WO2016039367A1 - 尿失禁予防用及び/又は治療用新規医薬組成物 - Google Patents
尿失禁予防用及び/又は治療用新規医薬組成物 Download PDFInfo
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- WO2016039367A1 WO2016039367A1 PCT/JP2015/075567 JP2015075567W WO2016039367A1 WO 2016039367 A1 WO2016039367 A1 WO 2016039367A1 JP 2015075567 W JP2015075567 W JP 2015075567W WO 2016039367 A1 WO2016039367 A1 WO 2016039367A1
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- urinary incontinence
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- MQXWPWOCXGARRK-HJGJAMNPSA-N NC(c(cc1)c[n]1-c1cnc(NC[C@](C2)(C[C@H]2F)c(nccc2)c2F)nc1)=O Chemical compound NC(c(cc1)c[n]1-c1cnc(NC[C@](C2)(C[C@H]2F)c(nccc2)c2F)nc1)=O MQXWPWOCXGARRK-HJGJAMNPSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the present invention relates to a novel pharmaceutical use as a pharmaceutical composition for preventing and / or treating urinary incontinence of a compound having an action of activating skeletal muscle fast muscle troponin.
- Urinary incontinence is a state of involuntary leakage of urine that is recognized objectively and is a problem socially or hygienically (J. Clin. Pharm. Ther., 25 (4) , 251-263 (2000)).
- urge incontinence urge incontinence
- stress urinary incontinence and mixed urinary incontinence in which they are mixed are known.
- the most common type of urinary incontinence is stress urinary incontinence, and about 50% of women who develop urinary incontinence are known to have stress urinary incontinence (Int. Urogynecol. J., 11 (5), 301-319 (2000)).
- Stress urinary incontinence refers to a disease in which urine leaks involuntarily even when the abdominal pressure increases due to coughing, sneezing, exercise, etc., even though the bladder does not contract. There are two main causes of stress urinary incontinence.
- bladder neck / urethral hypermobility bladder neck drop due to relaxation of the pelvic floor muscles causes poor transmission of abdominal pressure to the urethra, without increasing urethral pressure when abdominal pressure increases, Urinary bladder pressure increases and urine leaks.
- the other is leakage of urine when abdominal pressure increases due to a decrease in sphincter function due to intrinsic urethral sphincter failure.
- the onset of stress urinary incontinence is likely to involve weakening of the pelvic floor muscles due to aging and childbirth and decreased urethral function.
- pelvic trauma due to pregnancy and vaginal delivery is known as a risk factor for persistent stress urinary incontinence, and the incidence of stress urinary incontinence in the first 5 years after birth is reported to be about 30% (Neurourol) Urodyn., 21 (1), 2-29 (2002)).
- Urinary urinary incontinence is a disease in which urine leaks involuntarily immediately after a complaint (urinary urgency) that is difficult to put up with a strong, uncontrollable urinary urgency.
- Mixed urinary incontinence is a condition in which a plurality of urinary incontinence is accompanied, and many have developed urge incontinence and stress urinary incontinence.
- Urinary incontinence has a major impact on quality of life (QOL). This limits the range of activities of patients who are concerned about the symptoms and makes them feel socially isolated and lonely.
- SNRI serotonin / norepinephrine reuptake inhibitory action
- NRI selective norepinephrine reuptake inhibitory action
- SNRI and NRI drugs enhance the excitability of the Onuf nucleus and thereby excite the pudendal nerve, which is a somatic motor nerve, and increase the contractile force of the external urethral sphincter (non-patent literature). 1, 2).
- Non-patent Document 2 Non-patent Document 2
- NRI's (S, S) -reboxetine has been reported in clinical trials to increase urethral resistance and show efficacy against stress urinary incontinence (Non-patent Documents 3 and 4), but as a urinary incontinence treatment agent Has not yet obtained approval to sell pharmaceutical products.
- Non-patent Document 5 Drugs with ⁇ 1 receptor agonistic action have been shown to be effective in stress urinary incontinence in clinical trials by contracting the urethra via ⁇ 1 receptors present in urethral smooth muscle. Since it has cardiovascular side effects (Non-patent Document 5), it has not yet been approved to obtain a pharmaceutical product for treatment of stress urinary incontinence.
- the pelvic floor muscles that support the external urethral sphincter and the bladder and urethra are a kind of skeletal muscle.
- Myofibrils, contractile organs of skeletal muscle are made up of a series of sarcomere units consisting of thin actin filaments and thick myosin filaments.
- the skeletal muscle contracts as the two filaments slide past each other by the repetitive interaction between the actin filament and the myosin filament.
- the contraction reaction of skeletal muscle is caused by the release of calcium ions from the intracellular sarcoplasmic reticulum in response to the excitation of somatic motor nerves that control each skeletal muscle.
- Intracellular calcium ions bind to the troponin complex, which is one of the constituent proteins of the actin filament, and change the structure of the troponin complex, allowing interaction between the actin filament and myosin filament.
- the troponin complex functions as a regulatory protein that mediates the contraction response of skeletal muscle that is dependent on the calcium ion concentration in actin filaments.
- Skeletal muscles are classified into fast muscles and slow muscles, and fast muscles have functional characteristics such as higher muscle tension and faster contraction speed than slow muscles.
- the troponin complex forms a fast muscle type and a slow muscle type troponin complex by combining troponins of different isoforms in the fast muscle and the slow muscle.
- Non-Patent Document 6 Drugs that activate skeletal muscle fast-muscle troponin act on fast-muscle troponin complex and increase the sensitivity of troponin complex to intracellular calcium ions to increase fast muscle contractile force.
- Compound A is a compound having an action of activating skeletal muscle fast muscle troponin (Patent Document 1).
- Compound A has been shown to shift the concentration response curves of intracellular calcium ion concentration and muscle tension to the left in rat long-knee extensor and rat diaphragm myofibrils containing fast muscle components (Patent Document 2). , 3).
- Compound A enhances the contraction response of rat diaphragm induced by transmural electrical stimulation in vitro, and also potentiates the contraction response of long extensor extensor muscle by electrical stimulation of rat radial nerve in vivo.
- Patent Documents 2 and 3 It has been reported that the external urethral sphincter and the pelvic floor muscle are skeletal muscles containing a fast muscle component (Non-Patent Documents 7 and 8).
- a novel pharmaceutical composition for preventing and / or treating urinary incontinence which is different from conventional drugs, as a certain aspect, for preventing and / or treating stress urinary incontinence, as a certain aspect for preventing mixed urinary incontinence and A therapeutic pharmaceutical composition is provided.
- the present invention relates to 1- [2-( ⁇ [trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl] methyl ⁇ amino) pyrimidin-5-yl] -1H-pyrrole-3 -A pharmaceutical composition for preventing and / or treating urinary incontinence containing carboxamide or a salt thereof and a pharmaceutically acceptable excipient, and in one embodiment, a pharmaceutical composition for preventing and / or treating stress urinary incontinence In one embodiment, the present invention relates to a pharmaceutical composition for preventing and / or treating mixed urinary incontinence.
- the present invention also relates to 1- [2-( ⁇ [trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl] methyl ⁇ amino) pyrimidin-5-yl] -1H-pyrrole-3 -It relates to a preventive and / or therapeutic agent for urinary incontinence containing carboxamide or a salt thereof.
- the present invention also relates to 1- [2-( ⁇ [trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl] methyl ⁇ amino) pyrimidin-5-yl] -1H-pyrrole-3 -A urinary incontinence preventive and / or therapeutic agent containing a carboxamide or a salt thereof and a pharmaceutically acceptable excipient, as an aspect, a preventive and / or therapeutic agent for stress urinary incontinence, as a mixed type
- the present invention relates to a urinary incontinence preventive and / or therapeutic agent.
- the present invention provides, as an aspect, for producing a pharmaceutical composition for preventing and / or treating urinary incontinence, as an aspect for producing a pharmaceutical composition for preventing and / or treating stress urinary incontinence.
- 1- [2-( ⁇ [trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl] methyl ⁇ amino for the manufacture of a pharmaceutical composition for preventing and / or treating mixed urinary incontinence ) Pyrimidin-5-yl] -1H-pyrrole-3-carboxamide or a salt thereof; for certain aspects, for preventing and / or treating stress urinary incontinence, for preventing and / or treating urinary incontinence 1- [2-( ⁇ [trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl] methyl ⁇ amino) pyrimidin-5-yl for the prevention and / or treatment of mixed urinary incontinence ] -1H-pyrrole-3
- Compound A or a salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention enhances the contraction response of the external urethral sphincter induced by transmural electrical stimulation of the rat isolated urethra, and increases the urethral pressure by electrical stimulation of the pudendal nerve in rats Since the response is enhanced, the pharmaceutical composition for preventing and / or treating urinary incontinence, as one aspect, the pharmaceutical composition for preventing and / or treating stress urinary incontinence, and as the certain aspect for preventing mixed urinary incontinence and / or Alternatively, it is expected as an active ingredient of a therapeutic pharmaceutical composition.
- This specification includes the contents described in the specification, claims and drawings of Japanese Patent Application No. 2014-183434 which is the basis of the priority of the present application.
- FIG. 1 is a graph showing the results of Example 1.
- the vertical axis shows the ratio (%) of the value after test substance addition to the value before test substance addition in the contraction response of the external urethral sphincter induced by transmural electrical stimulation of the rat isolated urethra.
- * Indicates a significant difference with respect to the solvent addition group when tested at Dunnett's multiple comparison test at a significance level of less than 5% (p ⁇ 0.05). When tested at less than%, it indicates that a significant difference was observed with respect to the solvent addition group (p ⁇ 0.01).
- FIG. 2 is a graph showing the results of Example 2.
- the vertical axis shows the ratio (%) of the value after administration of the test substance to the value before administration of the test substance in the response to the increase in intraurethral pressure induced by pudendal nerve electrical stimulation in rats, and is expressed as the mean value ⁇ standard error.
- * Indicates a significant difference from the solvent-administered group when tested at Dunnett's multiple comparison test at a significance level of less than 1% (p ⁇ 0.01), and ** indicates a significance level of 0.1 using the above test method. When tested at less than%, it indicates that there was a significant difference from the solvent-administered group (p ⁇ 0.001).
- compound A is 1- [2-( ⁇ [trans-3-fluoro-1- (3-fluoropyridin-2-yl) cyclobutyl] methyl ⁇ amino) pyrimidin-5-yl] -1H -Pyrrole-3-carboxamide, which is the compound described in Example 14 of Patent Document 1 described above. Its chemical structure is shown below.
- urine incontinence is a disease in which urine leaks involuntarily, such as stress urinary incontinence, urge incontinence, mixed urinary incontinence, functional urinary incontinence, reflex urinary incontinence, etc. Is mentioned.
- Stress urinary incontinence is a disease that causes involuntary leakage of urine even when the abdominal pressure increases, such as coughing, sneezing, and exercise. Is a disease in which urine is involuntarily leaked immediately after a complaint (urinary urgency) that is difficult to put up with an uncontrollable strong urinary urgency.
- Mened urinary incontinence is a disease in which the stress urinary incontinence and urge urinary incontinence are combined.
- the use of the pharmaceutical composition of the present invention is urinary incontinence, and as one aspect, stress urinary incontinence or mixed urinary incontinence, as one aspect, stress urinary incontinence, and as one aspect, mixed type Urinary incontinence.
- the pharmaceutical composition of the present invention is used for diseases that can be prevented or treated by enhancing contraction of the external urethral sphincter.
- a pharmaceutical composition for preventing and / or treating urinary incontinence comprising Compound A and a pharmaceutically acceptable excipient.
- a pharmaceutical composition for preventing and / or treating stress urinary incontinence comprising Compound A and a pharmaceutically acceptable excipient.
- a pharmaceutical composition for preventing and / or treating mixed urinary incontinence comprising Compound A and a pharmaceutically acceptable excipient.
- the agent for preventing and / or treating stress urinary incontinence containing Compound A is shown below.
- a mixed urinary incontinence preventive agent and / or therapeutic agent comprising compound A.
- the use of Compound A for the prevention and / or treatment of mixed urinary incontinence (5) Compound A for the prevention and / or treatment of urinary incontinence. In one embodiment, compound A for prevention and / or treatment of stress urinary incontinence. In one embodiment, Compound A for the prevention and / or treatment of mixed urinary incontinence. (6) A method for preventing and / or treating urinary incontinence comprising, or consisting of, administering to a subject an effective amount of Compound A. In one embodiment, a method for preventing and / or treating stress urinary incontinence comprising, or consisting of, administering to a subject an effective amount of Compound A. In one embodiment, a method for preventing and / or treating mixed urinary incontinence comprising or consisting of administering an effective amount of Compound A to a subject.
- Compound A or a salt thereof can be obtained in accordance with the method described in Example 14 of Patent Document 1 (International Publication WO 2011/133888) or by a modification thereof.
- the “salt of compound A” means a pharmaceutically acceptable acid addition salt of compound A, and specifically includes inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. And acetic acid, propionic acid, glycolic acid, pyruvic acid, malic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, benzoic acid, cinnamic acid, mandelic acid, tartaric acid, citric acid, methanesulfone Examples thereof include acid addition salts with organic acids such as acid, ethanesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, stearic acid and salicylic acid.
- “Compound A or a salt thereof” includes a solvate of Compound A, specifically, for example, a hydrate or an ethanolate, and further includes an acid addition salt of a solv
- Compound A can be mentioned.
- a pharmaceutical composition containing Compound A or a salt thereof is prepared by a commonly used method using a commonly used excipient in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier. be able to.
- Administration is oral by tablet, pill, capsule, granule, powder, liquid, etc., or injection such as intra-articular, intravesical, intravenous, intramuscular, suppository, transdermal solution, ointment, Any form of parenteral administration by transdermal patch, transmucosal liquid, transmucosal patch, inhalant, etc. may be used.
- Tablets, powders, granules, etc. are used as solid compositions for oral administration.
- one or more active ingredients are mixed with at least one inert excipient.
- the composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
- Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol.
- the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
- the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
- aqueous solvent include distilled water for injection or physiological saline.
- Non-aqueous solvents include alcohols such as ethanol.
- Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
- the daily dose is preferably about 0.001 to 100 mg / kg, preferably 0.01 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. Or in 2 to 4 doses.
- the dose per day is suitably about 0.0001 to 10 mg / kg per body weight, and should be administered once to several times a day.
- about 0.001 to 100 mg / kg per body weight is administered in 1 to 3 times a day.
- the dosage is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
- the pharmaceutical composition of the present invention contains 0.01 to 99% by weight, and in one embodiment 0.01 to 50% by weight of Compound A or a salt thereof. Contains as an active ingredient.
- the pharmaceutical composition of the present invention can be used in combination with various therapeutic agents that are considered effective for urinary incontinence, particularly stress urinary incontinence and mixed urinary incontinence.
- the combination may be administered simultaneously, separately separately, or at desired time intervals. In the case of simultaneous administration, it may be a combination drug or separately formulated.
- Example 1 Experimental test method to evaluate the potentiating effect of Compound A on the contraction of external urethral sphincter induced by transmural electrical stimulation using the isolated rat urethra
- the urethra was removed from a 10-week-old SD female rat .
- the isolated urethra was longitudinally incised and then made into a strip-shaped specimen having a width of about 3 mm and suspended in a running direction in a 10 mL tissue bath filled with Krebs Henseleit buffer.
- the Krebs Henseleit buffer was aerated with 95% O 2 and 5% CO 2 and kept at 37 ° C.
- the static tension was approximately 0.5 g and isometric contraction was recorded using a tension transducer (TB-611T; Nihon Kohden), amplifier (AP-621G; Nihon Kohden) and interface (PowerLab 8/30; AD Instruments). .
- contraction reaction mimetic electrical stimulation (stimulation voltage: 20 V, pulse width: 30 ⁇ sec, stimulation frequency: 0.2 Hz, stimulation time: 15 sec) It was confirmed.
- the transuretal electrical stimulation (stimulation voltage: 20 V, pulse width: 30 ⁇ sec, stimulation frequency: 20 Hz, stimulation time: 1 sec) triggers the contraction of the external urethral sphincter three times at 30-second intervals
- a solvent dimethyl sulfoxide: DMSO
- a DMSO solution of Compound A in a final concentration of 10 or 30 ⁇ mol / L is added to the tissue bath.
- contraction by transmural electrical stimulation under the same conditions Reactions were evoked 3 times at 30 second intervals.
- Example 2 Experimental test method to evaluate the potentiating effect of Compound A on the urethral pressure increase response induced by electrical stimulation of rat pudendal nerves SD female rats (Japan SLC) weighing 200-350 g were urethane (1.2 g / kg, Anesthetized with sc (Sigma Aldrich), and a catheter (PE-50; Becton Dickinson) was placed in the jugular vein for administration of the test substance. The abdomen was opened and the top of the bladder was incised to drain urine from the bladder. For measuring the urethral pressure, a microchip pressure transducer catheter (3.5 Fr; Millar Instruments) was inserted from the mouth of the external urethra into the bladder.
- a microchip pressure transducer catheter 3.5 Fr; Millar Instruments
- the rat was placed in the prone position, the back was incised to isolate the left or right pudendal nerve, and the stimulation electrode was placed. Connect the microchip pressure transducer catheter to the amplifier (AP-601G; Nihon Kohden) and the interface (PowerLab 8/30; AD Instruments) and measure the pressure inside the urethra while maximizing the pressure inside the urethra. It was fixed so that it was located near the site (about 10-15 mm from the external urethral orifice). Electrical stimulation of the pudendal nerve (stimulation voltage: max.
- Compound A has been shown to increase urethral pressure by enhancing the contraction force of the external urethral sphincter depending on stimulation of the external urinary sphincter-dominating nerve, and maintain urinary inhibition by increasing urethral resistance The possibility was shown. Therefore, Compound A having a fast muscle troponin activating action is expected as a therapeutic and / or preventive agent for urinary incontinence, particularly stress urinary incontinence or mixed urinary incontinence.
- Compound A or a salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention is a pharmaceutical composition for preventing and / or treating urinary incontinence, and in one embodiment, a pharmaceutical composition for preventing and / or treating stress urinary incontinence, As an aspect, it is expected as an active ingredient of a pharmaceutical composition for preventing and / or treating mixed urinary incontinence.
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Abstract
Description
外尿道括約筋と骨盤底筋は、速筋成分を含む骨格筋であることが報告されている(非特許文献7、8)。
本明細書は、本願の優先権の基礎である特願2014-183434号の明細書、特許請求の範囲および図面に記載された内容を包含する。
上述の通り、化合物Aの化学名は1-[2-({[トランス-3-フルオロ-1-(3-フルオロピリジン-2-イル)シクロブチル]メチル}アミノ)ピリミジン-5-イル]-1H-ピロール-3-カルボキサミドであり、前述の特許文献1の実施例14に記載されている化合物である。その化学構造は以下に示すとおりである。
(1)化合物A、及び製薬学的に許容される賦形剤を含有する尿失禁予防用及び/又は治療用医薬組成物。ある態様として、化合物A、及び製薬学的に許容される賦形剤を含有する腹圧性尿失禁予防用及び/又は治療用医薬組成物。ある態様として、化合物A、及び製薬学的に許容される賦形剤を含有する混合型尿失禁予防用及び/又は治療用医薬組成物。
(2)化合物Aを含有する尿失禁予防剤及び/又は治療剤。ある態様として、化合物Aを含有する腹圧性尿失禁予防剤及び/又は治療剤。ある態様として、化合物Aを含有する混合型尿失禁予防剤及び/又は治療剤。
(3)尿失禁予防用及び/又は治療用医薬組成物の製造のための、化合物Aの使用。ある態様として、腹圧性尿失禁予防用及び/又は治療用医薬組成物の製造のための、化合物Aの使用。ある態様として、混合型尿失禁予防用及び/又は治療用医薬組成物の製造のための、化合物Aの使用。
(4)尿失禁予防及び/又は治療のための、化合物Aの使用。ある態様として、腹圧性尿失禁予防及び/又は治療のための、化合物Aの使用。ある態様として、混合型尿失禁予防及び/又は治療のための、化合物Aの使用。
(5)尿失禁予防及び/又は治療のための、化合物A。ある態様として、腹圧性尿失禁予防及び/又は治療のための、化合物A。ある態様として、混合型尿失禁予防及び/又は治療のための、化合物A。
(6)化合物Aの有効量を対象に投与することを含む、あるいは対象に投与することからなる、尿失禁予防及び/又は治療方法。ある態様として、化合物Aの有効量を対象に投与することを含む、あるいは対象に投与することからなる、腹圧性尿失禁予防及び/又は治療方法。ある態様として、化合物Aの有効量を対象に投与することを含む、あるいは対象に投与することからなる、混合型尿失禁予防及び/又は治療方法。
化合物A又はその塩を含有する医薬組成物は、当分野において通常用いられている賦形剤、即ち、薬剤用賦形剤や薬剤用担体等を用いて、通常使用されている方法によって調製することができる。
実施例1
ラット摘出尿道を用いた、経壁電気刺激により誘発される外尿道括約筋収縮反応に対する化合物Aの増強作用を評価する試験
実験方法
10 週齢のSD系雌性ラット(日本エスエルシー)から尿道を摘出した。摘出尿道を縦切開後、幅約3 mmの短冊状標本とし、クレブスヘンゼライト緩衝液で満たした10 mLの組織バス内に輪走方向に懸垂した。クレブスヘンゼライト緩衝液は95% O2、5% CO2で通気し、37 ℃に保温した。静止張力を約0.5 gとし、等尺性収縮を張力トランスデューサー(TB-611T;日本光電)、増幅器(AP-621G;日本光電)及びインターフェイス(PowerLab 8/30;AD Instruments)を用いて記録した。静止張力が安定した後、経壁電気刺激(刺激電圧:20 V,パルス幅:30 μsec,刺激頻度:0.2 Hz,刺激時間:15 sec)によって外尿道括約筋の収縮反応(mg)が認められることを確認した。被験物質非存在下において経壁電気刺激(刺激電圧:20 V,パルス幅:30 μsec,刺激頻度:20 Hz,刺激時間:1 sec)により外尿道括約筋の収縮反応を30 秒間隔で3 回惹起した後、溶媒(ジメチルスルホキシド:DMSO)、或いは最終濃度が10、又は30 μmol/Lとなる量の化合物A のDMSO溶液を組織バスに添加し、15 分後に同条件の経壁電気刺激による収縮反応を30 秒間隔で3 回惹起した。被験物質添加前後の各3 回の電気刺激による収縮反応の平均値をそれぞれ算出し、被験物質添加前の収縮反応に対する被験物質添加後の収縮反応の割合を各群について算出した。各群n=6で実施し、Dunnettの多重比較検定法により溶媒群と化合物A添加群を比較し、p<0.05の場合に有意な差と見なした。
結果
図1に示すように、化合物Aは、ラット摘出尿道の経壁電気刺激により誘発される外尿道括約筋の収縮反応を増強させた。
ラットの陰部神経の電気刺激により誘発される尿道内圧上昇反応に対する化合物Aの増強作用を評価する試験
実験方法
体重200-350 gのSD系雌性ラット(日本エスエルシー)をウレタン(1.2 g/kg,sc;シグマアルドリッチ)で麻酔し、被験物質投与のために頸静脈内にカテーテル(PE-50;ベクトンディッキンソン)を留置した。開腹し、膀胱内の尿を排出させるため膀胱頂部を切開した。尿道内圧測定のため、マイクロチップ圧トランスデューサーカテーテル(3.5Fr;Millar Instruments社)を外尿道口より膀胱に向かって挿入した。ラットを伏臥位にし、背部を切開し左右いずれかの陰部神経を単離し、刺激電極を留置した。マイクロチップ圧トランスデューサーカテーテルを増幅器(AP-601G;日本光電)及びインターフェイス(PowerLab 8/30;AD Instruments)につないで尿道内圧を測定しながら、尿道内の圧トランスデューサー部分を尿道内圧が最大になる部位付近(外尿道口から約10~15 mm)に位置するように固定した。陰部神経の電気刺激(刺激電圧:最大10 V,パルス幅:50 μsec,刺激頻度:20 Hz,刺激時間:400 msec)を1 分毎に行い、安定した尿道内圧上昇反応(mmHg)が得られることを確認した後に、溶媒(13.3%DMSO,13.3%ポリエチレングリコール400,13.3%Tween20,60%蒸留水)、或いは溶媒に溶解させた化合物Aを1 mL/kgで最終投与量3又は10 mg/kgとなる量で静脈内投与した。被験物質投与前3 回の電気刺激による尿道内圧上昇反応の平均値を被験物質投与前値として算出し、被験物質投与後約3 分における電気刺激による尿道内圧上昇反応の被験物質投与前値に対する割合を各投与量群で算出した。各群n=6で実施し、Dunnettの多重比較検定法により溶媒群と化合物A群を比較し、p<0.05の場合に有意な差と見なした。
結果
図2に示すように、化合物Aはラットの陰部神経電気刺激による尿道内圧上昇反応を増強させた。
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JPWO2016039367A1 (ja) | 2017-06-15 |
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