benign prostatic hyperplasia. On the other hand, it was found that the use of a compound in which a hydroxyl group or an oxo group is substituted at a predetermined site of the steroid skeleton shows a high therapeutic or ameliorating effect on dysuria regardless of the presence or absence of benign prostatic hyperplasia. The present invention has been completed based on these findings.

That is, the dysuria improving agent of the present invention contains a 2-oxapregnane compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. The steroid skeleton of the following formula (1) is assigned a position number.

(In the formula, R ₁ to R ₃ represent the same or different alkyl groups, R ₄ represents a hydrogen atom or an alkylcarbonyl group, X represents a halogen atom, and Y represents the 11th position and 15 of the steroid skeleton. (Indicating a hydroxyl or oxo group attached to the or 16-position)

R ₁ to R ₃ may be the same or different and may be a C _1-4 alkyl group (for example, a methyl group), and R ₄ may be a lower alkanoyl group or an acyl group (C _1-4 alkyl-carbonyl group). , For example, it may be an acetyl group. The 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 typical 2-oxapregnan compound represented by the formula (1) may be 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadien-3,20-dione. ..

The compound or a pharmaceutically acceptable salt thereof is useful for preventing, treating, ameliorating or alleviating dysuria or symptoms. Urination disorders include, for example, feeling of residual urination, weakened urination, delayed urination, abdominal pressure urination, terminal dripping, post-urination urination dripping, urinary incontinence (including urgency, stress, mixing, and overflow), and frequent urination. (Daytime, nighttime, including psychogenic), urinary urgency, bladder pain or bladder pain syndrome, incontinence pain, bladder atrophy, neurogenic bladder, micturition muscle overactivity or overactive bladder (essential, neurogenic) , Including refractory), chronic cystitis, interstitial cystitis, chronic prostatic inflammation, pelvic pain syndrome, inactive bladder, urinary muscle hyperreflex contractile insufficiency, etc. at least one micturition disorder (or disease) Or it may be a symptom. The dysuria improving agent of the present invention is useful for improving at least one dysuria or symptom selected from residual urine volume, urination efficiency, bladder capacity, bladder wet weight and renal wet weight. Specifically, the compound or a pharmaceutically acceptable salt thereof exhibits a high therapeutic or ameliorating effect on dysuria regardless of the presence or absence of benign prostatic hyperplasia. That is, the dysuria may be either a dysuria without benign prostatic hyperplasia or a dysuria with benign prostatic hyperplasia. Therefore, the subject having dysuria may be either male or female (male and female). In addition, the dysuria may be a dysuria associated with a disorder of smooth muscle contraction. Further, the dysuria may be a dysuria associated with at least one disease selected from the diseases that give rise to neurogenic bladder, diabetes, and the neuropathy associated with diabetes. The dysuria improving agent may improve or promote urination. Therefore, the urination disorder improving agent can also be referred to as a urination improving agent or a urination promoting agent.

The present invention administers a 2-oxapregnan compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to an object having dysuria to treat, improve or alleviate the dysuria. Also includes methods (as well as methods of improving or promoting urination). Further, use of the 2-oxapregnane compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient for treating, ameliorating or alleviating (and improving or promoting urination) urination disorder. It also includes the use of the 2-oxapregnane compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof for producing the urination disorder improving agent, the urination improving agent or the urination promoting agent. The dose to a human as a subject (or patient) may be about 0.01 to 100 mg per day in terms of the compound represented by the above formula (1).

The dysuria improving agent of the present invention may be a solid preparation. The carrier of the solid preparation may contain at least one carrier selected from excipients, binders and disintegrants.

Since the dysuria improving agent of the present invention contains a predetermined 2-oxapregnane compound or a pharmaceutically acceptable salt thereof, dysuria can be effectively treated or ameliorated (or alleviated). In addition, the compound or a pharmaceutically acceptable salt thereof is highly safe, and even if it is administered for a long period of time, dysuria can be improved with a high therapeutic or improving effect. Furthermore, since it has a hydroxyl group or an oxo group at a predetermined site of the steroid skeleton, dysuria can be treated or alleviated regardless of the degree or presence of benign prostatic hyperplasia.

FIG. 1 is a graph showing the relationship between the residual urine volume and the test substance under no anesthesia and under anesthesia in Test Example 1. FIG. 2 is a graph showing the relationship between the urination efficiency and the test substance under no anesthesia and under anesthesia in Test Example 1. FIG. 3 is a graph showing the relationship between the bladder capacity and the test substance in Test Example 1. FIG. 4 is a graph showing the relationship between the bladder wet weight and the test substance in Test Example 1. FIG. 5 is a graph showing the relationship between the wet weight of the kidney and the test substance in Test Example 1. FIG. 6 is a graph showing the relationship between the survival rate and the test substance in Test Example 1. FIG. 7 is a graph showing the relationship between the residual urine volume and the test substance in Test Example 2. FIG. 8 is a graph showing the relationship between the urination efficiency and the test substance in Test Example 2. FIG. 9 is a graph showing the relationship between the bladder contraction tension due to the electrical stimulation of the rectangular wave transwall in Test Example 3 and the test substance. FIG. 10 is a graph showing the relationship between the bladder contraction tension and the test substance due to Carbachol (muscarinic receptor stimulation) and KCl (depolarization-dependent Ca ²⁺ stimulation) in Test Example 3. FIG. 11 is a graph showing the relationship between the bladder volume and the test substance in cystometry (CMG) under awakening of Test Example 4. FIG. 12 is a graph showing the relationship between the residual urine volume and the test substance in cystometry (CMG) under awakening of Test Example 4. FIG. 13 is a graph showing the relationship between the urination efficiency and the test substance in cystometry (CMG) under awakening of Test Example 4. FIG. 14 is a graph showing the relationship between the bladder volume and the test substance in cystometry (CMG) under anesthesia of Test Example 4. FIG. 15 is a graph showing the relationship between the residual urine volume and the test substance in cystometry (CMG) under anesthesia of Test Example 4. FIG. 16 is a graph showing the relationship between the urination efficiency and the test substance in cystometry (CMG) under anesthesia of Test Example 4. FIG. 17 is a graph showing the results of nomogram analysis in Test Example 4. FIG. 18 is a graph showing the relationship between the uterine weight and the test substance in Test Example 5. FIG. 19 is a graph showing the relationship between the residual urine volume and the test substance in cystometry (CMG) under awakening of Test Example 6. FIG. 20 is a graph showing the relationship between the urination efficiency and the test substance in cystometry (CMG) under awakening of Test Example 6. FIG. 21 is a graph showing the results of nomogram analysis in Test Example 6.

[2-Oxapregnan compound or a pharmaceutically acceptable salt thereof]
The compound represented by the formula (1) is described in Patent Document 5 and is known. As mentioned above, this compound has high antiandrogen activity and is useful as a therapeutic agent for benign prostatic hyperplasia, but it is said that it effectively treats or ameliorate dysuria regardless of the enlargement of the prostate. There is a feature.

In the above formula (1), examples of the alkyl group represented by R ₁ to R ₃ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group, and a t-butyl group. Such as linear or branched C _1-6 alkyl group can be exemplified. The alkyl group is usually a linear or branched C _1-4 alkyl group, preferably a linear or branched C _1-3 alkyl group, more preferably a methyl group or an ethyl group, and is a methyl group. In many cases. Specifically, the alkyl groups represented by R ₁ to R ₃ may be the same or different, and both are often methyl groups.

_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 a linear group such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a t-butyryl group, a pentanoyl group (valeryl group) and a hexanoyl group. Alternatively, a branched C _1-10 alkyl-carbonyl group and the like can be exemplified. The alkylcarbonyl group is usually a linear or branched C _1-6 alkyl-carbonyl group, preferably a C _1-4 alkyl-carbonyl group, more preferably a C _1-3 alkyl-carbonyl group, and an acetyl group. In many cases. The alkylcarbonyl group represented by R ₄ may be hydrolyzed by a hydrolyzing enzyme and converted into a hydrogen atom, and the hydrogen atom represented by R ₄ may be converted into an alkylcarbonyl group by an acylating enzyme. May be.

The halogen atom represented by X includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Halogen atoms are often fluorine atoms, chlorine atoms, bromine atoms, especially chlorine atoms.

The substitution position of the hydroxyl group or the oxo group represented by Y may be any of the 11th, 15th or 16th positions of the steroid skeleton, and is usually bound to the 15th position of the steroid skeleton. ..

The oxo group and the hydroxyl group of the steroid skeleton may be mutually convertible by an in vivo redox enzyme. 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 represented by the following formula. For example, the hydroxyl group attached to the 15th position of the steroid skeleton may have a β-position configuration.

The compound represented by the formula (1) includes 17α-C _1-4 alkyl-carbonyloxy-6-halo-15β-hydroxy-2-oxa-4,6-pregnadien-3,20-dione, 17α-C. Includes _1-4 alkyl-carbonyloxy-6-halo-2-oxa-4,6-pregnadien-3,15,20-trione.

The preferred compound has a hydroxyl group represented by Y at the 11-position, 15-position or 16-position of the steroid skeleton and can be represented by the following formula (1a).

Representative compounds represented by the formula (1a) or pharmaceutically acceptable salts thereof include 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadien-3,20-. Examples include dione or pharmaceutically acceptable salts thereof.

The 2-oxapregnan compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be a racemate or an optically active substance (or an optically isomer). The 2-oxapregnane compound represented by (1) above or a pharmaceutically acceptable salt thereof may be a metabolite.

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

The 2-oxapregnan compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can be prepared according to a conventional method, for example, the method described in Patent Document 5.

The 2-oxapregnan compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may have antiandrogen activity or may act as an androgen receptor modulator. Furthermore, the compound may have both an anti-androgen action and an anti-progesterone action.

The dysuria improving agent of the present invention may contain at least the 2-oxapregnane compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and if necessary, other physiology. It may contain an active ingredient or a pharmacologically active ingredient (such as other urination improving agents). Other urination improving agents (second urination improving agents) include, for example, α1 receptor blocking agents (antihypertensive agents) or prostatic hyperplasia therapeutic agents (doxazocin mesylate, urapidil, prazosin hydrochloride, bunazocin hydrochloride, oxene). Delongest noron caproic acid ester, chlormaginone acetate, tamthrosin hydrochloride, naphthopidil, silodocin, etc.), 5α reductase inhibitor (dutasteride, etc.), anti-androgen drug (methyltestosterone, testosterone propionate, testosterone enanthate, bicartamide, etc.) Examples include enzaltamide), PDE5 inhibitors (tadalafil, etc.), and crude drugs. These second urination improving agents are prepared at a ratio of about 0.1 to 100 parts by mass (for example, 1 to 50 parts by mass) with respect to 100 parts by mass of the 2-oxapregnane compound represented by the above formula (1). You may use it.

The dysuria improving agent (or preparation) of the present invention is effective for the treatment and / or prevention of various dysuria, and improves or alleviates the dysuria. Therefore, the dysuria improving agent can also be said to be a therapeutic agent and / or a preventive agent for treating and / or preventing dysuria, and a palliative agent for alleviating dysuria.

Dysuria includes, for example, difficulty in urinating (difficulty urinating), feeling of residual urine, diminished urinary dysfunction, delayed urination, abdominal pressure urination, terminal incontinence, post-incontinence urinary incontinence, urinary incontinence (urgency, stress, mixedness). , Including overflow), frequent urination (including daytime, nighttime, psychogenic), urinary urgency, bladder pain or bladder pain syndrome, incontinence pain, bladder atrophy, neurogenic bladder, urinary muscle overactivity or Diseases such as overactive bladder (including essential, neurogenic, refractory), chronic cystitis, interstitial cystitis, chronic prostatic inflammation, pelvic pain syndrome, inactive bladder, dysuria or dysuria Symptoms can be exemplified. Further, 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 renal wet weight, and at least one such symptom. Two symptoms may be used as indicators or criteria for dysuria. Dysuria may be a disorder in which these multiple diseases or symptoms occur in combination. For example, difficulty in urinating may be accompanied by a feeling of residual urine and diminished urinary incontinence. Dysuria usually manifests as symptoms such as residual urine, weakened urine, urinary incontinence, pollakiuria or urinary urgency (eg, lower urinary tract symptoms). Therefore, in the present invention, urination may be improved or promoted.

The above-mentioned dysuria may or may not be accompanied by benign prostatic hyperplasia. That is, the dysuria may be either a dysuria without benign prostatic hyperplasia or a dysuria with benign prostatic hyperplasia. In the present invention, dysuria can be effectively treated or ameliorated regardless of the degree and / or presence / absence of benign prostatic hyperplasia.

The dysuria may be a dysuria associated with a smooth muscle contraction disorder (bladder smooth muscle contraction disorder). The types of dysuria include, for example, diseases that cause neurogenic bladder, diabetes, dysuria associated with diabetes (afferent or efferent neuropathy of the urinary reflex system), hyperglycemia, and nerves associated with hyperglycemia. Dysuria associated with diseases such as disorders can be mentioned. These dysurias may or may not be accompanied by benign prostatic hyperplasia; they are often dysuria without benign prostatic hyperplasia. Diseases that cause neurogenic bladder include, for example, cerebrovascular disorders (stroke), Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, spina bifida (spina bifida), tethered spinal cord syndrome, disc hernia. , Spinal cord stenosis, peripheral neuropathy to the bladder due to rectal cancer / uterine cancer surgery, etc. may be used. Specifically, for example, even without benign prostatic hyperplasia, disorders of the central or peripheral nerves, such as neurogenic bladder, may inhibit smooth muscle contraction and cause dysuria. In addition, in diabetic and / or hyperglycemic patients, central or peripheral nerves are injured, regardless of insulin-dependent or insulin-independent, and neuropathy as a complication (perception of the urinary reflex system (afferent)). Or efferent neuropathy, etc.) is known to cause urinary dysfunction. The diabetes may be either type I diabetes and / or type II diabetes. Thus, dysuria may be due to inhibition of bladder smooth muscle contraction through the neuropathy. It is also known clinically and non-clinically that dysuria (eg, underactive bladder, diabetic dysuria) is associated with bladder smooth muscle contraction disorder. In the present invention, even a dysuria without such benign prostatic hyperplasia can be effectively treated or ameliorated. Therefore, the subject having dysuria may be either male or female (male and female), and the compound of the present invention or a pharmaceutically acceptable salt thereof and the dysuria improving agent (or preparation) are of gender. Regardless of, it is effective in effectively treating or ameliorating dysuria.

The dysuria improving agent of the present invention may be formed by the 2-oxapregnane compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof alone, or may be formed by a carrier (pharmacologically or physiologically acceptable). It may be used as a pharmaceutical composition or a physiologically active composition in combination with a carrier or the like. The carrier of the dysuria improving agent (pharmaceutical composition, physiologically active composition) can be selected according to the form of the preparation (that is, the dosage form), the administration form, the use and the like. The dosage form is not particularly limited, and solid formulations [powder, powder, granules (granule, fine granule, etc.), rounds, pills, tablets, capsules (soft capsule, hard capsule, etc.), dry syrup, etc. It may be a suppository, a film or a sheet-like preparation], a semi-solid preparation (cream, ointment, gel, gummy, etc.), a liquid (injection, syrup, 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, a tablet or a capsule.

The powdered agent also includes a spray agent, an aerosol agent and the like. 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. Moreover, the formulation may be a freeze-dried formulation. Further, the dysuria improving agent (or preparation) of the present invention may be a preparation (sustained release preparation, immediate release preparation) in which the release rate of the drug is controlled. In addition, the administration route of the urinary disorder improving agent (or preparation) is not particularly limited, and it is an orally administered preparation (granule, powder, tablet (sublingual tablet, orally disintegrating tablet, etc.), capsule, film preparation, etc.). It may be a parenteral administration preparation (inhalation preparation, transdermal preparation, nasal administration preparation, suppository, injection, etc.). Further, the preparation may be a topically administered preparation (ointment, patch, poultice, etc.). The dysuria improving agent (or preparation) of the present invention is often a solid preparation (for example, an orally administered solid preparation). Therefore, in the following description, the components of the solid preparation will be mainly described.

The carriers are, for example, in addition to the 17th revised Japanese Pharmacopoeia (Pharmacopeia), (1) Handbook of Pharmaceutical Additives, Japan Pharmaceutical Additives Association, (2007), (2) "Encyclopedia of Pharmaceutical Additives 2016" (Pharmaceutical Affairs). Nippo, published in February 2016), (3) Pharmaceutics, 5th revised edition, Nanedo Co., Ltd. (1997), and (4) Pharmaceutical Additive Standards 2018 (Yakuji Nippo, July 2018), etc. It can be selected from the listed components (for example, excipients, binders, disintegrants, lubricants, coating agents, etc.) according to the administration route and the pharmaceutical use. As the carrier of the solid preparation, at least one selected from excipients and disintegrants, or at least one selected from excipients, binders and disintegrants is often used. In addition, the dysuria improving agent (or the preparation) may contain a lipid.

Examples of the excipient include sugars such as lactose (or lactose hydrate), starch (glucose), sucrose, malt sugar (martose or maltose hydrate), martitol, mannitol, sorbitol, xylitol, and isomalus hydrate. Or sugar alcohols; 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, sodium alginate; Carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium and other carboxymethyl cellulose or metal salts thereof (or cross-linked products thereof); low substitution hydroxypropyl cellulose; sodium carboxymethyl starch (sodium starch glycolate), low substitution Synthetic polymers such as polyvinylpyrrolidone-based polymers (polyvinylpyrrolidone (PVP, povidone), copolymers such as vinylpyrrolidone-vinyl acetate copolymer (copolyvidone), crosslinked polyvinylpyrrolidone (crosspovidone), etc.); Silicon oxide or silicate such as kaolin, light anhydrous silicic acid, calcium silicate, magnesium silicate, magnesium aluminometate, silicon dioxide, hydrous silicon dioxide; calcium monohydrogen phosphate, calcium dihydrogen phosphate, phosphorus anhydrous. Examples thereof include phosphates such as calcium hydrogen acid. These excipients can be used alone or in combination of two or more. Among these excipients, saccharides or sugar alcohols, starches such as corn starch, polysaccharides such as crystalline cellulose, and phosphates such as anhydrous calcium hydrogen phosphate are preferable from the viewpoint of excellent stability of the preparation. In particular, sugars such as lactose (or lactose hydrate) or sugar alcohols, corn starch, crystalline cellulose, anhydrous calcium hydrogenphosphate and the like are preferable.

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

As a binder, soluble starch such as pregelatinized starch and partially pregelatinized starch; starches such as corn starch and potato starch; crystalline cellulose (including microcrystalline cellulose), gum arabic, dextrin, sodium alginate, pectin, agar, Polysaccharides such as gelatin; polyvinylpyrrolidone-based polymers (polypolymers such as polyvinylpyrrolidone (PVP, povidone), vinylpyrrolidone-vinyl acetate copolymer (copolyvidone), etc.), polyvinyl alcohol (PVA), carboxyvinyl polymer, poly ( Meta) Acrylic acid-based polymers (methacrylic acid copolymers such as Eudragit L, S, L30D-55, aminoalkyl methacrylate copolymers such as Eudragit E, RS, etc.), polylactic acid, polyethylene glycol (polyethylene glycol 6000, etc.) Synthetic polymers such as: methyl cellulose (MC), ethyl cellulose (EC), carboxymethyl cellulose (carmellose, CMC), carboxymethyl cellulose sodium (carmellose sodium), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose ( Cellulose ethers such as HPMC); saccharides or sugar alcohols such as lactose (or lactose hydrate), glucose, sucrose, maltose (maltose or maltose hydrate), maltol, mannitol, sorbitol; waxes such as beeswax. Kind and the like can be exemplified. These binders can be used alone or in combination of two or more.

The total amount of the binder is, for example, 0.1 to 100 parts by mass, preferably 0.1 to 50 parts by mass, and more preferably 0.5 to 30 parts by mass with respect to 100 parts by mass of the excipient. It may be preferably about 1 to 15 parts by mass (for example, 2 to 10 parts by mass).

Disintegrants include soluble starches such as pregelatinized starch and partially pregelatinized starch; starches such as corn starch and potato starch; carboxymethyl cellulose such as carmellose, carmellose sodium, carmellose calcium and croscarmellose sodium or metal salts thereof. (Or a crosslinked product thereof); Synthetic polymer such as polyvinylpyrrolidone-based polymer (crosslinked polyvinylpyrrolidone (crosspovidone), etc.); Low-substituted hydroxypropyl cellulose; Sodium carboxymethyl starch (sodium starch glycolate), Low-substituted carboxymethyl Starch sodium; saccharides such as lactose (or lactose hydrate), glucose, sucrose, malt sugar (maltose or maltose hydrate), martitol, mannitol, sorbitol and the like, or sugar alcohols can be exemplified. These disintegrants can be used alone or in combination of two or more. Among the disintegrants, from the viewpoint of formulation stability, soluble starch such as pregelatinized starch and partially pregelatinized starch, carboxymethyl cellulose such as croscarmellose sodium or a metal salt thereof, crospovidone, low-degree-of-substitution hydroxypropyl cellulose and the like. Is preferably used.

The total amount of the disintegrant is, for example, 0.1 to 100 parts by mass, preferably 0.1 to 50 parts by mass, and more preferably 0.5 to 30 parts by mass with respect to 100 parts by mass of the excipient. It may be preferably about 1 to 25 parts by mass (for example, 1.5 to 20 parts by mass).

The lubricant includes minerals such as talc; higher fatty acids such as stearic acid, magnesium stearate, aluminum stearate, calcium stearate or metal salts thereof; glycerin fatty acid ester, sucrose fatty acid ester, and glycerin monostearate. , Higher fatty acid esters such as hardened oil; waxes such as carnauba wax, beeswax, lunauro, and mokuro; paraffins such as liquid paraffin; synthetic polymers such as polyethylene glycol (polyethylene glycol 6000 and the like) can be exemplified. These lubricants can be used alone or in combination of two or more. A preferred lubricant is magnesium stearate.

The total amount of the lubricant is, for example, 0.01 to 20 parts by mass, preferably 0.1 to 10 parts by mass, and more preferably 0.3 to 7 parts by mass with respect to 100 parts by mass of the excipient. More preferably, it may be about 0.5 to 5 parts by mass.

Examples of the coating agent include cellulose derivatives such as saccharides, ethyl cellulose and hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, and eudragit (methacryl). Acid / acrylic acid copolymer) and the like are used. The coating agent may be an enteric component such as cellulose phthalate, hydroxypropylmethyl cellulose phthalate, methyl methacrylate- (meth) acrylic acid copolymer, or a polymer containing a basic component such as dialkylaminoalkyl (meth) acrylate ( It may be a gastric-soluble component composed of (eudragit, etc.). Further, the pharmaceutical product may be a capsule containing these enteric-soluble components and gastric-soluble components in the skin.

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, it can be used to the extent that the medicinal efficacy and stability of the preparation are not impaired.

In the pharmaceutical product, known additives can be appropriately used depending on the administration route, dosage form and the like. Such additives include, for example, disintegrant aids, antioxidants or antioxidants, stabilizers, preservatives or preservatives, bactericides or antibacterial agents, antistatic agents, flavoring agents or masking agents, colorants, etc. Examples include deodorants or fragrances, refreshing agents, antifoaming agents and the like. These additives can be used alone or in combination of two or more.

In a pharmaceutical composition or a physiologically active composition in combination with a carrier (such as a pharmacologically or physiologically acceptable carrier), the 2-oxapregnane compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof. The content of the drug can be appropriately selected depending on the species, age, body weight, and condition (general condition, medical condition, presence or absence of complications, etc.), administration time, dosage form, administration method, etc., but for example, a unit. It may be about 0.1 to 20% by mass, preferably 0.5 to 15% by mass, and more preferably about 1 to 10% by mass per preparation (for example, one tablet).

The dysuria improving agent (pharmaceutical composition or preparation) of the present invention uses a conventional formulation method, for example, the 16th revised Japanese Pharmacopoeia, using a carrier component, an additive if necessary, etc. in addition to the active ingredient. It can be prepared by a production method or a method according to this production method.

The 2-oxapregnan compound or a pharmaceutically acceptable salt thereof is a known compound as described above, has been used for many years, and has high stability and safety.

The dysuria improving agent (pharmaceutical composition or preparation) of the present invention is a human and non-human animal, usually a mammal (for example, human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.). Can be safely administered. The dose can be selected according to the species, age, body weight, and condition (general condition, medical condition, presence or absence of complications, etc.), administration time, dosage form, administration method, and the like. For example, the dose (daily dose) to humans is, for example, 0.01 to 100 mg / day, preferably 0.05 to 75 mg / day (for example, 0.1) in terms of the compound represented by the formula (1). It may be about 50 mg / day), particularly about 0.1 to 30 mg / day (for example, 1 to 20 mg / day).

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

In the present invention, as described above, the 2-oxapregnane compound or a pharmaceutically acceptable salt thereof is administered as an active ingredient to an object having dysuria, or the dysuria improving agent (pharmaceutical composition or preparation). ) Is administered to treat, improve or alleviate dysuria (as well as to improve or promote urination). In addition, the use of the 2-oxapregnane compound or a pharmaceutically acceptable salt thereof as an active ingredient for treating, ameliorating or alleviating (and improving or promoting urination), or treating or ameliorating urinary disorders. Or use of the urination disorder improving agent (pharmaceutical composition or preparation) for alleviating (and improving or promoting urination); the above-mentioned 2-for producing the urination disorder improving agent, urination improving agent or urination promoting agent. Also includes the use of oxapregnan compounds or pharmaceutically acceptable salts thereof.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Test Example 1
Using a rat lower urinary tract obstruction model as a test system, the test substance was repeatedly orally administered to this lower urinary tract obstruction model for 2 weeks, and the effect of the lower urinary tract obstruction model on urinary function was investigated.

More specifically, the rat (female, Crl: CD (SD), 8 weeks old; Charles River Laboratories Japan) was operated on for lower urinary tract obstruction, and the test substance was applied once a day for 2 weeks. Repeated oral administration, after completion of administration, catheter placement in the bladder under anesthesia, cystometry under no anesthesia, cystometry under urethane anesthesia, euthanasia under deep anesthesia, tissue (bladder, bladder, The kidney) was removed. In addition, as a normal group, the rats were used without performing lower urinary tract obstruction surgery.

The test system, test substance and dosage are as follows.

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

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

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

[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.

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

[Bladder capacity]
The bladder capacity was calculated from the amount of urination and the amount of residual urine by the following formula.
Bladder capacity (mL) = urination volume (mL) + residual urine volume (mL)

In addition, the wet weight of the removed bladder and kidney was measured.

1 to 6 show the results of residual urine volume, urination efficiency, bladder capacity, wet weight of excised tissue (bladder, kidney) and survival rate in a female rat lower urinary tract obstruction model. Note that FIG. 1 shows the relationship between the residual urine volume and the test substance, and FIG. 2 shows the relationship between the urination efficiency and the test substance. Further, FIG. 3 shows the relationship between the bladder capacity and the test substance, FIGS. 4 and 5 show the relationship between the wet weight of the bladder and the kidney and the test substance, and FIG. 6 shows the relationship between the survival rate and the test substance.

As is clear from FIGS. 1 to 3, the B group (B3 group and B10 group) significantly increased the residual urine volume and the bladder capacity and decreased the urination efficiency as compared with the control group (solvent group). On the other hand, the group A significantly reduced the residual urine volume and the bladder capacity and increased the urination efficiency as compared with the control group. In addition, as is clear from FIGS. 4 and 5, Group A acted in a direction that significantly suppressed the increase in bladder and renal wet weight associated with lower urinary tract obstruction, while Group B acted in a direction that rather increased it. .. As described above, the group B did not improve the urinary function, or rather acted to worsen it, whereas the group A significantly improved the urinary function that decreased with the obstruction of the lower urinary tract. Furthermore, since group A significantly improved urinary function in the lower urinary tract obstruction model system of female rats without prostate, it can be seen that compound A improves dysuria regardless of the presence or absence of benign prostatic hyperplasia.

Furthermore, as is clear from FIG. 6, the group B reduced the survival rate of the rats with lower urinary tract obstruction, but the group A did not show a decrease in the survival rate. From this, it was also confirmed that compound A is highly safe.

Although it is not clear why the above results were obtained in female rats despite the fact that they belong to the same 2-oxapregnane compound (progesterones), it is considered as follows.

In clinical practice, it is believed that progesterone, which increases during pregnancy, relaxes the organs around the uterus, including the bladder. It has also been reported that pregnancy and progesterone affect bladder muscarinic receptors to increase bladder capacity and suppress bladder contraction in rats (Pharmacology. 50 (3): 192-200.1995). In addition to relaxation by progesterone, the bladder is functionally hypotonic due to mechanical compression from the back by the pregnant uterus. Therefore, residual urine and vesicoureteral reflux phenomenon may occur.

Group B has a strong progesterone-like action and is thought to suppress bladder contraction by the above mechanism.However, in a pathological model in which bladder function is strongly impaired, such as the female lower urinary tract obstruction model, group B It is possible that compound B excessively suppressed bladder contraction and worsened the condition.

On the other hand, compound A has a mild antiprogesterone effect. The sexual cycle of female rats is about 4 days, and in group A, compound A antagonizes endogenous progesterone, which increases with the sexual cycle, and is protective against further suppression of bladder function in the lower urinary tract obstruction model. It is possible that it acted on.

Test Example 2
Using a rat lower urinary tract obstruction model as a test system, the test substance was repeatedly orally administered to this lower urinary tract obstruction model for 14 days, and the effect of the lower urinary tract obstruction model on urinary function was investigated. The lower urinary tract obstruction model is not a benign prostatic hyperplasia model with an enlarged prostate.

More specifically, the rat (male, Crl: CD (SD), 8 weeks old; Charles River Laboratories Japan) was operated on for lower urinary tract obstruction, and the test substance was applied once / day for 14 days. Repeated oral administration was performed, and after the administration was completed, catheter placement was performed in the bladder under anesthesia, and cystometry was performed under no anesthesia to evaluate the residual urine volume and micturition efficiency.

The test substances and doses in the test system (male rat with lower urinary tract obstruction) are as follows.

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

The results are shown in FIGS. 7 and 8.

From FIGS. 7 and 8, it was suggested that in the male rat lower urinary tract obstruction model, group A had a stronger effect of improving urinary function (residual urine volume, urinary efficiency) than group C (dutasteride).

Test Example 3
The relationship between the bladder and urethral contraction reaction and the test substance in older male rats (22 weeks old; Charles River Laboratories, Japan) was investigated. The rat is a model in which the prostate is predicted to be enlarged due to the old age.

The test substance was repeatedly orally administered once / day to the above-mentioned old male rats for 2 weeks, and then the bladder specimen was removed. Then, using a bladder specimen, a constant temperature (37 ° C.) magnus tube filled with a physiological salt solution aerated with 95% O _2-5 % CO ₂ gas was suspended at a static tension of about 9.8 mN, and a square wave was passed. Wall 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) was applied and a contraction experiment was performed with isometric features.

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

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

The results are shown in FIGS. 9 and 10.

From FIGS. 9 and 10, in Group A, compared to Group C, due to rectangular wave transmural electrical stimulation (bladder efferent nerve stimulation), Carbachol (muscarinic receptor stimulation) and KCl (depolarization-dependent Ca ²⁺ stimulation). Bladder contractile tension was significantly stronger or in a stronger direction.

Test Example 4
As a model of dysuria, a model of dysuria associated with diabetes was prepared and evaluated for dysuria as follows. It should be noted that this model is a dysuria model associated with neuropathy and smooth muscle contraction without benign prostatic hyperplasia.

Rats (male, Crl: CD (SD), 5 weeks old; Charles River Laboratories, Japan) were weighed, and after an overnight fast, blood was drawn from the tail vein, fasting blood glucose was measured, and body weight and fasting. Based on blood glucose levels, they were grouped into two groups by multivariate blocking allocation. 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 given streptozosine (STZ; Sigma-aldrich). ) (50 mg / kg) was intraperitoneally administered. Streptozotocin (STZ) was administered as the above-mentioned citric acid buffer solution having a concentration of 5 mg / mL.

Approximately one week after administration of streptozotocin (STZ), body weight and fasting blood glucose were measured, and in the streptozotocin (STZ) -administered group (second group), individuals with a fasting blood glucose level of 300 mg / dL or more were induced to develop diabetes. Adopted as an animal. These diabetes-inducing animals are models with no abnormalities in the prostate (not benign prostatic hyperplasia). Diabetes-induced animals (models) were grouped into three groups by multivariable blocking allocation based on body weight and fasting blood glucose levels.

Grouped diabetes induction models with 0.5v / v% polysorbate 80 solution (0.5% P) (10 mL / kg) or compound A (3 or 10 mg / kg) once daily, weekdays only, 4 weeks Orally administered according to the administration schedule. In addition, 0.5v / v% polysorbate 80 solution (0.5% P) (10 mL / kg) was orally administered to the first group on the same administration schedule as above (normal group). On the final day of administration, a cannula was inserted and fixed to the apex of the bladder under isoflurane anesthesia, and cystometry (Cystometogram, CMG) was performed in the order of awakening and urethane anesthesia to measure bladder pressure, micturition volume and residual urine volume. .. After the measurement was completed, blood was collected under deep isoflurane anesthesia, and then the prostate (abdominal lobe, dorsal lobe), seminal vesicles, bladder and kidney were removed, and the weights of each were measured. In addition, the blood glucose level in the collected blood was measured.

The test substances and doses in the test system (rats with dysuria associated with diabetes) are as follows.

Normal group: Citric acid buffer 10 mL / kg (intraperitoneal administration), 0.5% P 10 mL / kg (oral administration) (n = 10)
Solvent 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)

Urination parameters:
The obtained data on bladder pressure, micturition volume and residual urine volume were analyzed, and bladder volume (mL), residual urine volume (mL), and micturition efficiency (%) were determined for each urination as urination parameters. For these urination parameters, the average value of the two measured values was calculated and used as the measured value of each individual.

Tissue weight:
The weight of the entire prostate was calculated from the weight of the ventral lobe of the prostate and the dorsal lobe of the prostate. The weights of the prostate, seminal vesicles, bladder and kidney were converted into the tissue weight per 100 g of body weight. Further, for the A3 group and the A10 group to which the compound A was administered, the suppression rate of the weight of the prostate and the seminal vesicle was calculated with respect to the weight of the prostate and the seminal vesicle of the solvent group (up to the first decimal place).

In the statistical analysis, the mean and standard deviation of each group were calculated for the final body weight, tissue weight per 100 g of body weight (prostate, seminal vesicles, bladder and kidney), blood glucose level, and various micturition parameters. For statistical analysis, a significant difference test was performed using a SAS statistical analysis system (SAS version 9.4; manufactured by SAS Institute Japan Co., Ltd.). Student's t-test on both sides was performed between the normal group and the solvent group, and it was judged that there was a statistically significant difference in the risk rate of less than 5%. In addition, Williams' multiple comparison test was performed between the solvent group and the A3 group and the A10 group, and it was judged that there was a statistically significant difference in the risk rate of less than 2.5%.

In addition, 5% significant (P <0.05 (against normal group) (Student's t-test)) is indicated by "*", and 2.5% significant (P <0.025 (against solvent group)) ( Williams' multiple comparison test)) is indicated by "#".

Bladder contractile force by nomogram analysis:
The maximum urinary flow rate (mL / sec) and the maximum intravesical pressure during urinary flow (cmH ₂ O) were determined by cystometry (CMG) under anesthesia, and the bladder contractile force during urination of each group was evaluated. That is, for each group, the average values of the maximum urinary flow rate Qmax (mL / sec), the maximum urinary bladder pressure PdetQmax (cmH ₂ O), and the bladder capacity BC (mL) were obtained, and the bladder at the maximum urinary flow on the X-axis was obtained. The maximum urine flow rate / bladder capacity is plotted on the Y-axis with respect to the internal pressure / bladder capacity. It was judged.

The results are shown in Table 1, FIGS. 11 to 13 (cystometry (CMG) data under awakening), FIGS. 14 to 16 (cystometry (CMG) data under anesthesia), and FIG. 17 (nomogram analysis result). .. In addition, "mean ± standard deviation" is described in each column in the table.

[Weight, tissue weight and blood glucose level]
In the solvent group (control group), the body weight was significantly reduced and the bladder and kidney weights were significantly increased as compared with the normal group. The blood glucose level also increased significantly. In contrast, in the A3 and A10 groups, the prostate and seminal vesicle weights were significantly reduced and did not affect body weight, blood glucose levels, and bladder and kidney weights.

As is clear from the blood glucose levels of the A3 group and the A10 group with respect to the solvent group, compound A has no therapeutic effect on diabetes. In addition, in the diabetes induction model, dysuria develops without enlargement of the prostate.

[Cistometry (CMG): bladder capacity, residual urine volume and urination efficiency]
The analysis results of the cystometry (CMG) measurement data under awakening are shown in FIGS. 11 to 13. In the solvent group (control group), the bladder volume and residual urine volume were significantly increased and the urination efficiency was significantly decreased as compared with the normal group. In the A3 group, the bladder volume and the residual urine volume were significantly reduced and the urination efficiency was improved as compared with the solvent group (control group). In group A10, bladder capacity and residual urine volume were significantly reduced, and micturition efficiency was significantly improved (P = 0.0359, Williams multiple comparison test).

The analysis results of the cystometry (CMG) measurement data under anesthesia are shown in FIGS. 14 to 16. In the solvent group (control group), the bladder volume and residual urine volume were significantly increased and the urination efficiency was significantly decreased as compared with the normal group. The residual urine volume was significantly reduced in the A3 group as compared with the solvent group (control group). In the A10 group as well, the residual urine volume was significantly reduced and the bladder capacity was also reduced (P = 0.0336, Williams' multiple comparison test). In addition, the urination efficiency was improved in the A3 group and the A10 group.

Further, in the nomogram analysis (FIG. 17), the A3 group and the A10 group are farther from the origin than the solvent group (control group), so that it is judged that the bladder contractile force at the time of urination is strong.

As described above, compound A has no therapeutic effect on diabetes (A3 group and A10 group), and even in a diabetes-induced model in which the prostate is not enlarged, dysuria can be significantly improved.

Test Example 5
Antiprogesterone activity was measured for compound A and compound D (mifepristone). That is, the test substance is repeatedly administered to the ovariectomized rat as a test system together with the sex hormone, and the antiprogesterone action (antiprogesterone activity) is based on the fluctuation of the uterine weight (suppressive action against weight increase) associated with the formation of rat decidua. It was investigated.

More specifically, rats (female, Crl: CD (SD), 5 weeks old: Charles River Laboratories, Japan) underwent ovariectomy, and one week after the surgery, a high dose of estrone 5 μg / animal was administered once / day. It was administered subcutaneously for 3 days. After a 1-day rest period, a low dose of estrone (1 μg / animal) was subcutaneously administered, progesterone (6 mg / kg) was intramuscularly administered, and the test substance was orally administered once a day for 8 days from the next day. On the 4th day after the start of administration, the right uterus was stimulated for a dedecidualization reaction, and the uterine weight (right body part) was measured the day after the final administration (n = 6). Group E was treated with ovariectomy and stimulation of the dedecidualization reaction, but not with hormones.

The test substances and doses in the test system (ovarian removed rat) are as follows.

Group E: Rats untreated with ovarian resection hormone
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, 3 mg / kg (n = 6)
Group A10: Compound A, 10 mg / kg (n = 6)
Group A30: Compound A, 30 mg / kg (n = 6)
Group D: Compound D (mifepristone), 3 mg / kg (n = 6)

The results are shown in FIG.

As shown in FIG. 18, a significant inhibitory effect (suppression rate 89.5%) was observed in the D group with respect to the solvent group. In addition, no significant inhibitory effect was observed in the A3 group (suppression rate 15.0%) with respect to the solvent group, but a significant inhibitory effect (suppression rate was 63.0% and 63.0%, respectively) in the A10 group and the A30 group. 83.3%) was observed, demonstrating that compound A has antiprogesterone activity.

Test Example 6
As described below, a dysuria model associated with streptozotocin-induced diabetes was prepared as a dysuria model according to Test Example 4, and the effects of the compounds A and C on the dysuria were evaluated. It should be noted that this model is a dysuria model associated with neuropathy and smooth muscle contraction without benign prostatic hyperplasia.

Rats (male, Crl: CD (SD), 5 weeks old; Charles River Laboratories, Japan) were weighed and grouped into two groups based on their weight. 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 given streptozosine (STZ; Sigma-aldrich). ) (50 mg / kg) was intraperitoneally administered. Streptozotocin (STZ) was administered as the above-mentioned citric acid buffer solution having a concentration of 5 mg / mL.

Approximately one week after administration of streptozotocin (STZ), body weight and fasting blood glucose were measured, and in the streptozotocin (STZ) -administered group (second group), individuals with a fasting blood glucose level of 300 mg / dL or more were induced to develop diabetes. Adopted as an animal. These diabetes-inducing animals are models with no abnormalities in the prostate (not benign prostatic hyperplasia). Diabetes-induced animals (models) were grouped into three groups by multivariable blocking allocation based on body weight and fasting blood glucose levels.

Grouped diabetes induction models include 0.5v / v% polysorbate 80 solution (0.5% P) (10 mL / kg), compound A (3 mg / kg) or compound C (dutasteride) (0.3 mg / kg). Was orally administered once a day only on weekdays with a 4-week administration schedule. In addition, 0.5v / v% polysorbate 80 solution (0.5% P) (10 mL / kg) was orally administered to the first group on the same administration schedule as above (normal group). On the final day of administration, a cannula was inserted and fixed to the apex of the bladder under isoflurane anesthesia, and cystometry (Cystometogram, CMG) was performed in the order of awakening and urethane anesthesia to measure bladder pressure, micturition volume and residual urine volume. .. After the measurement was completed, blood was collected under deep isoflurane anesthesia, and then the prostate (abdominal lobe, dorsal lobe) was removed and the weight of each was measured. In addition, the blood glucose level in the collected blood was measured.

The test substances and doses in the test system (rats with dysuria associated with diabetes) are as follows.

Normal group: Citric acid buffer 10 mL / kg (intraperitoneal administration), 0.5% P 10 mL / kg (oral administration) (n = 10)
Solvent 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)
C0.3 group: STZ 50 mg / kg (intraperitoneal administration), compound C (dutasteride) 0.3 mg / kg (oral administration) (n = 10)

Urination parameter: In the same manner as in Test Example 4, the residual urine volume (mL) and urination efficiency (%) were obtained for each urination as urination parameters, and the average value of the two measured values was measured for each individual. It was set as a value.

Prostate weight: In the same manner as in Test Example 4, the weight of the prostate (abdominal lobe, dorsal lobe and whole) was converted into the tissue weight per 100 g of body weight. In addition, for the A3 group to which the compound A was administered and the C0.3 group to which the compound C was administered, the suppression rate of the weight of the prostate was calculated with respect to the weight of the prostate in the solvent group (up to the first decimal place).

In the statistical analysis, a significant difference test was performed in the same manner as in Test Example 4. Student's t-test on both sides was performed between the normal group and the solvent group, and it was judged that there was a statistically significant difference in the risk rate of less than 5%, and it was indicated by "*" that it was 5% significant. .. In addition, Dunnett's multiple comparison test was performed between the solvent group and the A3 group and C0.3 group, and it was judged that there was a statistically significant difference in the risk rate of less than 5%, and it was determined to be 5% significant. Shown in.

Bladder contractile force by nomogram analysis: The bladder contractile force during urination of each group was evaluated in the same manner as in Test Example 4. In addition, the maximum urinary flow rate / bladder capacity is plotted on the Y-axis with respect to the bladder internal pressure / bladder capacity at the time of maximum urinary flow on the X-axis. It was judged that the farther the bladder was, the stronger the bladder contractile force was.

The results are shown in Table 2, FIGS. 19 and 20 (cystometry (CMG) data under awakening), and FIG. 21 (nomogram analysis results).

[Prostate weight and blood sugar level]
The A3 group and the C0.3 group significantly atrophied the weights of the abdominal lobe of the prostate, the dorsal lobe of the prostate, and the entire prostate with respect to the solvent group (P <0.05). Since there is no significant difference in prostate weight between the normal group and the solvent group, the diabetes induction model is a model in which the prostate is not enlarged. In such a diabetes model, the A3 group and the C0.3 group did not statistically affect the blood glucose level of the solvent group as in Test Example 4, so that the compound A and the compound C had diabetes. It was confirmed that no therapeutic effect was observed.

[Cistometry (CMG): Residual urine volume and urination efficiency]
From the analysis results of the cystometry (CMG) measurement data under awakening, as shown in FIGS. 19 and 20, the solvent group was associated with STZ treatment (diabetes induction), and the residual urine volume was higher than that of the normal group. Was significantly increased and urination efficiency was significantly reduced (p <0.05). From these facts, the diabetes induction model develops dysuria. On the other hand, the A3 group significantly reduced the residual urine volume with respect to the solvent group (p <0.05), while the C0.3 group statistically decreased the residual urine volume with respect to the solvent group. Did not affect. In addition, the A3 group significantly improved the micturition efficiency with respect to the solvent group (p <0.05), but the C0.3 group had no statistical effect on the micturition efficiency of the solvent group. .. Regarding urination efficiency, there was a tendency for statistical differences between the A3 group and the C0.3 group (p = 0.0757, Student's t-test).

Further, in the nomogram analysis (FIG. 21), the plot of the normal group was at the position farthest from the origin, and the C0.3 group was at almost the same position as the solvent group. On the other hand, the plot of the A3 group was located farther from the origin than the solvent group. From this, it is judged that the A3 group has a stronger bladder contractile force during urination than the solvent group and the C0.3 group.

As described above, compound A (A3 group) has no therapeutic effect on diabetes, and even in a diabetes-induced model in which the prostate is not enlarged, dysuria can be significantly improved.

Pharmaceutical example 1
100 g of active ingredient (17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadien-3,20-dione) and excipient (anhydrous calcium hydrogen phosphate (Fuji Chemical Industry Co., Ltd.) 2810 g of "Fujikarin"), corn starch (300 g of "Nippon Shokuhin Hokoku Corn Starch" manufactured by Nippon Shokuhin Kako Co., Ltd.) and 60 g of disintegrant (pregelatinized starch ("Swelstar PD-1" manufactured by Asahi Kasei Co., Ltd.)) And a lubricant (magnesium stearate (“magnesium stearate” manufactured by Taihei Kagaku Sangyo Co., Ltd.) 30 g) are mixed, and the resulting mixture is tableted to obtain the components shown in Table 3 below. A tablet containing (5 mg tablet) was produced.

Pharmaceutical example 2
75 g of the active ingredient (17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadien-3,20-dione) and an excipient (milk sugar hydrate (Freund Sangyo Co., Ltd.) "Dilacto's S ”) 2790 g, crystalline cellulose (“Theoras UF711” manufactured by Asahi Kasei Co., Ltd.) 1500 g, corn starch (“Nisshoku Bureau Corn Starch” manufactured by Nippon Shokuhin Kako Co., Ltd.) 450 g) and disintegrant (croscarmellose sodium). (90 g of "KICCOLATE" manufactured by Asahi Kasei Co., Ltd.) and a lubricant (magnesium stearate ("magnesium stearate" manufactured by Taihei Kagaku Sangyo Co., Ltd.) 45 g) are mixed, and the resulting mixture is tableted. Each tablet produced a tablet (2.5 mg tablet) containing the ingredients shown in Table 4 below.

Since the dysuria improving agent of the present invention contains the 2-oxapregnane compound represented by the formula (1), it can effectively improve dysuria such as feeling of residual urine, weakened urine, urinary incontinence, and frequent urination. Therefore, it is possible to improve and improve the quality of life of humans (particularly elderly people) suffering from dysuria.

Claims (12)

A dysuria improving agent containing a 2-oxapregnane compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

(In the formula, R ₁ to R ₃ represent the same or different alkyl groups, R ₄ represents a hydrogen atom or an alkylcarbonyl group, X represents a halogen atom, and Y represents the 11th position and 15 of the steroid skeleton. (Indicating a hydroxyl or oxo group attached to the or 16-position) In the above formula (1), R ₁ to R ₃ are methyl groups, R ₄ is an acetyl group, X is a chlorine atom, and Y is a hydroxyl group or an oxo group bonded to the 15-position of the steroid skeleton. The agent for improving urinary disorders according to claim 1. The dysuria according to claim 1 or 2, wherein the compound represented by the formula (1) is 17α-acetoxy-6-chloro-15β-hydroxy-2-oxa-4,6-pregnadien-3,20-dione. Improving agent. Residual urinary sensation, weakened urine, delayed urination, abdominal pressure urination, terminal dripping, post-urinary urinary dripping, urinary incontinence, frequent urination, urinary urgency, bladder pain or bladder pain syndrome, urinary pain, bladder atrophy, neuropathic At least one dysuria selected from bladder, incontinence dribbling or overactive bladder, chronic cystitis, interstitial cystitis, chronic prostatic inflammation, pelvic pain syndrome, inactive bladder, incontinence of incontinence of urinary muscle hyperreflexion or The dysuria improving agent according to any one of claims 1 to 3 for improving symptoms. The dysuria improving agent according to any one of claims 1 to 4, which improves at least one dysuria or symptom selected from residual urine volume, urination efficiency, bladder capacity, bladder wet weight and kidney wet weight. The agent for improving dysuria according to any one of claims 1 to 5, wherein the dysuria is a dysuria without benign prostatic hyperplasia. The dysuria improving agent according to any one of claims 1 to 6, wherein the dysuria is a dysuria associated with a disorder of smooth muscle contraction. The dysuria-improving agent according to any one of claims 1 to 7, wherein the dysuria is a dysuria associated with at least one disease selected from a disease causing neurogenic bladder, diabetes, and dysuria associated with diabetes. .. The dysuria improving agent according to any one of claims 1 to 8, which improves or promotes urination. The urinary disorder improving agent according to any one of claims 1 to 9, wherein the dose is 0.01 to 100 mg per day in terms of a compound represented by the above formula (1). The dysuria improving agent according to any one of claims 1 to 10, which is a solid preparation. The urinary disorder improving agent according to claim 11, wherein the carrier of the solid preparation contains at least one carrier selected from excipients, binders and disintegrants.

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