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WO2005000293A1 - Agent therapeutique pour vessie hyperactive accompagnant un trouble cerebrovasculaire - Google Patents

Agent therapeutique pour vessie hyperactive accompagnant un trouble cerebrovasculaire Download PDF

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Publication number
WO2005000293A1
WO2005000293A1 PCT/JP2004/009363 JP2004009363W WO2005000293A1 WO 2005000293 A1 WO2005000293 A1 WO 2005000293A1 JP 2004009363 W JP2004009363 W JP 2004009363W WO 2005000293 A1 WO2005000293 A1 WO 2005000293A1
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Prior art keywords
substituted
unsubstituted
therapeutic agent
overactive bladder
lower alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/JP2004/009363
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English (en)
Japanese (ja)
Inventor
Kaoru Atsuki
Shiro Shirakura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KH Neochem Co Ltd
Original Assignee
Kyowa Hakko Kogyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co Ltd filed Critical Kyowa Hakko Kogyo Co Ltd
Priority to JP2005511115A priority Critical patent/JPWO2005000293A1/ja
Publication of WO2005000293A1 publication Critical patent/WO2005000293A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a therapeutic agent for overactive bladder associated with cerebrovascular disorder, comprising a tricyclic compound or a pharmacologically acceptable salt thereof as an active ingredient.
  • Overactive bladder is a pathological condition observed in patients presenting with symptoms such as urgency and frequent urination. Urination is physiologically controlled by complex reflex pathways involving the central and peripheral nervous systems [Eurology, Vol. 50, Supplement 6A, pp. 36-52 (1997)]. Patients with cerebral vascular disorders such as cerebral infarction and cerebral hemorrhage begin to complain of frequent urination, urgency, and urge incontinence when it is time to recover from the acute phase and undergo rehabilitation.
  • a tricyclic compound having a prolonged bladder contraction interval or a pharmacologically acceptable salt thereof is known (W097 / 14672, W098 / 46587).
  • a therapeutic agent for overactive bladder containing the compound group as an active ingredient is known (W002 / 07810).
  • a therapeutic agent for bladder hypersensitivity (W002 / 07811) and a therapeutic agent for bladder irritation associated with benign prostatic hyperplasia (W002 / 07812) containing the compound group as an active ingredient are known.
  • An object of the present invention is to provide a therapeutic agent for overactive bladder associated with cerebrovascular disorder, comprising a tricyclic compound or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention relates to the following (1) to (27).
  • R 1 represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkoxy
  • X 1 -X and X 3 are CR ⁇ CR'-CR ⁇ CR 8
  • R 5 ⁇ R s , R 7 and R 8 are the same or different and are each a hydrogen atom, halogen, hydroxy, nitro, amino, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino, substituted or Represents an unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxy or a substituted or unsubstituted lower alkanoylamino]
  • R 1 and X′-X′-X have the same meanings as above, respectively, and Y a represents —CH 2 S0 2 —, —SCH Factory ⁇ —S0CH Factory, —S0iCH 2 — or —0CH 2 —.
  • Y a is - C3 ⁇ 4S0 2 -, - SCH ⁇ , - S0C3 ⁇ 4- or - S0 2 CH 2 - when it is, R represents a hydrogen atom, Amino, substituted or unsubstituted lower alkyl, substituted also properly non Substituted lower alkenyl, substituted or unsubstituted lower alkoxy, mono (substituted or unsubstituted lower alkyl) substituted amino, di (substituted or unsubstituted lower alkyl) substituted amino, substituted or unsubstituted aryl, substituted Or unsubstituted heteroaryl, substituted or unsubstituted aralkylamino, substituted or unsubstituted arylamino, substituted or unsubstituted alicyclic heterocyclic group or substituted or unsubstituted nitrogen-containing heterocyclic group, Y a is - 0C
  • n is 0 or 1
  • R 3 and IT are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted aryl or Represents a substituted or unsubstituted aralkyl
  • R 4 May form a cyclic alkyl with an adjacent carbon atom
  • Q represents a group represented by halogen, amino, hydroxy or substituted or unsubstituted lower alkoxy
  • Y a is - C S0 2 -, - SCH 2 -, - S0CH "or - S0 2 CH ⁇ a is the (2) overactive bladder therapeutic agent due to cerebrovascular failure according iota.
  • Y a is - 0CH 2 - a is the (2) overactive bladder therapeutic agent associated with cerebrovascular disorders mentioned.
  • Y a is - CH 2 S0 ⁇ , -S0 2 CH "or - 0C3 ⁇ 4- a is the (2), hyperactivity associated with cerebrovascular disorders mentioned or Re noise (5) and (6) Bladder treatment.
  • Y a is - CH 2 S0 ⁇ or - S0 2 C - a is the (2), (5) and overactive bladder therapeutic agent associated with cerebrovascular disorders placing serial to any one of (6).
  • Y a is - CH 2 S0 2 - at which the (2), (5) and overactive bladder therapeutic agent associated with cerebrovascular failure of any one of (6).
  • R 2a is the formula (II)
  • n, R 3 R 4 and Q have the same meanings as above, respectively, and the overactive bladder treatment associated with cerebrovascular disorder according to any one of the above (2) to (11), Agent.
  • (13) The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to the above (12), wherein n is 0.
  • R 1 is a hydrogen atom
  • Y a is - C S0 2 - and is
  • X 1 - X 2 - X 3 is in the S-CR ⁇ CR 8 (wherein, R 7 and R 8 it it the And R 21 is of the formula ( ⁇ )
  • the therapeutic agent for overactive bladder associated with cerebrovascular disorder according to the above (2) which is a group represented by the formula:
  • a therapeutic agent for overactive bladder associated with cerebrovascular disease comprising a tricyclic compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient.
  • Y 3 ⁇ 4 is - (C) p - (wherein, p is the same meanings as defined above) which is the (16) - (19) noise caused by cerebrovascular disorders according to any deviation overactive bladder treatment Agent.
  • Y 3 ⁇ 4 is - CH 2 S - or - overactive bladder therapeutic agent associated with cerebral vascular disorders according to any one of CH 2 S0- a is the (16) to (19).
  • a method for treating overactive bladder associated with cerebrovascular disorder comprising a step of administering an effective amount of the tricyclic compound or a pharmacologically acceptable salt thereof according to any of (1) to (25). Method of treatment.
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • compound (I) the compound represented by other formula numbers.
  • the lower alkyl includes, for example, linear or branched alkyl having 1 to 8 carbon atoms, more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Examples include sec-butyl, tert-butyl, pentyl, hexyl, 1,2,2-trimethylpropyl, heptyl, and octyl.
  • Halogen represents each atom of fluorine, chlorine, bromine, and iodine.
  • the lower alkyl moiety in lower alkoxy, mono (lower alkyl) -substituted amino and di (lower alkyl) -substituted amino is as defined above for lower alkyl.
  • Examples of the lower alkanoyl in the lower alkanoylamino include, for example, alkynoyl having 1 to 6 carbon atoms, more specifically, formyl, acetyl, propanoyl, butanoyl, pennoyl, 2,2-dimethylpropanol, Hexanoyl and the like.
  • lower alkenyl examples include straight-chain or branched alkenyl having 2 to 2 carbon atoms, more specifically, vinyl, aryl, toppropenyl, methacryl, tributenyl, crotyl, pentenyl, hexenyl and the like. .
  • Aryl and the aryl moiety of arylamino include, for example, phenyl, naphthyl and the like, and the heteroaryl include, for example, pyridyl, furyl, phenyl, quinolyl, imidazolyl, penzoimidazolyl, thiazolyl and the like.
  • aralkyl moiety of aralkylamino examples include aralkyl having 7 to 12 carbon atoms, and more specifically, benzyl, phenethyl, naphthylmethyl and the like.
  • the “heterocyclic group” includes, for example, an alicyclic heterocyclic group, a nitrogen-containing heterocyclic group and the like.
  • the alicyclic heterocyclic group include tetrahydrofuryl, tetrahydrophenyl, chromanyl and the like.
  • the nitrogen-containing heterocyclic group is, for example, a heterocyclic group containing 1 to 2 nitrogen atoms in its ring, and may further contain a heteroatom such as oxygen and sulfur, and more specifically, pyrrolidinyl, pipecolinyl, Piperazinyl, piperidyl, morpholinyl, thiomorpholinyl, oxazolyl and the like.
  • Substituents in substituted lower alkyl, substituted lower alkoxy, mono (substituted lower alkyl) substituted amino, di (substituted lower alkyl) substituted amino, substituted lower alkanoylamino and substituted lower alkenyl may be the same or different, and 1-substitutable number (preferably 1-6, more preferably 1-4) such as halogen, hydroxy, nitro, amino, mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, cyclic Alkyl, substituted cyclic alkyl [where the substituents in the substituted cyclic alkyl are the same or different and include, for example, halogen having 1 to 3 substituents, hydroxy, nitro, amino, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino , Lower alkoxy, etc.], aryl, substituted aryl (the substituted ary
  • the lower alkyl has two substituents on the same carbon atom, and the two substituents together with the carbon atom form an aliphatic ring. Is also good.
  • the substituents may be the same or different, for example, a lower alkyl or a substituted lower alkyl having 1 to 3 substituents [as a substituent in the substituted lower alkyl]
  • halogen having 1 to 3 substituents, hydroxy, nitro, amino, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino, lower alkoxy and the like] .
  • the substituted lower alkyl In the definition of the substituent in the substituted lower alkyl, the substituted lower alkoxy, the mono (substituted lower alkyl) substituted amino, the di (substituted f-substituted alkyl) substituted amino, the substituted lower alkanolamino and the substituted lower alkenyl, And lower alkyl, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino and the lower alkyl moiety in lower alkoxy have the same meanings as the above lower alkyl, and aryl is as defined above. is there.
  • Examples of the cyclic alkyl and the cyclic alkyl moiety of the aliphatic ring include a cyclic alkyl having 3 to 8 carbon atoms, more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • Examples of the aralkyl include aralkyl having 7 to 12 carbon atoms, more specifically, benzyl, phenethyl, naphthylmethyl and the like.
  • the substituents in the substituted aryl, the substituted heteroaryl, the substituted aralkylamino and the substituted arylamino are the same or different and include, for example, halogen having 1 to 3 substituents, hydroxy, amino, lower alkyl and the like.
  • substituted aryl substituted heteroaryl, substituted aralkylamino and substituted arylamino, halogen and lower alkyl are as defined above.
  • Substituents in the substituted heterocyclic group may be the same or different and include, for example, halogen having 1 to 3 substituents, hydroxy, lower alkyl and the like.
  • the lower alkyl includes, for example, a linear or branched alkyl having 1 to 6 carbon atoms, more specifically, methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, 1,2,2-trimethylpropyl and the like.
  • Halogen represents each atom of fluorine, chlorine, bromine, and iodine.
  • the lower alkyl moiety in lower alkoxy, mono (lower alkyl) -substituted amino and di (lower alkyl) -substituted amino has the same meaning as the above-mentioned lower alkyl.
  • the lower alkenyl includes, for example, straight-chain or branched alkenyl having 2 to 6 carbon atoms, more specifically, vinyl, aryl, topropropenyl, methacrylyl, 1-butenyl, crotyl, pentenyl, Xenyl and the like.
  • aryl moiety of aryl and arylamino includes, for example, phenyl, naphthyl and the like, and the heteroaryl includes, for example, pyridyl, furyl, chenyl, quinolyl, imidazolyl, benzimidazolyl, thiazolyl and the like.
  • aralkyl moiety of aralkyl and aralkylamino examples include aralkyl having 7 to 12 carbon atoms, more specifically, benzyl, phenethyl, naphthylmethyl and the like.
  • the nitrogen-containing heterocyclic group is, for example, a heterocyclic group containing 1 to 2 nitrogen atoms in its ring, and may further contain a hetero atom such as oxygen or sulfur, and the nitrogen atom in the ring is Represents a heterocyclic group bonded to an adjacent carbonyl group, and more specifically includes pyrrolidinyl, pipecolinyl, piperazinyl, piperidyl, morpholinyl, thiomorpholinyl, oxazolyl and the like.
  • cyclic alkyl examples include a cyclic alkyl having 3 to 8 carbon atoms, more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • the substituents in the substituted lower alkyl, the substituted lower alkoxy, the mono (substituted lower alkyl) substituted amino, the di (substituted lower alkyl) substituted amino, the substituted lower alkenyl and the substituted cyclic alkyl are the same or different.
  • ⁇ 3 halogens, hides Examples include mouth xy, nitro, amino, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino, lower alkoxy and the like.
  • the substituents may be the same or different and may be, for example, lower alkyl having 1 to 3 substituents, substituted lower alkyl [substituted with the substituent in the substituted lower alkyl, And the same or different, for example, halogen having 1 to 3 substituents, hydroxy, nitro, amino, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino, lower alkoxy, etc.], cyclic Alkyl, substituted cyclic alkyl [substituents in the substituted cyclic alkyl may be the same or different and include, for example, halogen having 1 to 3 substituents, hydroxy, nitro, amino, mono (lower alkyl) -substituted amino, di (lower) Alkyl) substituted amino, lower alkoxy, etc.], aryl,
  • Aralkyl, substituted aralkyl [substituents in the substituted aralkyl may be the same or different and include, for example, 1-3 substituted, hydroxy, halogen, nitro, amino, mono (lower alkyl) substituted amino, di ( Lower alkyl) substituted amino, lower alkoxy, etc.], substituted lower alkoxy [substituents in the substituted lower alkoxy may be the same or different and include, for example, halogen having 1 to 3 substituents, hydroxy, nitro, amino, Mono (lower alkyl) substituted amino, di (lower alkyl) substituted amino, lower alkoxy And the like). Further, it may have two substituents on the same carbon atom in methyl or ethyl of substituted methyl or substituted ethyl, and the two substituents may form an aliphatic ring together with the carbon atom. .
  • substituted lower alkyl substituted lower alkoxy
  • mono (substituted lower alkyl) substituted amino, di (substituted lower alkyl) substituted amino, substituted lower alkenyl and substituted cyclic alkyl, halogen, cyclic alkyl, aryl and aralkyl Has the same meaning as defined above
  • the lower alkyl moiety in lower alkyl, mono (lower alkyl) -substituted amino, di (lower alkyl) -substituted amino and lower alkoxy has the same meaning as the above-mentioned lower alkyl.
  • the alkyl moiety has the same meaning as the aforementioned cyclic alkyl.
  • substituents in the substituted aryl, the substituted heteroaryl, the substituted aralkyl, the substituted aralkylamino and the substituted arylamino include the same or different substituents, for example, halogen having 1 to 3 substituents, hydroxy, amino, lower alkyl and the like.
  • the substituent in the substituted aryl the substituted heteroaryl, the substituted aralkyl, the substituted aralkylamino and the substituted arylamino, the halogen and the lower alkyl are as defined above.
  • the substituents in the substituted alicyclic heterocyclic group and the substituted nitrogen-containing heterocyclic group may be the same or different and include, for example, lower alkyl having 1 to 3 substituents, hydroxy, halogen and the like.
  • Pharmaceutically acceptable salts of compound (I), compound (la) and compound (lb) include pharmacologically acceptable acid addition salts, for example, hydrochloride, hydrobromide, Inorganic acid salts such as borohydride, nitrate, sulfate, phosphate, etc., formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, Organic acid salts such as oxalate, glyoxylate, aspartate, methanesulfonate, ethanesulfonate and benzenesulfonate are exemplified.
  • pharmacologically acceptable acid addition salts for example, hydrochloride, hydrobromide, Inorganic acid salts such as borohydride, nitrate, sulfate, phosphate, etc., formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, Organic acid salts such as oxalate
  • the compound used in the present invention can be produced according to the methods disclosed in the above-mentioned publications or in accordance with them, and purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, It can be isolated and purified by drying, concentration, recrystallization, and various types of chromatography.
  • the compound when it is desired to obtain a salt of the compound used in the present invention, if the compound is obtained in the form of a salt, it may be purified as it is, or if it is obtained in the form of a free base, the free base may be purified. What is necessary is just to dissolve or suspend in an appropriate solvent and add an acid to form a salt.
  • some of the compounds used in the present invention may have optical isomers, all the possible stereoisomers and their mixtures are also used as the therapeutic agent for bladder overactivity associated with cerebrovascular disorders of the present invention. Can be used as an active ingredient.
  • the compound used in the present invention or a pharmacologically acceptable salt thereof may exist in the form of an adduct with water or various solvents. It can be used as an active ingredient of a therapeutic agent for bladder overactivity associated with vascular disorders.
  • Test compounds include (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N- (5,5,10-trioxo-4,10-dihydrocheno [ 3,2-c] [l] benzocepin-9-yl) propanamide [(S)-(+)-3,3,3-triflurooro-2-hydroxy-2-methyl-N- (5,5 , 10-tri oxo-4, 10-dihydrothieno [3, 2-c] [l] benzothiepin-9-yl) propanamide] was used.
  • the above compound is referred to as Compound 1 in this specification.
  • Compound 1 is the same as compound (Form 25) described in W098 / 46587.
  • Test example Improvement effect on pollakiuria associated with cerebrovascular disorder
  • a male Sprague-Dawley rat (weight: 200-220 g, supplied by Japan SLC) was used. Animals were kept in a breeding room at room temperature 19-25 ° C, humidity 30-70%, and 12 hours a day lighting (7 am to 7 pm).
  • a catheterization operation was performed on the rat's bladder. Under pentobarbital sodium anesthesia, a midline incision was made in the lower abdomen to expose the bladder. After making a small incision at the top of the bladder, a catheter (PE-50 polyethylene tube) was inserted into the bladder and fixed. The other end was subcutaneously drawn out of the back and neck and plugged, and the abdominal incision was sutured.
  • PE-50 polyethylene tube PE-50 polyethylene tube
  • rats Six to nine days after the catheterization surgery, rats were subjected to a system test.
  • the rat was housed in a Polman cage (KN-326-1, Natsume Seisakusho), and one end of the bladder catheter was attached to one end of a bladder catheter using a three-way cock (TS-TR2K, Terumo). 2219, Harvard Apparatus) and the other end were connected to a pressure transducer (TP200T, Nihon Kohden).
  • TP200T three-way cock
  • a physiological saline solution was continuously infused into the bladder at a rate of 6 mL / h, and at the same time, the bladder pressure was measured via a polygraph and recorded for about 3.5 hours with a thermal array recorder (RTA-1200M, Nihon Kohden).
  • the average value of the voiding contraction interval observed in one hour from 2.5 hours to 3.5 hours after the injection of physiological saline was defined as the voiding contraction interval before cerebral infarction preparation
  • a polyethylene tube (PE-10) was inserted from the left external carotid artery to the bifurcation of the common carotid artery and the internal carotid artery under pentobarbital sodium anesthesia. After injecting 60 JLL L (360 // g / body), a cerebral infarction-inducing substance, arachidonic acid (Sigma) dissolved at a concentration of 6 mg / L in physiological saline, the incision was made. Sutured.
  • the urination contraction interval after administration of the compound is 1 hour (0.5 to 1.5 hours, 1.5 to 2.5 hours, 2.5 to 3.5 hours) between the time points for a total of 3 time points 1, 2 and 3 hours after administration. ) Calculated as the average value of the voiding contraction interval in.
  • the urinary contraction interval was used as an index of hyperactive bladder.
  • the voiding contraction interval was converted to a relative value when the value before cerebral infarction operation was set to 100, and the average soil standard error was calculated for each group.
  • Table 1 shows the values (%) of the voiding interval before and after cerebral infarction preparation surgery and after administration of Compound 1.
  • Compound 1 was shown to be useful as a therapeutic agent for overactive bladder associated with cerebrovascular disorder, and Compound (I) or a pharmacologically acceptable salt thereof was useful for treating overactive bladder associated with cerebrovascular disorder. It is considered useful as an agent.
  • Compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms.
  • the pharmaceutical composition of the present invention comprises, as an active ingredient, an effective amount of compound (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. It can be manufactured by mixing uniformly.
  • These pharmaceutical compositions are desirably in a unit dosage form suitable, for example, for oral or parenteral (including intravenous) administration.
  • any useful pharmacologically acceptable carrier can be used.
  • capsules and tablets are excipients such as lactose, glucose, sucrose and mannitol; disintegrants such as starch and sodium alginate; lubricants such as magnesium stearate and talc; polyvinyl alcohol; hydroxypropyl cellulose And a binder such as gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin.
  • the injection can be prepared using a carrier composed of, for example, distilled water, a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. At this time, it is prepared as a solution, suspension or dispersion according to a conventional method using an appropriate auxiliary.
  • a carrier composed of, for example, distilled water, a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution. At this time, it is prepared as a solution, suspension or dispersion according to a conventional method using an appropriate auxiliary.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered orally or parenterally as an injection or the like in the above-mentioned pharmaceutical form.
  • 1 to 900 mg / 60 kg / day preferably 1 to 200 mg / 60 kg / day is appropriate.
  • a tablet having the following composition was prepared by a conventional method.
  • a capsule having the following composition was prepared by a conventional method.
  • An injection having the following composition is prepared by a conventional method. 1 g of Compound 1 and 5 g of D-mannitol are added to and mixed with distilled water for injection, and the pH is adjusted to 6 by adding hydrochloric acid and aqueous sodium hydroxide solution. To 1000 fflL. The obtained mixture is aseptically filled into glass vials in a volume of 2 mL each to obtain an injection (containing 2 active ingredients per vial). Formulation Compound 1 2 mg
  • a therapeutic agent for overactive bladder associated with cerebrovascular disorder comprising a tricyclic compound or a pharmacologically acceptable salt thereof as an active ingredient.

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Abstract

L'invention concerne un agent thérapeutique pour vessie hyperactive accompagnant des troubles cérébrovasculaires, qui renferme soit un composé tricyclique représenté par la formule (I), (dans laquelle R1 représente hydrogène, halogéno, alkyle (non) substitué, etc. ; X1-X2-X3 représente CR5=CR6-CR7=CR8, S-CR7=CR8, etc. ; Y représente CH2S-, -CH2SO-, -CH2SO2-, etc. ; et R2 représente hydrogène, etc.), soit un sel pharmacologiquement acceptable de ce composé en tant que principe actif.
PCT/JP2004/009363 2003-06-27 2004-06-25 Agent therapeutique pour vessie hyperactive accompagnant un trouble cerebrovasculaire Ceased WO2005000293A1 (fr)

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JP2005511115A JPWO2005000293A1 (ja) 2003-06-27 2004-06-25 脳血管障害に伴う過活動膀胱治療剤

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JP2003185476 2003-06-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008050853A1 (fr) 2006-10-26 2008-05-02 Kyowa Hakko Kirin Co., Ltd. Agents therapeutiques pour lutter contre le syndrome du colon irritable

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997014672A1 (fr) * 1995-10-16 1997-04-24 Kyowa Hakko Kogyo Co. Ltd. Composes tricycliques
WO1998046587A1 (fr) * 1997-04-15 1998-10-22 Kyowa Hakko Kogyo Co., Ltd. Composes tricycliques
WO2002078633A2 (fr) * 2001-03-30 2002-10-10 Kyowa Hakko Kogyo Co., Ltd. Agent de traitement de symptomes d'irritation de la vessie accompagnes d'hyperplasie benigne de la prostate
WO2002078711A1 (fr) * 2001-03-30 2002-10-10 Kyowa Hakko Kogyo Co., Ltd. Medicaments contre l'hyperesthesie vesicale
WO2002078712A1 (fr) * 2001-03-30 2002-10-10 Kyowa Hakko Kogyo Co., Ltd. Remedes de stimulation vesicale en association avec une hypertrophie de la prostate
WO2002078710A1 (fr) * 2001-03-30 2002-10-10 Kyowa Hakko Kogyo Co., Ltd. Medicaments contre l'hyperactivite vesicale

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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