WO1994016702A1 - Remedy for irregular bowel movement - Google Patents
Remedy for irregular bowel movement Download PDFInfo
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- WO1994016702A1 WO1994016702A1 PCT/JP1994/000096 JP9400096W WO9416702A1 WO 1994016702 A1 WO1994016702 A1 WO 1994016702A1 JP 9400096 W JP9400096 W JP 9400096W WO 9416702 A1 WO9416702 A1 WO 9416702A1
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- lower alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Definitions
- the present invention relates to a medicine for treating bowel movement abnormality.
- a compound represented by the following general formula (I) selectively antagonizes the adenosine receptor A receptor, and produces diuretic Sakugawa, renal protection Sakugawa, bronchodilation It is known to have a tonicity-improving action and a brain function-improving action (Japanese Patent Application Laid-Open Nos. 173889/1987 and 4-270222 / 1999).
- the xanthine-inducing compound contained in the compound (I) has an adenosine antagonistic activity [Naunyn-Schmiedberg ', et al. Archcol.Pharmol.), 33 ⁇ , 59 (1987), Japanese Patent Publication No. 2-247180, Journal of Medicinal 'Chemistry (J. Med.Cem.), 35, 924 and 3066 (1992) ].
- the compound exerts a defecation function promoting action.
- compound (I) it is found that a compound in which the 8-position of a xanthine derivative is a lower alkyl has a diuretic effect is described in Journal of Medicinal Chemistry (J.
- R ′, IT and R : i are the same or different and represent hydrogen or lower alkyl
- X 1 and X 2 are the same or different and represent oxygen or sulfur
- Q is lower alkyl
- R (Wherein, R 'and K' represent-) or represent a different or non-replaced fatty alkyl.] Or a pharmaceutically acceptable salt thereof as an active ingredient And a therapeutic agent for bowel movement disorders.
- the present invention relates to a method for treating bowel movement disorder, which comprises administering an effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient with bowel movement disorder.
- the present invention also relates to the use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for bowel movement disorders.
- lower alkyl is straight-chain or branched having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Neopentyl, hexyl and the like are included.
- Alkylene includes straight or branched ones having 1 to 4 carbon atoms, for example, methylene, ethylene, trimethylene, tetramethylene, methylmethylene, propylene, ethylethylene and the like.
- the alicyclic alkyl includes those having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.
- substituent of the alicyclic alkyl include the same or different substituents having 1 to 3 substituents, for example, lower alkyl, hydroxy, lower alkoxy, halogen, amino, nitro, etc., and alkyl of lower alkyl and lower alcohol.
- the moiety is the same as the definition of the lower alkyl described above, and the halogen includes atoms of fluorine, chlorine, bromine, and iodine.
- the pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
- Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate and phosphate, acetate, maleate, fumarate, tartrate, citrate and the like.
- Metal salts that are pharmacologically acceptable include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like.
- Ammonium salts include salts such as ammonium and tetramethylammonium.
- Pharmaceutically acceptable organic amine addition salts include addition salts such as morpholine and piperidine, and pharmaceutically acceptable amino acid additions. Examples of the salt include addition salts of lysine, glycine, phenylalanine and the like.
- the therapeutic agent for constipation abnormality of the present invention includes, for example, functional constipation [acute constipation or chronic constipation (relaxation). J or organ stool ⁇ inevitable cfei, tumor-, ulcerative, inflammatory scarring or vertebral injury, etc. ), Intestinal paralytic ileus (postoperative intestinal paralysis, appendectomy, hernia operation, gastrectomy or gallstone extraction, etc.), irritable bowel syndrome, various congenital gastrointestinal dysfunction or pseudo-intestinal obstruction (idiopathic) It can be used as an agent for eliminating intestinal contents during gastrointestinal examination or before and after surgery and for assisting defecation after surgery.
- Compound (I) can be obtained by a known production method [Journal of Medicinal Chemistry (J. Med. Chem.), 35, 924 (1992)].
- Table 1 shows examples of specific compounds used as therapeutic agents for bowel movement disorders of the present invention.
- Table 2 shows the physicochemical properties of the compounds in Table 1.
- Compound Melting point (° c) Molecular formula IR (KBr) (cm 1 )
- Test example 1 Acute toxicity test
- Test compounds were administered orally (OOnigZkg) using three dd male mice weighing 20 ⁇ lg per group. After the administration, the mortality was observed 7 times later, and the minimum lethal dose (MLD) value was determined.
- MLD minimum lethal dose
- the MLD is> 300 ing Zkg, and it is safe to use over a wide dose range with low toxicity.
- CMC carboxymethylcellulose
- test compound (0.0003 to 10 mg / kg) was orally administered in an amount of 0.5 ml per 250 g of rat weight, and the control group was orally administered a 0.33 ⁇ 4CMC solution in an amount of 0.5 ml orally per 250 g rat weight.
- Feces excreted 3 hours after administration of the test compound were collected, and the wet weight was measured. After drying the collected feces at 100 ° C for 6 hours, the dry weight was measured, and the moisture content was calculated from the wet weight and dry weight according to the following formula. Since there was no change, the wet weight was used as the amount of defecation.
- Moisture content (%) (wet weight-dry weight) Z (wet weight) X 100
- the significant difference test for defecation volume was determined using the Kruska Wallis test between the control group and the test compound administration group, after confirming that there was a difference in the mean value of each group, and then using Steel's multiple comparison test. Performed c When the risk rate was less than 5 (p ⁇ 0.05), there was a significant difference, and the lowest dose with a significant difference was defined as the minimum effective dose (MED).
- MED minimum effective dose
- Table 3 shows the results. Third compound number MED (mg / kg, oral)
- Compound (I) or a pharmaceutically acceptable salt thereof can be used as it is or in various pharmaceutical forms.
- the pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier as an active ingredient.
- These pharmaceutical compositions are desirably in a unit dosage form suitable for parenteral administration orally or as a formulation by injection or rectal administration.
- any useful pharmacologically acceptable carrier can be used.
- Oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive shine, soybean oil And oils such as p-hydroxybenzoic acid esters, etc., and fringes such as strobe leaf wrappers and peppermint.
- excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc
- a binder such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unitary oral dosage forms because of their ease of administration.
- solid pharmaceutical carriers are used.
- the injection can be prepared using a carrier consisting of 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 using an appropriate solubilizing agent according to a conventional method. .
- Formulations by rectal administration are preferably dissolved in a pharmaceutically acceptable carrier, such as a pH adjuster, base, disintegrant, excipient, diluent, coloring agent, fragrance, softener, wetting agent, etc. It can be prepared by uniformly dispersing or dissolving in the preparation together with adjuvants.
- a pharmaceutically acceptable carrier such as a pH adjuster, base, disintegrant, excipient, diluent, coloring agent, fragrance, softener, wetting agent, etc. It can be prepared by uniformly dispersing or dissolving in the preparation together with adjuvants.
- pH regulators are usually used for pharmaceuticals, and maintain the pH of the rectal fluid at 4.0 to 8.0 after administration of the preparation.
- succinic acid-borax lactic acid-sodium lactate, Potassium monocitrate-sodium hydroxide, sodium dicitrate-sodium hydroxide, potassium phosphate monobasic-sodium phosphate, potassium phosphate monobasic-borax and the like.
- the base may be an oily base or a water-soluble base that is commonly used.
- Examples of the oily base include cocoa butter, Rakkasi oil, coconut oil, vegetable oils such as corn oil, Hadofuatsu Bok glycerol esters of saturated fatty acids of natural fatty acids as a raw material (Uitepu zone Ichiru 'M: Dainamai Tonoberu (Pharmasol 1 M : manufactured by NOF Corporation) and mineral oils such as serine and paraffin.
- Examples of the water-soluble base include a polyethylene glycol-polypropylene glycol copolymer, propylene glycol, glycerin and the like. These bases can be used alone or in combination.
- Examples of the dosage form of the preparation include a rectal suppository of IS1 at room temperature or a soft capsule prepared by filling a liquid or soft substance into a capsule.
- Compound (I) or a pharmacologically acceptable salt thereof can be administered orally in the above-mentioned pharmaceutical form or parenterally as a preparation by injection or rectal administration.
- the dosage is usually 1 to 50 mg / kg, divided into 3 to 4 times per day, depending on the dosage form, patient age, body weight, symptoms, etc.
- a tablet having the following composition was prepared by a conventional method.
- Fine granules having the following composition were prepared by a conventional method.
- a forcepsel having the following composition was prepared by a conventional method.
- An injection having the following composition was prepared by a conventional method.
- a formulation for rectal administration having the following composition was prepared by a conventional method.
- Witebzole 1 M H 15 manufactured by Dynamite Nobel
- 290.9 g of Witepzol TM E75 manufactured by Dynamite Nobel
- 2.5 g of Compound A, 13.6 g of potassium monophosphate and 14.2 g of sodium diphosphate were uniformly mixed and dispersed therein. The mixture was dispersed and filled into a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
- a tablet having the following composition was prepared by a conventional method.
- Compound Flg was dissolved in purified soy lOOg, and purified egg yolk lecithin 12 g and glycerin for injection 25 g were added. This mixture was kneaded and emulsified in a conventional manner to 1000 ml with distilled water for injection. The resulting dispersion was aseptically filtered using a 0.2 im disposable membrane filter, and then aseptically filled into glass vials in 2 ml increments for injection (containing 2 mg of active ingredient per vial). To).
- a formulation for rectal administration having the following composition was prepared by a conventional method.
- the Witepuzo Ichiru ⁇ ⁇ ⁇ (manufactured Dainamai Tonoichi Bell) 1 5 678. 8g and Witebuzoru ⁇ ⁇ 7 5 (Dainamai Tonoberu Co.) 290. 9 g were melted at 40 to 50 ° C.
- the mixed and dispersed product was filled in a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
- a formulation for rectal administration having the following composition was prepared by a conventional method.
- Formulation Compound B 2.5 mg
- a formulation for rectal administration having the following composition was prepared by a conventional method.
- a formulation for rectal administration having the following composition was prepared by a conventional method.
- Formulation compound X 2. ⁇ mg
- a formulation for rectal administration having the following composition was prepared by a conventional method.
- the Witepuzo Ichiru 'Micromax Eta (manufactured Dainamai Tonoichi Bell) 1 5 678. 8g and Witebuzoru (manufactured Dainamai Bok Nobel) 1 M E 7 5 290. 9g melted at 40 to 50 ° C.
- 2.5 g of Compound AG, 13.6 g of potassium monophosphate and 14.2 g of sodium diphosphate were uniformly mixed and dispersed therein. The mixture was dispersed and filled into a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
- a formulation for rectal administration having the following composition was prepared by a conventional method.
- Formulation compound All 2.5 mg
- a therapeutic agent for bowel movement disorder is provided.
Abstract
A remedy for irregular bowel movement containing a xanthine derivative represented by general formula (I) or a pharmacologically acceptable salt thereof as the active ingredient, wherein R?1, R2 and R3¿ represent each hydrogen or lower alkyl; X?1 and X2¿ represent each oxygen or sulfur; and Q represents lower alkyl or a group represented by (a), (b), (c), (d) or (e), wherein Z?1 and Z2¿ represent each hydrogen or are combined together oxygen; Y represents a single bond or alkylene; n represents 0 or 1; symbol.^_.^_.^_ represents either a single or a double bond ; and R?4 and R5¿ represent each (un)substituted cycloalkyl.
Description
"J] ¾U "J] ¾U
匕， 便 通 異 ^ の 治 剂 The treatment of ^^
技 術 分 野 Technical field
本発明技は、 便通異常の治^のための薬剂に関する。 後述する一般式 （ I ) で表される化合物 〔以下、 化合物 （ I ) という〕 がアデノシン 受容体の A 受容体に対し選択的に拮抗作用を示し、 利尿作川、 腎保護作川、 気管支拡 張作用および脳機能改善作用を有することが知られている （特 ί¾- Ψ-3- 173889号公報、 4 - 270222号公報） 。 The present invention relates to a medicine for treating bowel movement abnormality. A compound represented by the following general formula (I) (hereinafter referred to as compound (I)) selectively antagonizes the adenosine receptor A receptor, and produces diuretic Sakugawa, renal protection Sakugawa, bronchodilation It is known to have a tonicity-improving action and a brain function-improving action (Japanese Patent Application Laid-Open Nos. 173889/1987 and 4-270222 / 1999).
また、 化合物 （ I ) に含まれるキサンチン誘導 ί本がアデノシン拮抗活性を有すること が知られている [ナウニンーシュミーデベルグズ■ァ一力イヴ ·ォブ ·ファーマコロジ ィ （Naunyn- Schmi edberg' s Arch. Pharmacol. ), 33^, 59( 1987)、 特 平 2- 247180号公 報、 ジャーナル ·ォブ · メディシナル 'ケミストリー (J. Med. C em. ), 35, 924および 3066(1992)] 。 しかし、 該化合物が排便機能促進作用を冇することは知られていない。 化合物（ I )に関連して、 キサンチン誘導体の 8位が低級アルキルである化合物が、 利 尿作用を示すことがジャーナル ·ォブ · メディシナル 'ケミストリー （J. Med. Chem. ), 14, 1202(1971 ) 等に、 気管支拡張作用を示すことが特開昭 57- 163381 号公報および特開 昭 63- 41478号公報等に、 抗炎症作用を示すことが W085/02542等にそれぞれ開示されてい また、 化合物 （ I ) に関して、 8 -（1-ァダマンチル） -1, 3, 7-卜リメチルキサンチンが テトラへドロン · レターズ [ (Tetrahedron Let t. ), 27, 6337(1986) ] に記載されてい るが、 その薬理作用については知られていない。 It is also known that the xanthine-inducing compound contained in the compound (I) has an adenosine antagonistic activity [Naunyn-Schmiedberg ', et al. Archcol.Pharmol.), 33 ^, 59 (1987), Japanese Patent Publication No. 2-247180, Journal of Medicinal 'Chemistry (J. Med.Cem.), 35, 924 and 3066 (1992) ]. However, it is not known that the compound exerts a defecation function promoting action. In connection with compound (I), it is found that a compound in which the 8-position of a xanthine derivative is a lower alkyl has a diuretic effect is described in Journal of Medicinal Chemistry (J. Med. 1971) and the like are disclosed in JP-A-57-163381 and JP-A-63-41478 and the like, and are disclosed in W085 / 02542 and the like to exhibit an anti-inflammatory effect. Regarding compound (I), 8- (1-adamantyl) -1,3,7-trimethylxanthine is described in Tetrahedron Letters [(Tetrahedron Lett.), 27, 6337 (1986)]. However, its pharmacological effects are not known.
ブルンストック（Burnstock) らが消化管平滑筋に対する非ァドレナリン性非コリン性 抑制性神経支配の一^ ^としてプリン作働性神経の存在を提唱 [プリティ ッシュ · ジャー ナル 'ォブ · ファーマコロジィ （Br. J. Pharmacol. ), 40, 668(1970)] して以来、 消化 管神経叢におけるアデノシン関連化合物の役割が注目され、 近年、 アデノシンがァセチ ルコリンなど各種神経伝達物質の遊離を抑制的に修飾することが知られてきた。 しかし、 消化管運動機能における内因性アデノシンの生理的な役割あるいはアデノシン拮抗薬の 作用については、 未だ明確にされていない。
本発明によれば、 一般式 （ I ) Burnstock et al. Propose the presence of purinergic nerves as a non-adrenergic non-cholinergic inhibitory innervation of gastrointestinal smooth muscle [Pretty Tissue Journal of Pharmacy ( Br. J. Pharmacol.), 40, 668 (1970)], and the role of adenosine-related compounds in the gastrointestinal plexus has been attracting attention. In recent years, adenosine has been shown to inhibit the release of various neurotransmitters such as acetylcholine. It has been known to qualify. However, the physiological role of endogenous adenosine in gastrointestinal motility or the effects of adenosine antagonists has not yet been clarified. According to the present invention, the general formula (I)
リ Re
[式中、 R'、 ITおよび R:iは同一または異なって、 水素または低級アルキルを表し、 X1および X2は同一または異なって、 酸素または硫黄を表わし、 Qは、 低級アルキル、 式 （a)
[Wherein R ′, IT and R : i are the same or different and represent hydrogen or lower alkyl, X 1 and X 2 are the same or different and represent oxygen or sulfur, Q is lower alkyl, a)
(式中、 Z'および Z 2は水素または Z'および Z 2がー緒になって酸素を表す） 式 （b)
(Wherein Z ′ and Z 2 represent hydrogen or oxygen by Z ′ and Z 2 ). Formula (b)
(式中、 Yは単結合またはアルキレンを表す） 、 式 （c)
(Wherein, Y represents a single bond or alkylene), formula (c)
(式中、 nは 0または〗を意味し、 Yは前記と同義である） 、 式 （d)
(Wherein n represents 0 or〗, and Y has the same meaning as described above), and formula (d)
(式中、 — - は単結合または二重結合を表し、 Yは前記と同義である） または式 （e) (Wherein,-represents a single bond or a double bond, and Y has the same meaning as described above).
,4 ,Four
FT FT
(e) (e)
R
(式中、 R 'および K 'は ] -または異なって、 もしくは非^換の脂^式アルキルを 表す） を表す] で表されるキサンチン誘導体またはその薬理的に許容される塩を有効成 分とする便通異常の治療剤に関する。 R (Wherein, R 'and K' represent-) or represent a different or non-replaced fatty alkyl.] Or a pharmaceutically acceptable salt thereof as an active ingredient And a therapeutic agent for bowel movement disorders.
さらに、 本発明によれば、 化合物 （ I ) またはその薬理的に許容される塩の有効量を 便通異常の患者へ投与することからなる便通異常の治療方法に関する。 Furthermore, the present invention relates to a method for treating bowel movement disorder, which comprises administering an effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient with bowel movement disorder.
また、 本発明によれば、 便通異常の治療剤の製造のための化合物 （ I ) またはその薬 理的に許容される塩の使用に関する。 The present invention also relates to the use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for bowel movement disorders.
化合物 （ I ) の各基の定義において、 低級アルキルは、 直鎖または分岐状の炭素数 1 〜6の、 例えばメチル、 ェチル、 プロピル、 イソプロピル、 ブチル、 イソブチル、 sec —ブチル、 tert プチル、 ペンチル、 ネオペンチル、 へキシル等が包含される。 アルキ レンは、 直鎖または分岐状の炭素数 1〜4の、 例えばメチレン、 エチレン、 トリメチレ ン、 テトラメチレン、 メチルメチレン、 プロピレン、 ェチルエチレン等が包含される。 また脂環式アルキルは炭素数 3〜 8の、 例えばシクロプロピル、 シクロブチル、 シクロ ペンチル、 シクロへキシル、 シクロォクチル等が包含される。 脂環式アルキルの置換基 としては、 同一または異なって置換数 1〜3の、 例えば低級アルキル、 ヒ ドロキシ、 低 級アルコキシ、 ハロゲン、 ァミノ、 ニトロ等があげられ、 低級アルキルおよび低級アル コキンのアルキル部分は、 前記低級アルキルの定義と同じであり、 ハロゲンはフッ素、 塩素、 臭素、 ヨウ素の各原子が包含される。 In the definition of each group of compound (I), lower alkyl is straight-chain or branched having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Neopentyl, hexyl and the like are included. Alkylene includes straight or branched ones having 1 to 4 carbon atoms, for example, methylene, ethylene, trimethylene, tetramethylene, methylmethylene, propylene, ethylethylene and the like. The alicyclic alkyl includes those having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. Examples of the substituent of the alicyclic alkyl include the same or different substituents having 1 to 3 substituents, for example, lower alkyl, hydroxy, lower alkoxy, halogen, amino, nitro, etc., and alkyl of lower alkyl and lower alcohol. The moiety is the same as the definition of the lower alkyl described above, and the halogen includes atoms of fluorine, chlorine, bromine, and iodine.
化合物 （ I ) の薬理的に許容される塩は、 薬理的に許容される酸付加塩、 金属塩、 ァ ンモニゥム塩、 有機ァミン付加塩、 ァミノ酸付加塩等を包含する。 化合物 （ I ) の薬理 的に許容される酸付加塩としては、 塩酸塩、 硫酸塩、 リン酸塩等の無機酸塩、 酢酸塩、 マレイン酸塩、 フマル酸塩、 酒石酸塩、 クェン酸塩等の有機酸塩があげられ、 薬理的に 許容される金属塩としてはナトリウム塩、 カリウム塩等のアルカリ金属塩、 マグネシゥ ム塩、 カルシウム塩等のアルカリ土類金属塩、 アルミニウム塩、 亜鉛塩等があげられ、 アンモニゥム塩としてはアンモニゥム、 テトラメチルアンモニゥム等の塩があげられ、 薬理的に許容される有機ァミン付加塩としてはモルホリン、 ピペリジン等の付加塩、 薬 理的に許容されるアミノ酸付加塩としてはリジン、 グリシン、 フヱニルァラニン等の付 加塩があげられる。 The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate and phosphate, acetate, maleate, fumarate, tartrate, citrate and the like. Metal salts that are pharmacologically acceptable include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like. Ammonium salts include salts such as ammonium and tetramethylammonium. Pharmaceutically acceptable organic amine addition salts include addition salts such as morpholine and piperidine, and pharmaceutically acceptable amino acid additions. Examples of the salt include addition salts of lysine, glycine, phenylalanine and the like.
本発明の便通異常の治療剤は、 例えば、 機能性便秘 〔急性便秘あるいは慢性便秘 （弛
緩性便秘、 痙攣性籠、、 排便困難あるいは ¾物性便秘など） j あるいは器 性便 ί必 Cfei 着、 腫痕-、 潰瘍性、 炎症性の瘢懇狭窄あるいは脊椎損傷などに分類される各種便秘） 、 腸管麻痺性ィレウス （術後腸管麻痺、 虫垂切除、 ヘルニア手術、 胃切除あるいは胆石摘 出など） 、 過敏性腸症候群、 各種先天性消化管機能異常あるいは偽性腸閉塞 （特発性） の治療剤、 消化管検査時または手術前後における腸管内容物の排除剤および術後の排便 補助 ·腸内ガスの駆除のための薬剤として使用できる。 The therapeutic agent for constipation abnormality of the present invention includes, for example, functional constipation [acute constipation or chronic constipation (relaxation). J or organ stool ί inevitable cfei, tumor-, ulcerative, inflammatory scarring or vertebral injury, etc. ), Intestinal paralytic ileus (postoperative intestinal paralysis, appendectomy, hernia operation, gastrectomy or gallstone extraction, etc.), irritable bowel syndrome, various congenital gastrointestinal dysfunction or pseudo-intestinal obstruction (idiopathic) It can be used as an agent for eliminating intestinal contents during gastrointestinal examination or before and after surgery and for assisting defecation after surgery.
化合物 （ I ) は、 公知の製造法 〔ジャーナル ·ォブ ' メディシナル ' ケミストリ一 (J. Med. Chem. ), 35 ， 924 ( 1992)) により得ることができる。 Compound (I) can be obtained by a known production method [Journal of Medicinal Chemistry (J. Med. Chem.), 35, 924 (1992)].
本発明の便通異常の治療剤として用いられる具体的化合物の例を第 1表に示す。
Table 1 shows examples of specific compounds used as therapeutic agents for bowel movement disorders of the present invention.
, N , N
X X
H H H H
0 0
Ό Ό
N N
2 000 Mf/IDd Z0i9l/f6 OM
H 2 000 Mf / IDd Z0i9l / f6 OM H
Ί - u Ί-u
O o 1 -" ΊO o 1-"Ί
O O 乙！ - u
OO Otsu! -u
O O 1D 'n'O-u 4 IO O 1D 'n'O-u 4 I
1 -11 H -u II1 - 11 H -u II
O O H -ΙΓΟ 丄O O H -ΙΓΟ 丄
O O II II oO O II II o
N 丫 tX N 丫 tX
o- N. o- N.
N N
cU cU
2X 2 X
^0,9l/W OM
第 1表 (4) ^ 0,9l / W OM Table 1 (4)
X2 X 2
R3 R 3
R1 R 1
Q Q
ク\ \
X1 N N X 1 NN
R2 化介物 R 1 R R:! X ' X Q
R 2 Kakai product R 1 RR:! X 'XQ
A A n-C,M7 !i-C_;H7 H ϋ O — CH(C2H5)2 AA nC, M 7 ! I-C_ ; H 7 H ϋ O — CH (C 2 H 5 ) 2
ΛΒ n-C,Il7 n-C,H7 II O O — C(CH3)3
1 ΛΒ nC, Il 7 nC, H 7 II OO — C (CH 3 ) 3 1
R2 化介物 R 1 R2 R3 X 1 2 Q R 2 compound R 1 R 2 R 3 X 1 2 Q
AC Coll, en, 11 o o AC Coll, en, 11 o o
AD C ll, II O o AD C ll, II O o
AE n-C4H n-C4Hy 〖I O O AE nC 4 H nC 4 H y 〖IOO
Aト n-C4H9 n-C4ll9 H O O A to nC 4 H 9 nC 4 ll 9 HOO
AG Cl iso- Hリ H O O AG Cl iso-H
Λ1! CI is()-C4 , H O OΛ1! CI is ()-C 4 , HOO
また第 1表中の化合物の理化学的性質を第 2表に示す。
化合物 融点 （°c) 分子式 I R(KBr) (cm 1 ) Table 2 shows the physicochemical properties of the compounds in Table 1. Compound Melting point (° c) Molecular formula IR (KBr) (cm 1 )
A 191.G-192.8 C 1 ( 1699, 1655 A 191.G-192.8 C 1 (1699, 1655
(エタノ-ル） (Ethanol)
B 170.5-171.7
1754, 1704, 1650, 1505 B 170.5-171.7 1754, 1704, 1650, 1505
(トルエン-シク Dへキサン） (Toluene-six D hexane)
C 100.1-101.6 Ci ΒΗ,,,Ν,Ο, 1699, 1653, 1499 C 100.1-101.6 Ci ΒΗ ,,, Ν, Ο, 1699, 1653, 1499
(へブタン） (Hebutane)
D 118.4-120.0 Ο,,,Η,,,Ν.Ο, 1699, 1652, 1497 D 118.4-120.0 Ο ,,, Η ,,, Ν.Ο, 1699, 1652, 1497
(へブタン） (Hebutane)
E 169.3-171.0 Ο,,Ηι,ηΝ,Ο, 1699, 1650, 1491 E 169.3-171.0 Ο ,, Ηι, ηΝ, Ο, 1699, 1650, 1491
(イソブ ϋパノ-ルー水） (Isobu @ Pano-Lu water)
F 190.0-191.0 C2 ΗΝ 1699 1651 1499 F 190.0-191.0 C 2 ΗΝ 1699 1651 1499
(へブタン） (Hebutane)
G 177.7-179.5 CH;)iiN,0, 1704, 1648 1498 G 177.7-179.5 CH ;) ii N, 0, 1704, 1648 1498
(ェタノ-ルー水） (Ethano-Lou water)
H 94.7-97.0 C2 ,H:J 1702, 1653 H 94.7-97.0 C 2 , H: J 1702, 1653
(エタノ-ルー水） (Ethano-Lou water)
79.8 - 80.9 C' H:,2N 1698, 1659 (ェタノ-ルー水） 79.8-80.9 C 'H:, 2N 1698, 1659 (Ethano-Lou water)
J 123.2-124.8 C,,H:I ,,Ν,Ο, 1698, 1661 J 123.2-124.8 C ,, H : I ,, Ν, Ο, 1698, 1661
(ェタノ-ルー水） (Ethano-Lou water)
K 91.3-92.4 C' HO 1698, 1661, 1535 K 91.3-92.4 C 'HO 1698, 1661, 1535
(ァセトニトリル) (Acetonitrile)
l o
第 2表 lo Table 2
化合物 融点 （°C) 分子式 R(KBr) レ ,,に, x (cm ') Compound Melting point (° C) Molecular formula R (KBr) レ ,,,, x (cm ')
L 111.2-112.2 C,:.H: N,0, 1700, 1662, 1536 L 111.2-112.2 C,:. H: N, 0, 1700, 1662, 1536
(エタノ-ル—水) (Ethanol-water)
M 252.8-257.9 C, «Η,,Ν,Ο, 1700, 1678 M 252.8-257.9 C, «Η ,, Ν, Ο, 1700, 1678
(エタノール—水) (Ethanol-water)
N 135. 1-137.2
1688, 1493 N 135. 1-137.2 1688, 1493
(エタノ-ル) (Ethanol)
0 > 290 C1 7I1 N 1698, 1660, 1500 0> 290 C 17 I1 N 1698, 1660, 1500
(ジォキサン一水） (Dioxane monohydrate)
P 214.2-216.0 C
1668, 1595 P 214.2-216.0 C 1668, 1595
(エタノ-ル—水) • 1/5 Η,Ο (Ethanol-water) • 1/5 Η, Ο
Q > 295 d oN 1719， 1656， 1649， 1503 Q> 295 dN 1719, 1656, 1649, 1503
(エタノ-ルー水） (Ethano-Lou water)
R 259.8-263. 1 C
1704, 1646, 1497 R 259.8-263.1 C 1704, 1646, 1497
(エタ ル—水) (Ethal-Water)
S 159.7-161.0 C' H N 1704, 1651, 1498 S 159.7-161.0 C 'H N 1704, 1651, 1498
(ェタノ-ルー水） (Ethano-Lou water)
T 266.0-268.7 ΟΜ,Η,ΒΝ,Ο. 1708, 1652, 1495 T 266.0-268.7 ΟΜ, Η, ΒΝ, Ο. 1708, 1652, 1495
(エタノ-ル—水） (Ethanol-water)
u 216.2-216.6 C HOS 1690, 1494 u 216.2-216.6 C HOS 1690, 1494
(イソプロパノ-ル） (Isopropanol)
V 128.5-130.4 C UOS 1682, 1597, 1495 V 128.5-130.4 C UOS 1682, 1597, 1495
(ァセトニトリル)
化合物 融点 （°C) 分子式 I R(KBr) i m,,x (cm ') (Acetonitrile) Compound mp (° C) Molecular Formula IR (KBr) i m ,, x (cm ')
W 94.2-96.6 Ο,,,Η,,, ^ : 1604, 1504, 1088 W 94.2-96.6 Ο ,,, Η ,,, ^: 1604, 1504, 1088
(ァセトニトリル) 0. 1CH:XN · 0.2H.0 (Acetonitrile) 0.1 CH: XN0.2H.0
X 129. 1-130.4 C, ,,Η,Γ,Ν.Ο, 1700, 1654, 1498 X 129. 1-130.4 C, ,, Η, Γ, Ν.Ο, 1700, 1654, 1498
(ェタノ-ルー水） (Ethano-Lou water)
Y 121.6-122.8
1698, 1653, 1497 Y 121.6-122.8 1698, 1653, 1497
(イソブ D/り-ルー水） (Isobu D / Ri-ru water)
Z 150.9-152.0 C, ,,Η,,-,Ν,Ο 1700, 1650, 1497 Z 150.9-152.0 C, ,, Η ,,-, Ν, Ο 1700, 1650, 1497
(イソプ□/ -ルー水） (Isop □ / -Lou water)
AA 88.0-90.4 ϋ,πΗ,,Ν,Ο, 1703, 1656, 1651, 1497 AA 88.0-90.4 ϋ, πΗ ,, Ν, Ο, 1703, 1656, 1651, 1497
(イソブ D /り-ルー水) (Isobu D / Ri-ru water)
AB 148.2-148.6 C,
1703， 1655， 1554， 1502 AB 148.2-148.6 C, 1703, 1655, 1554, 1502
(イソブ D /り-ルー水） (Isobu D / Ri-ru water)
AC 180.4-181.6 C, 1700, 1646, 1552, 1505 AC 180.4-181.6 C, 1700, 1646, 1552, 1505
(シクロへキサン） (Cyclohexane)
AD 166.0-168.7 C JI^N.O, 1710, 1657, 1652, 1500 AD 166.0-168.7 C JI ^ N.O, 1710, 1657, 1652, 1500
(ジォキサン一水） (Dioxane monohydrate)
AE 115.6-116.5 ',Η 1705, 1657, 1651， 1497 AE 115.6-116.5 ', Η 1705, 1657, 1651, 1497
(へブタン） (Hebutane)
AF 171.6-172.7 C, ι,Η,,,Ν.,0, 1699, 1657, 1502 AF 171.6-172.7 C, ι, Η ,,, Ν., 0, 1699, 1657, 1502
(ジォキサン一水） (Dioxane monohydrate)
AG 201.8-203.9 C, Γ,Η,¾Ν,ϋ, 1704, 1651， 1556, 1504 AG 201.8-203.9 C, Γ, Η, ¾ Ν, ϋ, 1704, 1651, 1556, 1504
(イソブ Dパノ-ルー水) (Isobu D pano-ru water)
AH 169.8-173.8 C, τΗ,,Ν.,0, 1704, 1648, 1495 AH 169.8-173.8 C, τΗ ,, Ν., 0, 1704, 1648, 1495
(へブタン）
次に化合物 （ 1 ) の薬理作川について試験例で説明する。 (Hebutane) Next, the pharmacological production of compound (1) will be described with reference to test examples.
試験例 1 急性毒性試験 Test example 1 Acute toxicity test
体重 20± lgの dd系雄マウスを 1群 3匹用い、 試験化合物を経口 OOnigZkg) で投与し た。 投与後 7曰後の死亡状況を観察し最小致死量 (MLD) 値を求めた。 Test compounds were administered orally (OOnigZkg) using three dd male mice weighing 20 ± lg per group. After the administration, the mortality was observed 7 times later, and the minimum lethal dose (MLD) value was determined.
化合物 A〜C、 E〜H、 J、 し〜 Pおよび R〜Yについては、 M L Dは〉 300ingZkg で、 毒性が弱く幅広い用量範囲で安全に用いることができる。 For compounds A to C, E to H, J, to P and R to Y, the MLD is> 300 ing Zkg, and it is safe to use over a wide dose range with low toxicity.
試験例 2 排便量に対する作用 Test example 2 Effect on defecation volume
Sprague-Dawl ey系雄性ラッ ト （体重 200〜250g、 1群 10匹） を絶食用ケージに個別に 入れ、 水のみを自由に摂取させた。 ラッ 卜の試験化合物投与時のストレスに対して馴化 させるために 0. 3 % カルボキシメチルセルロース（CMC) 溶液を体重 250gあたり 0. 5ml 経 口投与し、 その後、 ラッ トを絶食用ケージに馴化させるために試験化合物投与前に約 3 時間放置した。 この間に下痢や軟便の認められたラッ トは実験に使用しなかった。 Male rats of the Sprague-Dawley strain (body weight: 200-250 g, 10 animals per group) were individually placed in a fasting cage, and were allowed only free access to water. To adapt the rat to the stress caused by the administration of the test compound, 0.3% carboxymethylcellulose (CMC) solution is orally administered at a volume of 0.5 ml per 250 g of body weight, and then the rat is adapted to the fasting cage. Was left for about 3 hours before administration of the test compound. Rats with diarrhea or loose stools during this time were not used in the experiment.
試験化合物（0. 0003 〜10mg/kg)をラッ 卜の体重 250gあたり 0. 5ml 経口投与し、 対照群 には 0. 3 ¾CMC 溶液をラッ 卜の体重 250gあたり 0. 5ml 経口投与した。 The test compound (0.0003 to 10 mg / kg) was orally administered in an amount of 0.5 ml per 250 g of rat weight, and the control group was orally administered a 0.3¾CMC solution in an amount of 0.5 ml orally per 250 g rat weight.
試験化合物投与後 3時間に***された糞を回収し、 湿重量を測定した。 また回収した 糞を 100°Cで 6時間乾燥させた後、 乾重量を測定し、 湿重量と乾重量とから下記の式に より水分含量を算出したが、 全ての実験で水分含量に有意な変動がなかったので、 湿重 量を排便量とした。 Feces excreted 3 hours after administration of the test compound were collected, and the wet weight was measured. After drying the collected feces at 100 ° C for 6 hours, the dry weight was measured, and the moisture content was calculated from the wet weight and dry weight according to the following formula. Since there was no change, the wet weight was used as the amount of defecation.
水分含量 （％) = (湿重量一乾重量） Z (湿重量） X 1 0 0 Moisture content (%) = (wet weight-dry weight) Z (wet weight) X 100
排便量の有意差検定は、 対照群と試験化合物投与群との間で Kruska卜 Wal l i sの検定に より各群の平均値に差があることを確認した後、 Steel の多重比較検定を用いて行った c 尚、 危険率が 5 未満（pく 0. 05)の場合を有意差ありとし、 有意差が認められる最低用量を 最小有効用量 (MED) とした。 The significant difference test for defecation volume was determined using the Kruska Wallis test between the control group and the test compound administration group, after confirming that there was a difference in the mean value of each group, and then using Steel's multiple comparison test. Performed c When the risk rate was less than 5 (p <0.05), there was a significant difference, and the lowest dose with a significant difference was defined as the minimum effective dose (MED).
結果を第 3表に示す。
第 3 化合物番号 MED (mg/kg，経口） Table 3 shows the results. Third compound number MED (mg / kg, oral)
A 0. A 0.
B 0. B 0.
E 1. E 1.
F 0. F 0.
Q 0. Q 0.
R 0. R 0.
S 0. S 0.
T 1. T 1.
3 o3030003333 - 1.11 - I- 1 3 o3030003333-1.11-I-1
X 0. 3 Y 1. X 0.3 Y 1.
Z 1. Z 1.
AA 0. AA 0.
AB 0. AB 0.
AC 0. AC 0.
AD 0. AD 0.
AG 0. AG 0.
AH 0， 以上の結果より、 本発明に用いる化合物は、 排便量の増加作用を示し、 便通異常の治 療剤として有用であることが確認された。 AH 0 From the above results, it was confirmed that the compound used in the present invention exhibited an effect of increasing the amount of defecation, and was useful as a therapeutic agent for bowel movement disorders.
化合物 （ I ) またはその薬理的に許容される塩はそのままあるいは各種の製薬形態で 使用することができる。 本発明の製薬組成物は活性成分として、 有効な量の化合物 （ I ) またはその薬理的に許容される塩を薬理的に許容される担体と均一に混合して製造でき る。 これらの製薬組成物は、 経口的に、 または注射剤あるいは直腸投与による製剤とし て非経口的な投与に対して適する単位服用形態にあることが望ましい。
経口服用形態にある組成物の^製においては、 何りかの有用な薬理的に許容し る担 体が使用できる。 例えば懸濁剤およびシロップ剤のような経口液体調製物は、 水、 シュ —クロース、 ソルビトール、 フラク 卜ース等の糖類、 ポリエチレングリコール、 プロピ レングリコール等のグリコール類、 ゴマ油、 オリーブ汕、 大豆油等の油類， p—ヒ ドロ キシ安息香酸エステル類等の防腐剤、 ストロべリーフレーパ一、 ペパーミ ント等のフレ 一 一類等を使用して製造できる。 Compound (I) or a pharmaceutically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier as an active ingredient. These pharmaceutical compositions are desirably in a unit dosage form suitable for parenteral administration orally or as a formulation by injection or rectal administration. In preparing the compositions in oral dosage form, any useful pharmacologically acceptable carrier can be used. Oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive shine, soybean oil And oils such as p-hydroxybenzoic acid esters, etc., and fringes such as strobe leaf wrappers and peppermint.
粉剤、 丸剤、 カプセル剤および錠剤は、 ラク トース、 グルコース、 シュ一クロース、 マンニトール等の賦形剤、 でん粉、 アルギン酸ソ一ダなどの崩壊剤、 ステアリン酸マグ ネシゥ厶、 タルク等の滑沢剤、 ポリビニルアルコール、 ヒ ドロキシプロピルセルロース、 ゼラチン等の結合剤、 脂肪酸エステル等の界面活性剤、 グリセリ ン等の可塑剤等を用い て製造できる。 錠剤およびカプセル剤は投与が容易であるという理由で、 最も有用な単 位経口投与剤である。 錠剤や力プセル剤を製造する際には固体の製薬担体が用いられる。 注射剤は、 蒸留水、 塩溶液、 グルコース溶液または塩水とグルコース溶液の混合物か らなる担体を用いて調製することができる。 この際、 常法に従い適当な溶解補助剤を用 いて溶液、 懸濁液または分散液として調製される。 . For powders, pills, capsules and tablets, excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc It can be produced using a binder such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. Tablets and capsules are the most useful unitary oral dosage forms because of their ease of administration. When manufacturing tablets and capsules, solid pharmaceutical carriers are used. The injection can be prepared using a carrier consisting of 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 using an appropriate solubilizing agent according to a conventional method. .
直腸投与による製剤は、 製剤上許容される担体、 例えば p H調節剤、 基剤、 崩壊剤、 賦形剤、 希釈剤、 着色剤、 芳香剤、 軟化剤、 湿潤剤等を用い、 適当な溶解補助剤と共に 製剤中に均一に分散または溶解させて調製することができる。 Formulations by rectal administration are preferably dissolved in a pharmaceutically acceptable carrier, such as a pH adjuster, base, disintegrant, excipient, diluent, coloring agent, fragrance, softener, wetting agent, etc. It can be prepared by uniformly dispersing or dissolving in the preparation together with adjuvants.
p H調節剤は、 通常医薬品に用いられ、 製剤投与後、 直腸内液の p Hを 4. 0〜8. 0 に 維持するもので、 例えば、 コハク酸—ほう砂、 乳酸—乳酸ナトリウム、 第一クェン酸力 リウム—水酸化ナトリウム、 第二クェン酸ナトリウム—水酸化ナトリウム、 第一リン酸 力リウムー第二リン酸ナトリウムおよび第一リン酸カリウムーほう砂等があげられる。 基剤は、 通常用いられる油性基剤または水溶性基剤のいずれでもよい。 油性基剤として は、 例えばカカオ脂、 ラッカセィ油、 ヤシ油、 トウモロコシ油等の植物性油脂類、 天然 脂肪酸を原料とした飽和脂肪酸のグリセリンエステルであるハードフアツ 卜 （ウイテプ ゾ一ル' M： ダイナマイ トノーベル社製、 ファーマゾール1 M： 日本油脂社製等） およびヮ セリン、 パラフィンなどの鉱物油等があげられる。 水溶性基剤としては、 例えばポリエ チレングリコ一ルーポリプロピレングリコール共重合体、 プロピレングリコール、 グリ セリン等があげられる。 これらの基剤は単独または組み合わせて用いることができる。
製剤の剤型としては、 例えば、 常温で IS1体の肛門坐剤または液状もしくは軟 状のも のをカプセルに充埙した軟カプセル剤などがあげられる。 pH regulators are usually used for pharmaceuticals, and maintain the pH of the rectal fluid at 4.0 to 8.0 after administration of the preparation. For example, succinic acid-borax, lactic acid-sodium lactate, Potassium monocitrate-sodium hydroxide, sodium dicitrate-sodium hydroxide, potassium phosphate monobasic-sodium phosphate, potassium phosphate monobasic-borax and the like. The base may be an oily base or a water-soluble base that is commonly used. Examples of the oily base include cocoa butter, Rakkasi oil, coconut oil, vegetable oils such as corn oil, Hadofuatsu Bok glycerol esters of saturated fatty acids of natural fatty acids as a raw material (Uitepu zone Ichiru 'M: Dainamai Tonoberu (Pharmasol 1 M : manufactured by NOF Corporation) and mineral oils such as serine and paraffin. Examples of the water-soluble base include a polyethylene glycol-polypropylene glycol copolymer, propylene glycol, glycerin and the like. These bases can be used alone or in combination. Examples of the dosage form of the preparation include a rectal suppository of IS1 at room temperature or a soft capsule prepared by filling a liquid or soft substance into a capsule.
化合物 （ I ) もしくはその薬理的に許容される塩は、 上記製薬形態で経口的に、 また は注射剤あるいは直腸投与による製剤として非経口的に投与することができ、 その有効 用量および投与回数は、 投与形態、 患者の年齢、 体重、 症状等により異なるが、 通常 1 日あたり、 l〜50mg/kgを 3〜4回に分けて投与する。 Compound (I) or a pharmacologically acceptable salt thereof can be administered orally in the above-mentioned pharmaceutical form or parenterally as a preparation by injection or rectal administration. The dosage is usually 1 to 50 mg / kg, divided into 3 to 4 times per day, depending on the dosage form, patient age, body weight, symptoms, etc.
以下に、 本発明の態様を実施例により説明する。 Hereinafter, embodiments of the present invention will be described with reference to examples.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
実施例 1 錠剤 Example 1 Tablet
常法により次の組成からなる錠剤を調製した。 A tablet having the following composition was prepared by a conventional method.
処方 化合物 A 20 mg Formulation Compound A 20 mg
ラク トース 143. 4 mg Lactose 143.4 mg
馬鈴薯でんぷん 30 mg Potato starch 30 mg
ヒドロキシブ口ピルセルロース G mg Hydroxybutyl mouth pill cellulose G mg
ステアリン酸マグネシウム 0. 6 mg 0.6 mg of magnesium stearate
200 mg 200 mg
化合物 A 40g、 ラク トース 286. 8gおよび馬鈴薯でんぷん 60gを混合し、 ヒ ドロキシプロ ピルセルロースの 10%水溶液 120gを加えた。 この混合物を常法により練合し、 造粒して 乾燥させた後、 整粒し打錠用顆粒とした。 これにステアリン酸マグネシウム 1. 2gを加え て混合し、 径 8誦の杵をもった打錠機 （菊水社製 R T— 1 5型） で打錠を行って、 錠剤 Compound A (40 g), lactose (286.8 g) and potato starch (60 g) were mixed, and a 10% aqueous solution of hydroxypropyl cellulose (120 g) was added. The mixture was kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Then, 1.2 g of magnesium stearate was added and mixed, and the mixture was compressed using a tableting machine equipped with a punch with a diameter of 8 (Kikusui R-T-15 type).
( 1錠あたり活性成分 20mgを含有する） を得た。 (Containing 20 mg of active ingredient per tablet) was obtained.
実施例 2 細粒剤 Example 2 Fine granules
常法により次の組成からなる細粒剤を調製した。 Fine granules having the following composition were prepared by a conventional method.
処方 化合物 A 20 mg Formulation Compound A 20 mg
ラク ト一ス 655 mg Lactose 655 mg
とうもろこしでんぷん 285 mg Corn starch 285 mg
ヒドロキシプロビルセルロ-ス 40 mg Hydroxypropyl cellulose 40 mg
1, 000 mg 1,000 mg
1 G
化合物 A20g、 ラタ トース 655gおよびとうもろこしてんぷん 28 を¾合し、 L j- o -1 シプロピルセルロースの 10%水溶液 400gを加えた。 この混合物を常法により練合し、 造 粒した後乾燥させて、 細粒剤 （細粒剤 l , 000mgあたり活性成分 20mgを含有する） を得た c 実施例 3 カプセル剤 1 G Compound A20g, ratatoose 655g, and corn starch 28 were combined, and a 10% aqueous solution of Lj-o-1 cypropylcellulose 400g was added. This mixture was kneaded by a conventional method, granulated and dried to obtain a fine granule (containing 20 mg of active ingredient per l, 000 mg of fine granule) c Example 3 Capsule
常法により次の組成からなる力プセル剤を調製した。 A forcepsel having the following composition was prepared by a conventional method.
処方 化合物 A 20 mg Formulation Compound A 20 mg
了ビセル 99. 5 mg Ryobisel 99.5 mg
ステアリン酸マグネシウム 0. 5 mg Magnesium stearate 0.5 mg
120 mg 120 mg
化合物 A200g、 アビセル 995gおよびステアリン酸マグネシウム 5gを常法により混合し た。 この混合物をカプセル充填機 （Zanas i社製， L Z— 64型） により、 ハードカプセル 4号 （ 1カプセルあたり 120mg容量） に充¾し、 カプセル剂 （ 1カプセルあたり活性成 分 20iiigを含有する） を得た。 200 g of Compound A, 995 g of Avicel and 5 g of magnesium stearate were mixed by a conventional method. This mixture was filled into Hard Capsule No. 4 (120 mg capacity per capsule) using a capsule filling machine (Zanasi, LZ-64 type) to obtain capsules (containing 20iiig of active ingredient per capsule). Was.
実施例 4 注射剤 Example 4 Injection
常法により次の組成からなる注射剤を調製した。 An injection having the following composition was prepared by a conventional method.
処方 化合物 A 2 mg Formulation Compound A 2 mg
精製ダイズ油 200 mg Refined soybean oil 200 mg
精製卵黄レシチン 24 mg Purified egg yolk lecithin 24 mg
注射用グリセリン 50 mg Glycerin for injection 50 mg
注射用蒸留水 1. 72 ml 1.72 ml of distilled water for injection
2. 00 ml 2.00 ml
化合物 A lgを精製ダイズ lOOgに溶解させ、 精製卵黄レシチン 12gおよび注射用グリセ リン 25gを加えた。 この混合物を常法により注射用蒸留水で 1000mlとして練合 ·乳化し た。 得られた分散液を のディスポ一ザブル型メンブランフィルターを用いて無 菌濾過後、 ガラスバイアルに 2mlずつ無菌的に充塡して、 注射剤 （ 1バイアルあたり活 性成分 2mgを含有する） を得た。 Compound Alg was dissolved in purified soy lOOg, and purified egg yolk lecithin 12 g and glycerin for injection 25 g were added. This mixture was kneaded and emulsified in a conventional manner to 1000 ml with distilled water for injection. The resulting dispersion is aseptically filtered using a disposable membrane filter, and then aseptically filled into glass vials in 2 ml increments to obtain an injection (containing 2 mg of active ingredient per vial). Was.
実施例 5 肛門坐剤 Example 5 Rectal suppositories
常法により次の組成からなる直腸投与の製剤を調製した。 A formulation for rectal administration having the following composition was prepared by a conventional method.
された^ ：( 則 91)
処方 化合物 Λ 2. mg It was ^: (rule 91) Prescription compound Λ 2. mg
ゥィテブゾール Η 1 678. 8 mg Ditebsol Η 1 678.8 mg
ゥィテブゾール Ε 7 5 290. 9 mg Zitebsol Ε 7 5 290.9 mg
第一リン酸カリウム 13. 6 mg Potassium monophosphate 13.6 mg
第二リ ン酸ナトリウム 14. 2 mg Sodium diphosphonate 14.2 mg
1000 mg 1000 mg
ウイテブゾール1 M H 1 5 (ダイナマイ トノーベル社製） 678. 8gおよびウイテプゾ一ル ™ E 7 5 (ダイナマイ 卜ノーベル社製） 290. 9gを 40~50UCで溶融させた。 これに化合物 A 2. 5g、 第一リン酸カリウム 13. 6gおよび第二リン酸ナトリゥム 14. 2gをそれぞれ均一 に混合分散させた。 ついで該混合分散したものをプラスチック製の坐剤の型に充^した 後、 徐々に冷却して肛門坐剤 （1製剤あたり活性成分 2. 5mgを含有する） を得た。 678.8 g of Witebzole 1 M H 15 (manufactured by Dynamite Nobel) and 290.9 g of Witepzol ™ E75 (manufactured by Dynamite Nobel) were melted at 40 to 50 U C. 2.5 g of Compound A, 13.6 g of potassium monophosphate and 14.2 g of sodium diphosphate were uniformly mixed and dispersed therein. The mixture was dispersed and filled into a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
実施例 6 錠剤 Example 6 Tablet
常法により次の組成からなる錠剤を調製した。 A tablet having the following composition was prepared by a conventional method.
処方 化合物 F 20 mg Formulation Compound F 20 mg
ラク トース 143. 4 mg Lactose 143.4 mg
馬鈴薯でんぷん 30 mg Potato starch 30 mg
ヒドロキシプロピルセルロ-ス 6 mg Hydroxypropyl cellulose 6 mg
ステアリ ン酸マグネシウム 0. 6 mg Magnesium stearate 0.6 mg
200 mg 200 mg
化合物 F 40g、 ラク トース 286. 8gおよび馬鈴薯でんぷん 60gを混合し、 ヒドロキシプ 口ピルセルロースの 10 水溶液 120gを加えた。 この混合物を常法により練合し、 造粒し て乾燥させた後、 整粒し打錠用顆粒とした。 これにステアリン酸マグネシウム 1. 2gを加 えて混合し、 径 8mmの杵をもった打錠機 （菊水社製 R T— 1 5型） で打錠を行って、 錠 剤 （ 1錠あたり活性成分 20mgを含有する） を得た。 Compound F (40 g), lactose (286.8 g), and potato starch (60 g) were mixed, and a 10 aqueous solution of hydroxypyruxyl cellulose was added (120 g). The mixture was kneaded by a conventional method, granulated, dried, and then sized to obtain granules for tableting. To this, add 1.2 g of magnesium stearate, mix and compress with a tableting machine (RT-15 type, manufactured by Kikusui) having a punch of 8 mm in diameter. Tablets (20 mg of active ingredient per tablet) (Containing).
実施例 7 注射剤 Example 7 Injection
常法により次の組成からなる注射剤を調製した。
処方 化合物ド リ mg An injection having the following composition was prepared by a conventional method. Formulation compound dolly mg
精製ダイズ油 200 mg Refined soybean oil 200 mg
精製卵黄レシチン 24 mg Purified egg yolk lecithin 24 mg
注射用グリセリン 50 mg Glycerin for injection 50 mg
注射用蒸留水 1. 72 ml 1.72 ml of distilled water for injection
2. 00 ml 2.00 ml
化合物 F lgを精製ダイズ lOOgに溶解させ、 精製卵黄レシチン 12gおよび注射用グリセ リン 25gを加えた。 この混合物を常法により注射用蒸留水で 1000mlとして練合 ·乳化し た。 得られた分散液を 0. 2 i mのディスポ一ザブル型メンブランフィルターを用いて無 菌濾過後、 ガラスバイアルに 2mlずつ無菌的に充塡して、 注射剤 （ 1バイアルあたり活 性成分 2mgを含有する） を得た。 Compound Flg was dissolved in purified soy lOOg, and purified egg yolk lecithin 12 g and glycerin for injection 25 g were added. This mixture was kneaded and emulsified in a conventional manner to 1000 ml with distilled water for injection. The resulting dispersion was aseptically filtered using a 0.2 im disposable membrane filter, and then aseptically filled into glass vials in 2 ml increments for injection (containing 2 mg of active ingredient per vial). To).
実施例 8 肛門坐剤 Example 8 Rectal suppository
常法により次の組成からなる直腸投与の製剤を調製した。 A formulation for rectal administration having the following composition was prepared by a conventional method.
処方 化合物 F 2. 5 mg Formulation Compound F 2.5 mg
ゥィテプゾ一ル H 1 5 678. 8 mg Diepzol H 15 678.8 mg
ゥィテブゾール E 7 5 290. 9 mg Ditebsol E 7 5 290.9 mg
第一リン酸カリウム 13. 6 mg Potassium monophosphate 13.6 mg
第二リン酸ナトリウム 14. 2 mg Sodium diphosphate 14.2 mg
1000 mg 1000 mg
ゥィテプゾ一ル Ί Μ Η 1 5 (ダイナマイ トノ一ベル社製） 678. 8gおよびゥィテブゾール ΐΜ Ε 7 5 (ダイナマイ トノーベル社製） 290. 9gを 40〜50°Cで溶融させた。 これに化合物 F 2. 5g、 第一リン酸カリウム 13. 6gおよび第二リン酸ナトリウム 14. 2gをそれぞれ均一に 混合分散させた。 ついで該混合分散したものをプラスチック製の坐剤の型に充塡した後、 徐々に冷却して肛門坐剤 （ 1製剤あたり活性成分 2. 5mgを含有する） を得た。 The Witepuzo Ichiru Ί Μ Η (manufactured Dainamai Tonoichi Bell) 1 5 678. 8g and Witebuzoru ΐΜ Ε 7 5 (Dainamai Tonoberu Co.) 290. 9 g were melted at 40 to 50 ° C. 2.5 g of Compound F, 13.6 g of potassium monophosphate and 14.2 g of sodium diphosphate were uniformly mixed and dispersed therein. The mixed and dispersed product was filled in a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
実施例 9 肛門坐剤 Example 9 Rectal suppository
常法により次の組成からなる直腸投与の製剤を調製した。
処方 化合物 B 2. 5 mg A formulation for rectal administration having the following composition was prepared by a conventional method. Formulation Compound B 2.5 mg
ゥィテブゾール H 1 5 678. 8 mg Ditebsol H 15 678. 8 mg
ゥィテブゾール E 7 5 290. 9 mg Ditebsol E 7 5 290.9 mg
第一リン酸カリウム 13. 6 mg Potassium monophosphate 13.6 mg
第二リン酸ナトリウム 14. 2 mg Sodium diphosphate 14.2 mg
1000 mg 1000 mg
ゥィテブゾール'1 M H 1 5 (ダイナマイ トノ一ベル社製） 678. 8gおよびゥィテプゾ一ル1 M E 7 5 (ダイナマイ トノーベル社製） 290. 9gを 40〜50°Cで溶融させた。 これに化合物 B 2. 5g、 第一リン酸カリウム 13. 6gおよび第二リン酸ナトリゥム 14. 2gをそれぞれ均一に 混合分散させた。 ついで該混合分散したものをプラスチック製の坐剤の型に充塡した後、 徐々に冷却して肛門坐剤 （1製剤あたり活性成分 2. 5mgを含有する） を得た。 68.8 g of Ditebzol ' 1 MH 15 (manufactured by Dynamite Tonobel) and 290.9 g of ditebsol 1 M E75 (manufactured by Dynamite Tonobel) were melted at 40 to 50 ° C. Compound B (2.5 g), potassium monophosphate (13.6 g) and sodium diphosphate (14.2 g) were uniformly mixed and dispersed therein. The mixture was dispersed and filled into a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
実施例 1 0 肛門坐剤 Example 10 Rectal Suppository
常法により次の組成からなる直腸投与の製剤を調製した。 A formulation for rectal administration having the following composition was prepared by a conventional method.
処方 化合物 R 2. 5 mg Formulation Compound R 2.5 mg
ウイテブゾール H 1 5 678. 8 mg Witebsol H 15678.8 mg
ウイテブゾール E 7 5 290. 9 mg Witebsol E 7 5 90.9 mg
第一リン酸カリウム 13. 6 mg Potassium monophosphate 13.6 mg
第二リン酸ナトリウム 14. 2 mg Sodium diphosphate 14.2 mg
1000 mg 1000 mg
ゥィテプゾ一ル1 ·Μ Η 1 5 (ダイナマイ トノ一ベル社製） 678. 8gおよびゥィテブゾール1 M E 7 5 (ダイナマイ トノーベル社製） 290. 9gを 40〜50°Cで溶融させた。 これに化合物 R 2. 5g、 第一リン酸カリウム 13. 6gおよび第二リン酸ナトリウム 14. 2gをそれぞれ均一に 混合分散させた。 ついで該混合分散したものをプラスチック製の坐剤の型に充填した後、 徐々に冷却して肛門坐剤 （1製剤あたり活性成分 2. 5mgを含有する） を得た。 61.8 g of diptosol 1 · Μ Η 15 (manufactured by Dynamite Tonobel) and 290.9 g of ditebsol 1 ME75 (manufactured by Dynamite Nobel) were melted at 40 to 50 ° C. 2.5 g of Compound R, 13.6 g of potassium monophosphate and 14.2 g of sodium diphosphate were uniformly mixed and dispersed therein. Then, the mixed and dispersed product was filled in a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
実施例 1 1 肛門坐剤 Example 11 1 Rectal suppository
常法により次の組成からなる直腸投与の製剤を調製した。
処方 化合物 X 2. Ό mg A formulation for rectal administration having the following composition was prepared by a conventional method. Formulation compound X 2.Ό mg
ゥィテプゾ一ル H 1 5 678. 8 mg Diepzol H 15 678.8 mg
ゥィテプゾ一ル E 7 5 290. 9 mg Diepsol E 7 5 290.9 mg
第一りン酸カリウム 13. 6 mg Potassium monophosphate 13.6 mg
第二りン酸ナトリウム 14. 2 mg Sodium dibasic acid 14.2 mg
1000 mg 1000 mg
ゥィテブゾール'1 M H 1 5 (ダイナマイ トノ一ベル社製） 678. 8gおよびゥィテブゾール1 M E 7 5 (ダイナマイ 卜ノーベル社製） 290. 9gを 40〜50°Cで溶融させた。 これに化合物 X 2. 5gs 第一リン酸カリウム 13. 6gおよび第二リン酸ナトリウム 14. 2gをそれぞれ均一に 混合分散させた。 ついで該混合分散したものをプラスチック製の坐剤の型に充塡した後、 徐々に冷却して肛門坐剤 （ 1製剤あたり活性成分 2. 5mgを含有する） を得た。 678.8 g of Ditebsol ' 1 MH 15 (manufactured by Dynamite Tonobel) and 290.9 g of Ditebsol 1 M E75 (manufactured by Dynamit Nobel) were melted at 40 to 50 ° C. This compound X 2. 5 g s potassium phosphate monobasic 13. 6 g and dibasic sodium phosphate 14. 2 g were uniformly mixed and dispersed, respectively. The mixed and dispersed product was filled in a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
実施例 1 2 肛門坐剤 Example 1 2 Rectal suppository
常法により次の組成からなる直腸投与の製剤を調製した。 A formulation for rectal administration having the following composition was prepared by a conventional method.
処方 化合物 AG 2. 5 mg Formulation Compound AG 2.5 mg
ゥィテブゾール H 1 5 678. 8 mg Ditebsol H 15 678. 8 mg
ウイテブゾール E 7 5 290. 9 mg Witebsol E 7 5 90.9 mg
第一リン酸カリウム 13. 6 mg Potassium monophosphate 13.6 mg
第二リン酸ナトリウム 14. 2 mg Sodium diphosphate 14.2 mg
1000 mg 1000 mg
ゥィテプゾ一ル ' Μ Η 1 5 (ダイナマイ トノ一ベル社製） 678. 8gおよびゥィテブゾール1 M E 7 5 (ダイナマイ 卜ノーベル社製） 290. 9gを 40〜50°Cで溶融させた。 これに化合物 AG 2. 5g、 第一リン酸カリゥム 13. 6gおよび第二リン酸ナ卜リゥム 14. 2gをそれぞれ均一に 混合分散させた。 ついで該混合分散したものをプラスチック製の坐剤の型に充塡した後、 徐々に冷却して肛門坐剤 （1製剤あたり活性成分 2. 5mgを含有する） を得た。 The Witepuzo Ichiru 'Micromax Eta (manufactured Dainamai Tonoichi Bell) 1 5 678. 8g and Witebuzoru (manufactured Dainamai Bok Nobel) 1 M E 7 5 290. 9g melted at 40 to 50 ° C. 2.5 g of Compound AG, 13.6 g of potassium monophosphate and 14.2 g of sodium diphosphate were uniformly mixed and dispersed therein. The mixture was dispersed and filled into a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 mg of active ingredient per preparation).
実施例 1 3 肛門坐剤 Example 1 3 Rectal suppository
常法により次の組成からなる直腸投与の製剤を調製した。
処方 化合物 All 2. 5 mg A formulation for rectal administration having the following composition was prepared by a conventional method. Formulation compound All 2.5 mg
ゥィテプゾ一ル H 1 5 678. 8 mg Diepzol H 15 678.8 mg
ウイテプゾ一ル E 7 5 290. 9 mg Witepsol E 7 5 290.9 mg
第一リン酸カリウ厶 13. 6 mg 13.6 mg potassium phosphate
第二リン酸ナトリウム 14. 2 mg Sodium diphosphate 14.2 mg
1000 mg 1000 mg
ゥィテプゾ一ル ' Μ Η 1 5 (ダイナマイ トノ一ベル社製） 678. 8gおよびゥィテブゾール' M E 7 5 (ダイナマイ トノーベル社製） 290. 9gを 40〜50°Cで溶融させた。 これに化合物 AH 2, 5g、 第一リン酸カリウム 13. 6gおよび第二リン酸ナトリウム 14. 2gをそれぞれ均一に 混合分散させた。 ついで該混合分散したものをプラスチック製の坐剤の型に充塡した後、 徐々に冷却して肛門坐剤 （1製剤あたり活性成分 2. 5nigを含有する） を得た。 The Witepuzo Ichiru 'Micromax Eta (manufactured Dainamai Tonoichi Bell) 1 5 678. 8g and Witebuzoru' M E 7 5 (Dainamai Tonoberu Co.) 290. 9 g were melted at 40 to 50 ° C. Compound AH (2.5 g), potassium monophosphate (13.6 g) and sodium diphosphate (14.2 g) were uniformly mixed and dispersed therein. The mixture was dispersed and filled into a plastic suppository mold, and then gradually cooled to obtain a rectal suppository (containing 2.5 nig of active ingredient per preparation).
産業上の利用可能性 Industrial applicability
本発明によれば、 便通異常の治療剤が提供される。
According to the present invention, a therapeutic agent for bowel movement disorder is provided.
Claims
詰 求 の 範 囲 Scope of request
i i
又 or
式 Expression
(I)
(I)
〔式中、 R1 、 IT および R:' は同一または異なって、 水素または低級アルキルを表し、 X1 および X2 は同一または異なって、 酸素または硫黄を表し、 Qは、 低級アルキル、 式 （a)
[Wherein, R 1 , IT and R : 'are the same or different and represent hydrogen or lower alkyl, X 1 and X 2 are the same or different and represent oxygen or sulfur, Q is lower alkyl, a)
(式中、 Z 1および Z 2は水素または Z 1および Z 2が一緒になつて酸素を表す） (Wherein Z 1 and Z 2 represent hydrogen or oxygen together with Z 1 and Z 2 )
式 （b)
Equation (b)
(式中、 Yは単結合またはアルキレンを表す） 、 式 （c) (Wherein, Y represents a single bond or alkylene), formula (c)
(式中、 nは 0または 1を意味し、 Yは前記と同義である） 、 式 （d)
(式中、 二 は単結合または二重結合を表し、 Yは前^と向義である） ま は式 （e) (In the formula, n means 0 or 1, and Y has the same meaning as described above.) (Wherein, 2 represents a single bond or a double bond, and Y has the same meaning as the preceding ^).
R4 R 4
— ( (c) — ((C)
R5 R 5
(式中、 R4および R「'は同一または異なって、 置換もしくは非置換の脂環式アルキル を表す） を表す〕 で表されるキサンチン誘導体またはその薬理的に許容される塩を有効 成分とする便通異常の治療剤。 (Wherein, R 4 and R “′ are the same or different and each represents a substituted or unsubstituted alicyclic alkyl.)] Or a pharmaceutically acceptable salt thereof as an active ingredient A therapeutic agent for bowel movement disorders.
2. 一般式 （ I ) 2. General formula (I)
式 （a) Equation (a)
(I)
(I)
〔式中、 R' 、 R2 および R:1 は同一または異なって、 水素または低級アルキルを表し- X' および X2 は同一または異なって、 酸素または硫黄を表し、 Qは、 低級アルキル、 式 （a) ひ 22 (a) Wherein, R ', R 2 and R: 1 are the same or different and each represents hydrogen or lower alkyl - X' and X 2 are the same or different, represents oxygen or sulfur, Q is lower alkyl, wherein (a) shed 22 (a)
(式中、 Z1および Z2は水素または Z1および Z2が一緒になつて酸素を表す） 、 式 （b) - I ヽ (Wherein Z 1 and Z 2 represent hydrogen or oxygen together with Z 1 and Z 2 ), formula (b) -I ヽ
(b) (b)
(式中、 Yは単結合またはアルキレンを表す） 、 式 （c) (Wherein, Y represents a single bond or alkylene), formula (c)
(式中、 ― は単結合または二重結合を表し、 Yは前記と同義である） または式 （e) Wherein-represents a single bond or a double bond, and Y has the same meaning as described above.
R4 R 4
— (e) — (E)
(式中、 ITおよび R5は同一または異なって、 置換もしくは非置換の脂環式アルキル を表す） を表す〕 で表されるキサンチン誘導体またはその薬理的に許容される塩の有効 量を便通異常の患者へ投与することからなる便通異常の治療方法。 (Wherein, IT and R 5 are the same or different and each represents a substituted or unsubstituted alicyclic alkyl).] The effective amount of the xanthine derivative represented by the formula For treating bowel abnormalities, comprising administering to patients.
3. 便通異常の治療剤の製造のための一般式 （ I ) 3. General formula for the manufacture of a therapeutic agent for bowel movement disorders (I)
〔式中、 R1 、 R2 および R:i は同一または異なって、 水素または低級アルキルを表し- X1 および X2 は同一または異なって、 酸素または硫黄を表し、 Qは、 低級アルキル、 式 （a)
[Wherein, R 1 , R 2 and R : i are the same or different and represent hydrogen or lower alkyl, -X 1 and X 2 are the same or different and represent oxygen or sulfur, and Q is a lower alkyl; (A)
(式中、 Z 1および Z 2は水素または Z 1および Z 2がー緒になつて酸素を表す） (Wherein, Z 1 and Z 2 represent hydrogen or oxygen linked to Z 1 and Z 2 )
式 （b)
Equation (b)
(式中、 Yは単結合またはアルキレンを表す） 、 式 （c)
(Wherein, Y represents a single bond or alkylene), formula (c)
(式中、 nは 0または 1を意味し、 Yは前記と同義である） 、 式 （d)
(In the formula, n means 0 or 1, and Y has the same meaning as described above.)
(式中、 二 は単結合または二重結合を表し、 Yは前記と同義である） または式 （e ) (Wherein, 2 represents a single bond or a double bond, and Y has the same meaning as described above).
R4 R 4
— < (e) — <(E)
(式中、 ITおよび Rf 'は同一または異なって、 置換もしくは非置換の脂環式アルキルを 表す） を表す〕 で表されるキサンチン誘導体またはその薬理的に許容される塩の使用。
(Wherein IT and R f ′ are the same or different and each represents a substituted or unsubstituted alicyclic alkyl).] Or a pharmacologically acceptable salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1088693 | 1993-01-26 | ||
| JP5/10886 | 1993-01-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994016702A1 true WO1994016702A1 (en) | 1994-08-04 |
Family
ID=11762804
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1994/000096 WO1994016702A1 (en) | 1993-01-26 | 1994-01-25 | Remedy for irregular bowel movement |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1994016702A1 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995011904A1 (en) * | 1993-10-28 | 1995-05-04 | University Of Florida Research Foundation, Inc. | Novel a1 adenosine receptor agonists and antiagonists |
| WO1998005334A1 (en) * | 1996-08-07 | 1998-02-12 | Kyowa Hakko Kogyo Co., Ltd. | Fat emulsion containing xanthine derivative |
| US5736528A (en) * | 1993-10-28 | 1998-04-07 | University Of Florida Research Foundation, Inc. | N6 -(epoxynorborn-2-yl) adenosines as A1 adenosine receptor agonists |
| US5789416A (en) * | 1996-08-27 | 1998-08-04 | Cv Therapeutics | N6 mono heterocyclic substituted adenosine derivatives |
| WO1999054331A1 (en) * | 1998-04-16 | 1999-10-28 | Boehringer Ingelheim Pharma Kg | Novel asymmetrically substituted xanthine derivatives, method for producing them and their use as medicaments with an adenosine-antagonistic effect |
| WO2001034610A1 (en) * | 1999-11-12 | 2001-05-17 | Biogen, Inc. | Polycycloalkylpurines as adenosine receptor antagonists |
| WO2001080893A1 (en) * | 2000-04-26 | 2001-11-01 | Eisai Co., Ltd. | Medicinal compositions promoting bowel movement |
| US6576619B2 (en) | 1999-05-24 | 2003-06-10 | Cv Therapeutics, Inc. | Orally active A1 adenosine receptor agonists |
| US6605600B1 (en) | 1999-11-12 | 2003-08-12 | Biogen, Incorporated | Adenosine receptor antagonists and methods of making and using the same |
| US7160892B2 (en) | 2001-10-22 | 2007-01-09 | Eisai Co., Ltd. | Pyrimidone compounds and pharmaceutical compositions containing the same |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03173889A (en) * | 1989-09-01 | 1991-07-29 | Kyowa Hakko Kogyo Co Ltd | Xanthine derivative |
-
1994
- 1994-01-25 WO PCT/JP1994/000096 patent/WO1994016702A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03173889A (en) * | 1989-09-01 | 1991-07-29 | Kyowa Hakko Kogyo Co Ltd | Xanthine derivative |
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995011904A1 (en) * | 1993-10-28 | 1995-05-04 | University Of Florida Research Foundation, Inc. | Novel a1 adenosine receptor agonists and antiagonists |
| US5631260A (en) * | 1993-10-28 | 1997-05-20 | University Of Florida Research Foundation, Inc. | Xanthine epoxides as A1 adenosine receptor agonists and antagonists |
| US5668139A (en) * | 1993-10-28 | 1997-09-16 | University Of Flordia Research Foundation, Inc. | A1 adenosine receptor agonists and antagonists |
| US5736528A (en) * | 1993-10-28 | 1998-04-07 | University Of Florida Research Foundation, Inc. | N6 -(epoxynorborn-2-yl) adenosines as A1 adenosine receptor agonists |
| US5998387A (en) * | 1993-10-28 | 1999-12-07 | University Of Florida Research Foundation, Inc. | Method for using A1 adenosine receptor agonists |
| WO1998005334A1 (en) * | 1996-08-07 | 1998-02-12 | Kyowa Hakko Kogyo Co., Ltd. | Fat emulsion containing xanthine derivative |
| US6210687B1 (en) | 1996-08-07 | 2001-04-03 | Kyowa Hakko Kogyo Co., Ltd. | Fat emulsion containing xanthine derivative |
| JP2008231117A (en) * | 1996-08-07 | 2008-10-02 | Kyowa Hakko Kogyo Co Ltd | Fat emulsion containing xanthine derivative |
| US5789416A (en) * | 1996-08-27 | 1998-08-04 | Cv Therapeutics | N6 mono heterocyclic substituted adenosine derivatives |
| WO1999054331A1 (en) * | 1998-04-16 | 1999-10-28 | Boehringer Ingelheim Pharma Kg | Novel asymmetrically substituted xanthine derivatives, method for producing them and their use as medicaments with an adenosine-antagonistic effect |
| US6576619B2 (en) | 1999-05-24 | 2003-06-10 | Cv Therapeutics, Inc. | Orally active A1 adenosine receptor agonists |
| EP2070930A1 (en) * | 1999-11-12 | 2009-06-17 | Biogen Idec MA, Inc. | Polycycloalkylpurines as adenosine receptor antagonists |
| US6605600B1 (en) | 1999-11-12 | 2003-08-12 | Biogen, Incorporated | Adenosine receptor antagonists and methods of making and using the same |
| US6649600B1 (en) | 1999-11-12 | 2003-11-18 | Biogen, Inc. | Adenosine receptor antagonists and methods of making and using the same |
| WO2001034610A1 (en) * | 1999-11-12 | 2001-05-17 | Biogen, Inc. | Polycycloalkylpurines as adenosine receptor antagonists |
| JP2003513982A (en) * | 1999-11-12 | 2003-04-15 | バイオジェン インコーポレイテッド | Polycycloalkylpurines as adenosine receptor antagonists |
| US7579354B2 (en) | 1999-11-12 | 2009-08-25 | Kiesman William F | Adenosine receptor antagonists and methods of making and using the same |
| BG65720B1 (en) * | 1999-11-12 | 2009-08-31 | Biogen, Inc. | Polycycloalkylpurines as adenosine receptor antagonists |
| EP2305684A1 (en) * | 1999-11-12 | 2011-04-06 | Biogen Idec MA Inc. | Poycyloalkylpurines as adenosine receptor antagonists |
| WO2001080893A1 (en) * | 2000-04-26 | 2001-11-01 | Eisai Co., Ltd. | Medicinal compositions promoting bowel movement |
| US7189717B2 (en) | 2000-04-26 | 2007-03-13 | Eisai Co., Ltd. | Medicinal compositions promoting bowel movement |
| EP1510222A3 (en) * | 2000-04-26 | 2007-05-23 | Eisai R&D Management Co., Ltd. | Medicinal compositions promoting bowel movement |
| KR100782091B1 (en) * | 2000-04-26 | 2007-12-04 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Medicinal compositions promoting bowel movement |
| US7160892B2 (en) | 2001-10-22 | 2007-01-09 | Eisai Co., Ltd. | Pyrimidone compounds and pharmaceutical compositions containing the same |
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