WO2005000293A1

WO2005000293A1 - Therapeutic agent for overactive bladder accompanying cerebrovascular disorder

Info

Publication number: WO2005000293A1
Application number: PCT/JP2004/009363
Authority: WO
Inventors: Kaoru Atsuki; Shiro Shirakura
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 2003-06-27
Filing date: 2004-06-25
Publication date: 2005-01-06
Also published as: JPWO2005000293A1; TW200501938A; AR044870A1

Abstract

A therapeutic agent for overactive bladder accompanying cerebrovascular disorders which contains either a tricyclic compound represented by the formula (I): (I) (wherein R1 represents hydrogen, halogeno, (un)substituted lower alkyl, etc.; X1-X2-X3 represents CR5=CR6-CR7=CR8, S-CR7=CR8, etc.; Y represents -CH2S-, -CH2SO-, -CH2SO2-, etc.; and R2 represents hydrogen, etc.) or a pharmacologically acceptable salt of the compound as an active ingredient.

Description

Specification

Overactive bladder for cerebrovascular disease

Technical field

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.

Background art

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. Cerebral vascular disorders 50-70% of patients are reported to experience urinary incontinence at any time after onset [Asoyoshiro, ed., Clinical Clinic for Urinary Incontinence, Chugai Medical, Chapter 4: Cerebrovascular Disease Urinary incontinence, pp. 111-124

(1992)]. Impaired blood flow above the brainstem pontine voiding center, such as the cerebral cortex and basal ganglia, prevents voluntary control of the brainstem pontine voiding center, resulting in overactive bladder and a small amount of urine in the bladder It has been attributed to urinary reflexes that occur just after the treatment [Yasuo Shiraiwa, Osamu Yamaguchi, Visual dysuria, Medical Review, Chapter 4: Major diseases causing urinary dysfunction and their pathological conditions, Pages 15-16

(1995)].

As a therapeutic agent for urinary incontinence, a tricyclic compound having a prolonged bladder contraction interval or a pharmacologically acceptable salt thereof is known (W097 / 14672, W098 / 46587). Also, a therapeutic agent for overactive bladder containing the compound group as an active ingredient is known (W002 / 07810). Further, 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.

The discovery of the battle

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). (1) Equation (I)

Wherein 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 [Formula Wherein R ⁵ヽ 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], N (0) _m = CR ^f -CR ⁷ = CR ⁸ (wherein R ^f , R ⁷ and R ⁸ are as defined above, and m represents 0 or 1), CR ^s = CR ^f -N (0) _m = CR ⁸

(Wherein, R ⁵ , R ^f , R ⁸ and in are as defined above), CR ^s = CR ^f -CR ⁷ = N (0) _B (where R ⁵ , R ^f , R ⁷ and m are the same meanings as defined ^{^{above), CR 5 = CR S -}} 0 ( wherein, the R ^s and R ^f Waso the same meaning as it ^{^{said), CR 5 = CR f -}} S ( wherein, R ^s and R ^f are as defined above, 0-CR ⁷ = CH ⁸ (where and and are as defined above), S-CR ⁷ = CR ⁸ (where R ⁷ and R ⁸ are as defined above, or 0-CR ⁷ = N, wherein R ⁷ is as defined above, and Y is -CH ₂ S-, -CH ₂ S0- _{_{, - CH 2 S0 2 -,}} -C¾0-, - CH = CH -, - (C) p - ( wherein, p is an integer of 0 to 2), -SCH厂, - S0C -, - S0 ₂ C¾ - or - represents 0CH, R ² is a hydrogen atom, Amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted 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 Represents a tricyclic compound represented by aralkylamino, substituted or unsubstituted arylamino or substituted or unsubstituted heterocyclic group} or a pharmacologically acceptable salt thereof as an active ingredient. Active bladder treatment. (2) Equation (la)

[Wherein, R ¹ and X′-X′-X have the same meanings as above, respectively, and Y ^a represents —CH ₂ S0 ₂ —, —SCH Factory ヽ —S0CH Factory, —S0iCH ₂ — or —0CH ₂ —. the stands, Y ^a is - C¾S0 ₂ -, - SCH厂, - S0C¾- 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 - is when a, R "is a hydrogen atom, Amino, trifluoromethyl, substituted or unsubstituted 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, substituted or unsubstituted nitrogen-containing heterocycle Cyclic group or formula (II)

(In the formula, n is 0 or 1, and 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, and R ⁴ May form a cyclic alkyl with an adjacent carbon atom, and Q represents a group represented by halogen, amino, hydroxy or substituted or unsubstituted lower alkoxy). An agent for treating overactive bladder associated with cerebrovascular disease, comprising a cyclic compound or a pharmacologically acceptable salt thereof as an active ingredient.

(3) Y ^a is _{- C S0 2 -, - SCH} 2 -, - S0CH "or - S0 ₂ CH厂a is the (2) overactive bladder therapeutic agent due to cerebrovascular failure according ^iota.

(4) Y ^a is - 0CH ₂ - a is the (2) overactive bladder therapeutic agent associated with cerebrovascular disorders mentioned.

(5) The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to any of (2) to (4), wherein R ¹ is a hydrogen atom, halogen, or substituted or unsubstituted lower alkoxy.

(6) The therapeutic agent for overactive bladder associated with cerebrovascular disease according to any of (2) to (4), wherein R ¹ is a hydrogen atom.

(7) Y ^a is - CH ₂ S0广, -S0 ₂ CH "or - 0C¾- a is the (2), hyperactivity associated with cerebrovascular disorders mentioned or Re noise (5) and (6) Bladder treatment.

(8) Y ^a is - CH ₂ S0广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).

(9) 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).

(10) Any of the above (2) to (9), wherein X and X ² -X ³ are S-CR ⁷ = CR ⁸ (wherein R ⁷ and R ⁸ are each as defined above). The therapeutic agent for overactive bladder associated with the cerebrovascular disorder described in the above.

(11) XL ^ -X ³ is ^{^{^{CR S = CR S - CR 7}}} = CR 8 ( wherein, R ⁵ヽR ^s, R ⁷ and R ⁸ it it the same meanings as defined above) wherein a (2) The remedy for overactive bladder associated with cerebrovascular disease according to any one of to (9).

(12) R ^2a is the formula (II)

Wherein 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.

(14) The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to (13), wherein R ³ is methyl, is trifluoromethyl, and Q is hydroxy.

(15) 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 (ΙΠ)

(ΠΙ)

The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to the above (2), which is a group represented by the formula:

Equation (16) (lb)

[In the formula, R ¹ and X ¹ - Χ ² -Χ ³ has the same meaning as that which the, Y ^b is _{- CH 2 0 -, - CH} 2 S -, - CH 2 S 0 -, -CH = CH -Or-(C) _p- (wherein p is as defined above), and is represented by the formula (III)

(ΠΙ)

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.

(17) X ¹ -Χ-X ³ is CR ⁵ = CR ^S -CR ⁷ = CR ⁸ (wherein, R ⁵ヽ R ^f , R ⁷ and R ⁸ are as defined above) or CR ^S = The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to the above (16), wherein CR ^S -CR ⁷ = N (wherein, H ⁵ and R ⁷ are each as defined above).

(18) X ¹ -Χ ^2- Χ ³ is CR ^s = CR ^f -0 (wherein, R ^s and R ^f are each as defined above) or The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to the above (16), wherein CR ⁵ = CR ^f -S (wherein, R ^s and are each as defined above).

^{^{(19) X 1 - X 2}} - ( wherein, R ⁷ and H ^e are respectively the same as the aforementioned) X ³ is 0- CR CR ⁸ or S-CR '= CR ⁸ (wherein, R ⁷ and R ⁸ is the same as defined above). The remedy for overactive bladder associated with cerebrovascular disorder according to the above (16).

(20) The therapeutic agent for overactive bladder associated with cerebrovascular disease according to any of (16) to (19), wherein -C¾0-.

(21) Y ^¾ 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.

(22) The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to the above (21), wherein p is 0.

(23) The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to the above (21), wherein p is 2.

(24) The therapeutic agent for overactive bladder associated with cerebrovascular disease according to any of (16) to (19), wherein ^Yk is -CH = CH-.

(25) Y ^¾ 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).

(26) Use of the tricyclic compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (25) for the manufacture of a therapeutic agent for overactive bladder associated with cerebrovascular disorder.

(27) 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.

Hereinafter, the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds represented by other formula numbers.

In the definition of each group of the formula (I), 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.

Examples of lower alkenyl 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.

Examples of the aralkyl moiety of aralkylamino 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. Examples of 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 aryl) The substituent in the substituted aryl is the same as the substituent in the substituted aryl described below), aralkyl, substituted aralkyl (the substituent in the substituted aralkyl is the same as the substituent in the substituted aralkyl described below), lower alkoxy, substituted Lower alkoxy [the substitution in the substituted lower alkoxy] Examples of the substituents 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.] and the like. Can be In the above substituted lower alkyl, 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. Further, when the substituted lower alkyl is a substituted methyl or a substituted ethyl, 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] 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 and the like] . 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.

In the definition of substituents in 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.

In the definition of the substituent in the substituted heterocyclic group, lower alkyl and halogen W It is as defined above.

In the definition of each group of the formula (la) and the formula (lb), 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.

The 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.

Examples of the aralkyl moiety of aralkyl and aralkylamino include aralkyl having 7 to 12 carbon atoms, more specifically, benzyl, phenethyl, naphthylmethyl and the like.

Examples of the alicyclic heterocyclic group include, for example, tetrahydrofuryl, tetrahydrothenyl, and chromatane). 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.

Examples of the cyclic alkyl 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. When the substituted lower alkyl is a substituted methyl or a substituted ethyl, 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, substituted aryl [for the substituted aryl] Examples of the substituents which may be the same or different 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. 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. .

In the definition of substituent in 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, and 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. Examples of the substituent 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.

In the definition of 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. '

In the definition of the substituent in the substituted alicyclic heterocyclic group and the substituted nitrogen-containing heterocyclic group, lower alkyl and halogen are as defined above.

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.

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.

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. Although 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.

Next, the pharmacological action of the representative compound (I) will be specifically described by test examples. 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. Hereinafter, 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

For the experiment, 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.

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). 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 surgery.

The day after the cystometry test was performed, 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.

Two to four days after the cerebral infarction operation, another cystometry test was performed. After the micturition contraction interval stabilized, the value before compound administration was measured for 1 hour, and Compound 1 was administered. Compound 1 was suspended at a concentration of 0.05 mg / mL in a 0.5 w / v% methylcellulose 400 cP (Wako Pure Chemical) aqueous solution and administered at a volume of 2 mL / kg (0.1 mg / kg). As a control, a group to which only 2 mL / kg of a 0.5 w / v% methylcellulose 400 cP (Wako Pure Chemical) aqueous solution was administered was provided. 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. For the results, Table 1 shows the values (%) of the voiding interval before and after cerebral infarction preparation surgery and after administration of Compound 1.

Table 1

###: p <0.001 (Comparison with before cerebral infarction operation) (n = 6-9; paired-test)

*: P <0.05, ***: p <0.001 (compared to after cerebral infarction surgery) (n = 6-9; paired ί-test) According to the results of the test examples, compound 1 was It showed an effect of extending the voiding contraction interval.

That is, 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.

In preparing the compositions in oral dosage form, any useful pharmacologically acceptable carrier can be used. For example, 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.

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. Depending on the patient's age, weight, symptoms, etc., 1 to 900 mg / 60 kg / day, preferably 1 to 200 mg / 60 kg / day is appropriate.

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to these Examples.

BEST MODE FOR CARRYING OUT THE INVENTION ''

Example 1: Tablet

A tablet having the following composition was prepared by a conventional method.

250 g of Compound 1, 1598.5 g of mannitol, 100 g of sodium starch glycolate, 10 g of light citric anhydride, 40 g of magnesium stearate and 1.5 g of yellow iron sesquioxide were mixed by a conventional method. Using this mixture, tableting was performed using a tableting machine having a punch with a diameter of 8 mm (Purepress Correct-12, manufactured by Kikusui) to obtain tablets (each tablet containing 25 mg of the active ingredient). Compound 1 25 mg

Mannitol 159., 85 mg

Sodium starch glycolate 10 mg

Light caffeic anhydride 1 mg

Magnesium stearate 4 mg

Yellow ferric oxide 0.15 ins

200 mg Example l: Capsule

A capsule having the following composition was prepared by a conventional method.

Compound 1 (500 g), lactose (300 _N ), 100 g of light caffeic anhydride and sodium lauryl sulfate (100 g) were mixed by a conventional method. This mixture was filled into a hard capsule No. 1 (capacity of 100 mg / capsule) using a capsule filling machine (LZ-64, manufactured by Zanas i), and a capsule (containing 50 mg of active ingredient per capsule) was prepared. Obtained. Formulation compound 1 50 mg

Lactose 30 mg

Light caffeic anhydride 10 mg

Sodium lauryl sulfate 10 mg

100 mg Example 3: Injection

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

D-mannitol 100 mg

Hydrochloric acid

Sodium hydroxide aqueous solution

Appropriate amount of distilled water for injection

2.00 mL

Industrial use

According to the present invention, there is provided a therapeutic agent for overactive bladder associated with cerebrovascular disorder, comprising a tricyclic compound or a pharmacologically acceptable salt thereof as an active ingredient.

Claims

The scope of the claims

1. Formula (I)

①

(Wherein, R ¹ represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkoxy, and X, X and X ³ represent CR ⁵ = CR and CR ⁷ = GR ⁸ [Formula Wherein R ^s , R ^{ , R ⁷ and R «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 unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy or substituted or unsubstituted lower alkanoylamino], N (0) _m = CR ^s -CR ⁷ = CR ⁸ (wherein RR ⁷ And R ⁸ are as defined above, and m represents 0 or 1), CR ⁵ = CR ⁶ -N (0) _m = CR ^e

(Where R ^s , RR ⁸ and m are as defined above), CR ⁵ = CR ^f -CR ⁷ = N (0) _n (where R ⁵ , R ^f , R ⁷ and m are it it the same meanings as defined above), CR ^{^S} = CR ^S - in 0 (wherein, 11 ^5, and R ⁵ Waso are the same meanings as it ^{^{said), CR 5 = CR f -}} S ( wherein, R ⁵ and R ^{ has the same meaning as above), 0-CR ⁷ = CR ⁸ (wherein, R ⁷ and R ⁸ J have the same meanings as above), S-CR ⁷ = CR ^S (wherein, R7 and R ⁸ represents it it the same meanings as defined above) or 0-CR ⁷ = N (wherein, R ⁷ is synonymous with the), Y is _{- CH 2 S -, -CHjSO-} s - _{C¾S0 2 -s - C 0-, -} CH = CH -, - (C¾)厂(wherein, p is an integer of 0~2), -SC -, -S0CH广, - S0 ₂ CH "or - represents 0CH广, R ² is a hydrogen atom, Amino, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkoxy, Mo (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, Represents a substituted or unsubstituted arylamino or a substituted or unsubstituted heterocyclic group}, or a tricyclic compound represented by the formula or a pharmacologically acceptable salt thereof as an active ingredient. Therapeutic agent.

2. Expression (la)

[In the formula, R ¹ and X'-X ² -X have the same meanings as Re it Resona 'the, Y ^a is _{_{- C¾S0 2 -, - SCH 2}} -, - S0 (¾-, - S0 2 C - or - 0CH ₂ - represents, Y ^a is - CH _₂ S0 ₂ -ヽ- SCH厂, -S0C¾- or - S0 _₂ CH ₂ - when it is, R "is a lower hydrogen atom, Amino, substituted or unsubstituted Alkyl, 'substituted or unsubstituted 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 a heterocyclic group, Y ^a is - 0C¾ - is when a, R ^{2 a} is hydrogen Hara , Amino, trifluoromethyl, substituted or unsubstituted 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, substituted or unsubstituted nitrogen-containing heterocycle Group or formula (II)

(Π)

(In the formula, n is 0 or 1, and R ³ is the same or different and is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted aryl or Represents a substituted or unsubstituted aralkyl, or R ³ and R ⁴ May form a cyclic alkyl with the adjacent carbon atom, and Q represents a group represented by halogen, ′ -amino, hydroxy or substituted or unsubstituted lower alkoxy). A therapeutic agent for overactive bladder associated with cerebrovascular disease, comprising a tricyclic compound or a pharmacologically acceptable salt thereof as an active ingredient.

3. Y ^a is _{_{- CH 2 S0 2 -, -}} SC¾ -, - S0C¾ - or - S0 ₂ C¾ - overactive bladder therapeutic agent associated with cerebrovascular disorders according to claim 2, wherein a.

4. Y ^a is - 0C - overactive bladder therapeutic agent associated with cerebrovascular disorders according to claim 2, wherein a.

5. The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to any one of claims 2 to 4, wherein R ¹ is a hydrogen atom, a halogen, or a substituted or unsubstituted lower alkoxy.

6. The therapeutic agent for overactive bladder associated with cerebrovascular disorders according to any one of claims 2 to 4, wherein R ¹ is a hydrogen atom.

7. Y ^a is - CH ₂ S0广, - S0 ₂ C - or - 0C¾- range 2 claims is, '5 and overactive bladder therapeutic agent associated with cerebrovascular disorders as claimed in any one of 6. '

8. Y ^a is - CH ₂ S0 "or - S0 ₂ CH ₂ - overactive bladder therapeutic agent associated with cerebrovascular disorder according to any one of claims 2, 5 and 6 according to a.

9. Y ^a is - C S0 ₂ - accompanied cormorants overactive bladder therapeutic agent in cerebrovascular disorders according to any one of claims 2, 5 and 6 according to a.

10. X ¹ - X ² -X ³ is S- CR ⁷ = CR ⁸ (wherein, R ⁷ and R ⁸ it it the same meaning as defined above) according to any of the billed range 2-9 is For overactive bladder associated with cerebrovascular disorders.

^{^{11. X 1 - X 2 - X}} 3 is ^{^{CR 5 = - CR 7 = CR}} 8 ( ^{^{wherein, R 5, R 8, R}} 1 and R ⁸ it Ru it the same meaning der) claims a 10. The therapeutic agent for overactive bladder associated with cerebrovascular disease according to any one of 2 to 9.

12. H ^{2 a} is the formula (II)

Wherein n, R ³ , R ⁴ and Q have the same meanings as defined above, respectively.

12. The therapeutic agent for overactive bladder associated with vascular disorders according to any one of 11.

13. The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to claim 12, wherein n is 0.

14. The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to claim 13, wherein R ³ is methyl, R ⁴ is trifluoromethyl, and Q is hydroxy.

15. R ¹ is a hydrogen atom, Y ^a is - C S0 ₂ - and ^{^{is, X 1 - X 2 - X}} 3 is S- CR ⁷ = CR ⁸ (wherein, R ⁷ and R ⁸ it it the And R "is of the formula (III)

(ΠΙ)

3. The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to claim 2, which is a group represented by the formula:

16. Expression (lb)

[In the formula, R ¹ and 'X'-X ² -X ³ have the same meanings as it it the, Y ^b is _{- CH 2 0 -, - CS} -, -CH 2 S0 -, - CH = CH- or -(C) _p- wherein p is as defined above; R ^2b is a group represented by the formula (III)

(m)

17. X ¹ -X ² -X ³ is CR ^s = CR ^f -CR '= CR ⁸ (wherein, R ^s , R, R ⁷ and ^Re are each as defined above) or

(Wherein R ⁵ , R ^s and R ¹ have the same meanings as described above), respectively.

18. Χ'-Χ ² -X ³ is CR ⁵ = C-0 (where R ^s and ^ are as defined above) or CR ⁵ = CR ^S -S (wherein, R ^s and R ^e it it the same meaning as defined above) overactive bladder therapeutic agent associated with the range 16 SL placement of cerebrovascular disorders as claimed is.

19. XLX ² -X ³ is (3-CR ⁷ = CR ⁸ (wherein, R ⁷ and are as defined above) or S-CR '= CR ⁸ (where β ⁷ and R ⁸ are respectively 17. The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to claim 16, which is the same as defined above.

20. Upsilon ^¾ is - over activities bladder therapeutic agent associated with cerebrovascular disorders as claimed in any one of C 0- in which the claims 16-19.

21. The therapeutic agent for overactive bladder associated with cerebrovascular disorders according to any one of claims 16 to 19, wherein is-(C) _p- (wherein p is as defined above).

22. The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to claim 21, wherein p is 0.

23. The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to claim 21, wherein p is 2.

24. The therapeutic agent for overactive bladder associated with cerebrovascular disorder according to any one of claims 16 to 19, wherein ^Yk is -CH = CH-.

25. Y ^¾ is - C S- or - overactive bladder therapeutic agent associated with cerebrovascular disorders as claimed in any one of claims 1-19 is C¾S0-.

26. Use of the tricyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25 for the manufacture of a therapeutic agent for overactive bladder associated with cerebrovascular disorder.

27. A method for treating overactive bladder associated with cerebrovascular disorder, comprising a step of administering an effective amount of the tricyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25.