WO2009157397A1 - Therapeutic agent for intestinal tract injury accompanying administration of a non-steroid anti-inflammatory agent - Google Patents

Therapeutic agent for intestinal tract injury accompanying administration of a non-steroid anti-inflammatory agent Download PDF

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WO2009157397A1
WO2009157397A1 PCT/JP2009/061286 JP2009061286W WO2009157397A1 WO 2009157397 A1 WO2009157397 A1 WO 2009157397A1 JP 2009061286 W JP2009061286 W JP 2009061286W WO 2009157397 A1 WO2009157397 A1 WO 2009157397A1
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alkyl
injury
pharmaceutical composition
formula
group
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PCT/JP2009/061286
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French (fr)
Japanese (ja)
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隆 興井
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日本新薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a non-steroid containing a heterocyclic derivative represented by the following general formula (1) (hereinafter referred to as “the present heterocyclic derivative (1)”) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention relates to a pharmaceutical composition for treating intestinal injury associated with the administration of sex anti-inflammatory agents (hereinafter referred to as “NSAIDs”).
  • NSAIDs sex anti-inflammatory agents
  • R 1 and R 2 are the same or different and are each a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy
  • R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl
  • R 5 represents a hydrogen atom, an alkyl or a halogen atom
  • Y represents N or N ⁇ O
  • A represents NR 6 and R 6 represents a hydrogen atom, alkyl, alkenyl or cycloalkyl
  • D represents alkylene or alkenylene optionally substituted with hydroxy, or A and D together represent a divalent group represented by the following formula (2); [In the formula (2), r represents
  • E represents phenylene or a single bond, or D and E together represent a divalent group represented by the following formula (3); [In the formula (3), u represents an integer of 0 to 2, and v represents 0 or 1. ] G represents O, S, SO or SO 2 ; Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl or a group represented by the following formula (4).
  • R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkyl Any one of the following 1) to 4) which may be substituted with 1 to 3 substituents selected from the group consisting of amino, dialkylamino, carboxy, cyano and nitro; 1) alkyl, 2) aryl, 3) Aryloxy, 4) A heterocyclic group. ]
  • this heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof has already been reported to be useful as a PGI 2 receptor agonist in the treatment of pulmonary hypertension and obstructive arteriosclerosis (for example, see Patent Document 1).
  • An object of the present invention is mainly to provide a novel pharmaceutical composition for treating intestinal injury associated with administration of NSAIDs.
  • the present inventor has found that the present heterocyclic derivative (1) has a therapeutic effect on small intestinal ulcer caused by administration of indomethacin, which is one of NSAIDs, in rats, and has completed the present invention.
  • the present invention includes, for example, a pharmaceutical composition for treating intestinal injury associated with administration of NSAIDs (hereinafter referred to as “the composition of the present invention” containing the present heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof as an active ingredient. ) ").
  • FIG. 1 shows the inhibition of small intestinal ulcer formation with 2- ⁇ 4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy ⁇ acetic acid (hereinafter referred to as “Compound A”). Shows the effect.
  • the vertical axis represents the number of small intestinal ulcers.
  • FIG. 2 shows 2- ⁇ 4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy ⁇ -N- (methylsulfonyl) acetamide (hereinafter referred to as “Compound B”). Shows the inhibitory action on the formation of small intestinal ulcer.
  • the vertical axis represents the number of small intestinal ulcers.
  • R 1 and R 2 are the same or different and are phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, alkyl and alkoxy;
  • R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl;
  • R 5 is a hydrogen atom, Y is N,
  • A is NR 6 ,
  • R 6 is alkyl,
  • D is alkylene
  • E is a single bond,
  • G O,
  • Q is carboxy or a group represented by formula (4),
  • R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl Any one of the following 1) to 4) optionally substituted with 1 to 3 substituents selected from the group consisting of alkylsulfonyl, hydroxy, amino
  • Compound A and Compound B are preferable.
  • alkyl in the present invention is a linear or branched one having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Examples include butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. In particular, those having 1 to 4 carbon atoms are preferred.
  • Haloalkyl “Haloalkyl”, “arylalkyl”, “alkylthio”, “alkoxyalkyl”, “alkylsulfonyl”, “monoalkylamino”, “dialkylamino”, “monoalkylcarbazoyl” and “dialkylcarbamoyl” in the present invention
  • Examples of the moiety include the same alkyl groups as those described above.
  • alkoxy is a straight or branched chain having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- Examples include butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy and isohexyloxy. In particular, those having 1 to 4 carbon atoms are preferred.
  • alkoxy moiety of “alkoxycarbonyl” and “alkoxyalkyl” in the present invention include the same as the above alkoxy.
  • alkenyl is linear or branched having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, Examples thereof include 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. In particular, those having 3 or 4 carbon atoms are preferred.
  • cycloalkyl in the present invention include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, those having 5 to 7 carbon atoms are preferred.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • aryl includes 6 to 10 carbon atoms, such as phenyl, 1-naphthyl and 2-naphthyl. In particular, phenyl is preferred.
  • arylalkyl As the aryl moiety of “arylalkyl” and “aryloxy” in the present invention, the same aryl as the above aryl can be exemplified.
  • alkylene in the present invention, linear or branched ones having 1 to 8 carbon atoms such as methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, tetramethylene, pentamethylene, Examples include hexamethylene, heptamethylene, and octamethylene. In particular, those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are particularly preferred.
  • alkenylene in the present invention, linear or branched ones having 2 to 8 carbon atoms such as ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 4-methyl-3-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, 1-heptenylene, 2- Examples include heptenylene, 3-heptenylene, 4-heptenylene, 5-heptenylene, 6-heptenylene, 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-octenylene, 6-octenylene and 7-octenylene. .
  • those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are preferred, and those
  • heterocyclic group examples include the following (1) or (2).
  • an atom or a sulfur atom such a nitrogen atom or sulfur atom may form an oxide.
  • piperidino, piperazinyl, 3-methylpiperazin-1-yl, homopiperazinyl, monophorino, thiomonophorino, 1-pyrrolidinyl, 2-pyrrolidinyl, 2-tetrahydrofuranyl can be mentioned.
  • the present heterocyclic derivative (1) can be synthesized by the method described in Patent Document 1 (International Publication No. 02/088084 pamphlet).
  • the present heterocyclic derivative (1) can be used as a medicine as a free base or acid, but can also be used in the form of a medically acceptable salt by a known method.
  • a salt of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, or hydrobromic acid, or acetic acid, List organic acid salts of tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, or camphorsulfonic acid Can do.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium
  • the present heterocyclic derivative (1) has geometric isomers (Z-form and E-form), and each geometric isomer and a mixture thereof are also included in the present heterocyclic derivative (1).
  • some of the heterocyclic derivatives (1) have asymmetric carbons, but each optical isomer and their racemates are also included in the heterocyclic derivatives (1).
  • the optical isomer is obtained from the racemate obtained as described above using its basicity and using an optically active acid (for example, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid), It can be optically resolved by a known method, or can be produced using a previously prepared optically active compound as a raw material.
  • the NSAIDs according to the present invention are not particularly limited, and examples thereof include diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib and the like.
  • the intestinal tract injury according to the present invention is not particularly limited as long as it occurs in the duodenum, small intestine, and large intestine, and examples thereof include mucosal injury such as erosion that occurs in the duodenum, small intestine, and large intestine, and ulcers.
  • composition of the present invention comprises the present heterocyclic derivative (1) in a range of 0.01 to 99.5%, preferably 0.5%, as it is or in a pharmaceutically acceptable non-toxic and inert carrier. It is contained within the range of ⁇ 90%.
  • the carrier examples include solid, semi-solid or liquid diluents, fillers, and other formulation aids. One or more of these can be used.
  • composition of the present invention is a solid or liquid dosage unit, and is a powder, capsule, tablet, dragee, granule, powder, suspension, liquid, syrup, elixir, troche, etc.
  • parenteral preparations such as injections and suppositories can be used. It may be a sustained-release preparation.
  • oral preparations such as tablets are particularly preferable.
  • the powder can be produced by making the present heterocyclic derivative (1) fine.
  • the powder can be produced by making the present heterocyclic derivative (1) fine and then mixing it with a finely divided pharmaceutical carrier such as edible carbohydrates such as starch and mannitol.
  • a finely divided pharmaceutical carrier such as edible carbohydrates such as starch and mannitol.
  • flavor, etc. can be added arbitrarily.
  • Capsules are manufactured by first filling the powdered powdered powder or powder as described above into granules as described in the section of tablets, for example, into capsule shells such as gelatin capsules. can do.
  • Lubricants and fluidizers such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol are mixed with powdered powder and powder, and then filled. It can also be manufactured.
  • disintegrators and solubilizers are added, such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, sodium carbonate
  • the fine powder of the present heterocyclic derivative (1) can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant and wrapped in a gelatin sheet to form a soft capsule.
  • Tablets are manufactured by adding excipients to the powdered heterocyclic derivative (1) to form a powder mixture, granulating or slugging, then adding a disintegrant or lubricant, and then tableting. can do.
  • the powder mixture can be produced by mixing the present heterocyclic derivative (1), which has been appropriately pulverized, with a diluent or a base.
  • a binder for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol
  • a dissolution retardant for example, paraffin
  • a resorbent for example, a quaternary salt
  • An adsorbent for example, bentonite, kaolin or the like
  • the powder mixture can first be moistened with a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and pulverized into granules.
  • a tablet can also be manufactured by directly compressing after mixing this heterocyclic derivative (1) with a fluid inert carrier, without going through the granulation and slagging steps as described above. it can. Film tablets and sugar coatings can be applied to the tablets thus produced.
  • a transparent or translucent protective coating made of a shellac hermetic coating, a coating of sugar or polymer material and a polishing coating made of wax can also be used.
  • oral dosage forms such as solutions, syrups, troches, and elixirs may also be in dosage unit form so that a given amount contains a certain amount of the heterocyclic derivative (1).
  • the syrup can be produced by dissolving the present heterocyclic derivative (1) in a suitable flavor aqueous solution.
  • An elixir can be produced by using a non-toxic alcoholic carrier.
  • the suspending agent can be produced by dispersing the present heterocyclic derivative (1) in a non-toxic carrier. If necessary, solubilizers and emulsifiers (for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (for example, peppermint oil, saccharin), etc. may be added. it can.
  • solubilizers and emulsifiers for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • preservatives for example, peppermint oil, saccharin, etc.
  • a dosage unit formulation for oral administration can be microencapsulated.
  • the formulation can also be extended in action time or sustained release by being coated or embedded in a polymer, wax or the like.
  • the parenteral preparation can take the form of a liquid dose unit for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension.
  • the parenteral preparation is prepared by suspending or dissolving a certain amount of the heterocyclic derivative (1) in a non-toxic liquid carrier suitable for injection purposes, for example, an aqueous or oily medium, and then suspending the suspension. Or it can manufacture by sterilizing a solution.
  • Non-toxic salts and salt solutions can be added to make the injection solution isotonic.
  • stabilizers, preservatives, emulsifiers, and the like can be added.
  • the suppository is obtained by dissolving the heterocyclic derivative (1) in a low-melting water-soluble or insoluble solid such as polyethylene glycol, cacao butter, semi-synthetic oil [for example, Witepsol (registered trademark)], higher esters ( For example, it can be prepared by dissolving or suspending in myristyl palmitate ester) or a mixture thereof.
  • a low-melting water-soluble or insoluble solid such as polyethylene glycol, cacao butter, semi-synthetic oil [for example, Witepsol (registered trademark)], higher esters ( For example, it can be prepared by dissolving or suspending in myristyl palmitate ester) or a mixture thereof.
  • the dose of the composition of the present invention varies depending on the patient's condition such as body weight and age, administration route, degree of symptom, etc., but generally the amount of the present heterocyclic derivative (1) is 1 for adults.
  • the range of 0.001 mg to 100 mg per day is appropriate, and the range of 0.01 mg to 10 mg is more preferable. In some cases, a lower dose may be sufficient, and vice versa.
  • it can be administered once to several times a day or at intervals of 1 day to several days.
  • Test example 1 (1) Test method Indomethacin (manufactured by Sigma) was orally administered at 20 mg / kg to non-fasting SD rats (male, 7 weeks old) (manufactured by SLC Japan). The test substance was administered 1 hour before and 9 hours after administration of indomethacin, and was orally administered twice a day on the next day and the next day after indomethacin administration. Three days after administration of indomethacin, the small intestine was removed and the number of small intestine ulcers was evaluated. As test substances, compound A (3 mg or 5 mg / kg) and compound B (3 mg or 5 mg / kg) were used. The test substance was administered suspended in a 0.5% methylcellulose aqueous solution.
  • Test example 2 In accordance with the method described in the literature (Nutr Hosp. 2008; 23 (4): 326-331), NSAIDs are administered to rats to cause intestinal injury. Pharmacology of Compound A and Compound B by administering Compound A or Compound B before or after administration of NSAIDs and examining changes in disaccharide hydrolase activity and tissue structure of the intestinal brush border membrane The effective effect.
  • Test example 3 Indomethacin is administered to rats according to the method described in the literature (J Pharmacol Sci 2007; 103: 40-47) to cause intestinal injury.
  • Compound A or Compound B before or after indomethacin administration, and examining changes in myeloperoxidase activity, changes in thiobarbituric acid reactant, changes in expression of inducible nitric oxide synthase mRNA, etc.
  • the pharmacological effects of Compound A and Compound B are evaluated.
  • Test example 4 Indomethacin is administered to rats according to the method described in the literature (Inflammopharmacology 2007; 15: 266-272) to cause intestinal injury.
  • the compound A or compound B is administered before or after indomethacin administration, and the pharmacological effects of the compound A and compound B are evaluated by examining changes in the number of intestinal bacteria and motility of the small intestine. .

Abstract

Disclosed is a pharmaceutical composition for treating intestinal tract injury accompanying administration of a non-steroid anti-inflammatory agent. Disclosed is a pharmaceutical composition for treating intestinal tract injury accompanying administration of a non-steroid anti-inflammatory agent, which contains as an active ingredient a heterocyclic derivative represented by general formula (1) or a pharmaceutically acceptable salt thereof. [EQUATION 1] In formula (1), R１ and R2, which can be the same or different, represent an optionally substituted aryl, R3 and R4, which can be the same or different, represent a hydrogen atom or alkyl, R5 represents a hydrogen atom, alkyl or a halogen atom, Y represents N or N→O, A represents NR6, R6 represents a hydrogen atom, alkyl or the like, D represents an optionally hydroxy substituted alkylene or alkenylene, E represents phenylene or a single bond, G represents O, S, or the like, and Q represents carboxy, alkoxycarbonyl, or the like.

Description

非ステロイド性抗炎症剤投与に伴う腸管傷害治療剤Treatment for intestinal injury associated with nonsteroidal anti-inflammatory drugs
　本発明は、次の一般式（１）で表される複素環誘導体（以下、「本複素環誘導体（１）」という。）又はその医薬上許容される塩を有効成分として含有する、非ステロイド性抗炎症剤（以下、「ＮＳＡＩＤｓ」という。）投与に伴う腸管傷害を治療するための医薬組成物に関するものである。
Figure JPOXMLDOC01-appb-C000005
 　式（１）中、Ｒ１、Ｒ２は、同一又は異なって、ハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる１～３個の置換基で置換されていてもよいアリールを表し；
　Ｒ３、Ｒ４は、同一又は異なって、水素原子又はアルキルを表し；
　Ｒ５は水素原子、アルキル又はハロゲン原子を表し；
　ＹはＮ又はＮ→Ｏを表し；
　ＡはＮＲ６を表し、Ｒ６は水素原子、アルキル、アルケニル又はシクロアルキルを表し；
　Ｄはヒドロキシで置換されていてもよいアルキレン又はアルケニレンを表すか、又はＡとＤとが一緒になって、次の式（２）で表される二価の基を表し；
Figure JPOXMLDOC01-appb-C000006
 　［式（２）中、ｒは０～２の整数を表し、ｑは２又は３を表し、ｔは０～４の整数をそれぞれ表す。］
　Ｅは、フェニレン又は単結合を表すか、又はＤとＥとが一緒になって、次の式（３）で表される二価の基を表し；
Figure JPOXMLDOC01-appb-C000007
 　［式（３）中、ｕは０～２の整数を表し、ｖは０又は１を表す。］
　Ｇは、Ｏ、Ｓ、ＳＯ又はＳＯ２を表し；
　Ｑは、カルボキシ、アルコキシカルボニル、テトラゾリル、カルバモイル、モノアルキルカルバモイル、ジアルキルカルバモイル又は次の式（４）で表される基を表す。
Figure JPOXMLDOC01-appb-C000008
 　［式（４）中、Ｒ７は、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる１～３個の置換基で置換されていてもよい下記１）～４）のいずれかの基を表す；
　１）アルキル、
　２）アリール、
　３）アリールオキシ、
　４）複素環基。］
　 The present invention relates to a non-steroid containing a heterocyclic derivative represented by the following general formula (1) (hereinafter referred to as “the present heterocyclic derivative (1)”) or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention relates to a pharmaceutical composition for treating intestinal injury associated with the administration of sex anti-inflammatory agents (hereinafter referred to as “NSAIDs”).
Figure JPOXMLDOC01-appb-C000005
 In formula (1), R 1 and R 2 are the same or different and are each a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy Represents aryl optionally substituted with 1 to 3 substituents selected from the group consisting of cyano and nitro;
R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl;
R 5 represents a hydrogen atom, an alkyl or a halogen atom;
Y represents N or N → O;
A represents NR 6 and R 6 represents a hydrogen atom, alkyl, alkenyl or cycloalkyl;
D represents alkylene or alkenylene optionally substituted with hydroxy, or A and D together represent a divalent group represented by the following formula (2);
Figure JPOXMLDOC01-appb-C000006
 [In the formula (2), r represents an integer of 0 to 2, q represents 2 or 3, and t represents an integer of 0 to 4, respectively. ]
E represents phenylene or a single bond, or D and E together represent a divalent group represented by the following formula (3);
Figure JPOXMLDOC01-appb-C000007
 [In the formula (3), u represents an integer of 0 to 2, and v represents 0 or 1. ]
G represents O, S, SO or SO 2 ;
Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl or a group represented by the following formula (4).
Figure JPOXMLDOC01-appb-C000008
 [In the formula (4), R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkyl Any one of the following 1) to 4) which may be substituted with 1 to 3 substituents selected from the group consisting of amino, dialkylamino, carboxy, cyano and nitro;
1) alkyl,
2) aryl,
3) Aryloxy,
4) A heterocyclic group. ]
　ＮＳＡＩＤｓ投与に伴う副作用として、胃腸傷害が良く知られており、その発症部位に関して、欧米ではＮＳＡＩＤｓ投与患者の６０－７０％に小腸を含めた下部消化管に何らかの病変が認められることが報告されている。最近、関節リウマチ患者及び健常人でのカプセル内視鏡を用いた検討において、ＮＳＡＩＤｓ投与により７０％の高率で小腸粘膜傷害が認められることが報告されている（例えば、非特許文献１及び２を参照）。 As a side effect associated with administration of NSAIDs, gastrointestinal injury is well known. Regarding the onset site, it has been reported that 60-70% of NSAIDs administration patients have some lesions in the lower gastrointestinal tract including the small intestine. Yes. Recently, in studies using capsule endoscopes in rheumatoid arthritis patients and healthy subjects, it has been reported that small intestinal mucosal injury is observed at a high rate of 70% by administration of NSAIDs (for example, Non-Patent Documents 1 and 2). See).
　一方、本複素環誘導体（１）又はその医薬上許容される塩は、ＰＧＩ２受容体作動剤として、肺高血圧症や閉塞性動脈硬化症の治療に有用であることが既に報告されている（例えば、特許文献１を参照）。 On the other hand, this heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof has already been reported to be useful as a PGI 2 receptor agonist in the treatment of pulmonary hypertension and obstructive arteriosclerosis ( For example, see Patent Document 1).
国際公開第０２／０８８０８４号パンフレットInternational Publication No. 02/088084 Pamphlet
　本発明の目的は、主として、ＮＳＡＩＤｓ投与に伴う腸管傷害を治療するための新規な医薬組成物を提供することにある。
  An object of the present invention is mainly to provide a novel pharmaceutical composition for treating intestinal injury associated with administration of NSAIDs.
　本発明者は、本複素環誘導体（１）が、ラットにおいて、ＮＳＡＩＤｓの一つであるインドメタシンを投与することにより生じる小腸潰瘍に対する治療効果を有することを見出し、本発明を完成した。 The present inventor has found that the present heterocyclic derivative (1) has a therapeutic effect on small intestinal ulcer caused by administration of indomethacin, which is one of NSAIDs, in rats, and has completed the present invention.
　本発明としては、例えば、本複素環誘導体（１）又はその医薬上許容される塩を有効成分として含有する、ＮＳＡＩＤｓ投与に伴う腸管傷害を治療するための医薬組成物（以下、「本発明組成物」という。）を挙げることができる。
  The present invention includes, for example, a pharmaceutical composition for treating intestinal injury associated with administration of NSAIDs (hereinafter referred to as “the composition of the present invention” containing the present heterocyclic derivative (1) or a pharmaceutically acceptable salt thereof as an active ingredient. ) ").
図１は、２－｛４－［Ｎ－（５，６－ジフェニルピラジン－２－イル）－Ｎ－イソプロピルアミノ］ブチルオキシ｝酢酸（以下、「化合物Ａ」という。）についての小腸潰瘍の形成抑制作用を示す。縦軸は小腸潰瘍の個数（個）を表す。FIG. 1 shows the inhibition of small intestinal ulcer formation with 2- {4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy} acetic acid (hereinafter referred to as “Compound A”). Shows the effect. The vertical axis represents the number of small intestinal ulcers.
図２は、２－｛４－［Ｎ－（５，６－ジフェニルピラジン－２－イル）－Ｎ－イソプロピルアミノ］ブチルオキシ｝－Ｎ－（メチルスルホニル）アセトアミド（以下、「化合物Ｂ」という。）についての小腸潰瘍の形成抑制作用を示す。縦軸は小腸潰瘍の個数（個）を表す。FIG. 2 shows 2- {4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy} -N- (methylsulfonyl) acetamide (hereinafter referred to as “Compound B”). Shows the inhibitory action on the formation of small intestinal ulcer. The vertical axis represents the number of small intestinal ulcers.
　本複素環誘導体（１）において、例えば、
　Ｒ１、Ｒ２が、同一又は異なって、ハロゲン原子、アルキル及びアルコキシからなる群から選ばれる１～３個の置換基で置換されていてもよいフェニルであり、
　Ｒ３、Ｒ４が、同一又は異なって、水素原子又はアルキルであり、
　Ｒ５が水素原子であり、
　ＹがＮであり、
　ＡがＮＲ６であり、Ｒ６がアルキルであり、
　Ｄがアルキレンであり、
　Ｅが単結合であり、
　ＧがＯであり、
　Ｑが、カルボキシ又は式（４）で表される基であり、Ｒ７が、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる１～３個の置換基で置換されていてもよい下記１）～４）のいずれかの基である化合物が好ましい。
　１）アルキル、
　２）アリール、
　３）アリールオキシ、
　４）複素環基 In the present heterocyclic derivative (1), for example,
R 1 and R 2 are the same or different and are phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, alkyl and alkoxy;
R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl;
R 5 is a hydrogen atom,
Y is N,
A is NR 6 , R 6 is alkyl,
D is alkylene,
E is a single bond,
G is O,
Q is carboxy or a group represented by formula (4), R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl Any one of the following 1) to 4) optionally substituted with 1 to 3 substituents selected from the group consisting of alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro Compounds that are groups are preferred.
1) alkyl,
2) aryl,
3) Aryloxy,
4) Heterocyclic group
　具体的には、例えば、化合物Ａ及び化合物Ｂが好ましい。 Specifically, for example, Compound A and Compound B are preferable.
　本発明における「アルキル」としては、直鎖状又は分枝鎖状の炭素数１～６のもの、例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ｎ－ヘキシル、イソヘキシルを挙げることができる。とりわけ、炭素数１～４のものが好ましい。 The “alkyl” in the present invention is a linear or branched one having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Examples include butyl, n-pentyl, isopentyl, n-hexyl and isohexyl. In particular, those having 1 to 4 carbon atoms are preferred.
　本発明における「ハロアルキル」、「アリールアルキル」、「アルキルチオ」、「アルコキシアルキル」、「アルキルスルホニル」、「モノアルキルアミノ」、「ジアルキルアミノ」、「モノアルキルカルバゾイル」及び「ジアルキルカルバモイル」のアルキル部分としては、前記のアルキルと同じものを挙げることができる。 “Haloalkyl”, “arylalkyl”, “alkylthio”, “alkoxyalkyl”, “alkylsulfonyl”, “monoalkylamino”, “dialkylamino”, “monoalkylcarbazoyl” and “dialkylcarbamoyl” in the present invention Examples of the moiety include the same alkyl groups as those described above.
　本発明における「アルコキシ」としては、直鎖状又は分枝鎖状の炭素数１～６もの、例えば、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ｎ－ペンチルオキシ、イソペンチルオキシ、ｎ－ヘキシルオキシ、イソヘキシルオキシを挙げることができる。とりわけ、炭素数１～４のものが好ましい。 In the present invention, “alkoxy” is a straight or branched chain having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- Examples include butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy and isohexyloxy. In particular, those having 1 to 4 carbon atoms are preferred.
　本発明における「アルコキシカルボニル」及び「アルコキシアルキル」のアルコキシ部分としては、前記のアルコキシと同じものを挙げることができる。 Examples of the alkoxy moiety of “alkoxycarbonyl” and “alkoxyalkyl” in the present invention include the same as the above alkoxy.
　本発明における「アルケニル」としては、直鎖状又は分枝鎖状の炭素数２～６のもの、例えば、ビニル、１－プロペニル、２－プロペニル、１－ブテニル、２－ブテニル、３－ブテニル、１－ペンテニル、２－ペンテニル、３－ペンテニル、４－ペンテニル、４－メチル－３－ペンテニル、１－ヘキセニル、２－ヘキセニル、３－ヘキセニル、４－ヘキセニル、５－ヘキセニルを挙げることができる。とりわけ、炭素数３又は４のものが好ましい。 In the present invention, “alkenyl” is linear or branched having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, Examples thereof include 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. In particular, those having 3 or 4 carbon atoms are preferred.
　本発明における「シクロアルキル」としては、炭素数３～８のもの、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルを挙げることができる。とりわけ、炭素数５～７のものが好ましい。 Examples of “cycloalkyl” in the present invention include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, those having 5 to 7 carbon atoms are preferred.
　本発明における「ハロゲン原子」としては、例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子を挙げることができる。 Examples of the “halogen atom” in the present invention include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
　本発明における「アリール」としては、炭素数６～１０もの、例えば、フェニル、１－ナフチル、２－ナフチルを挙げることができる。とりわけ、フェニルが好ましい。 In the present invention, “aryl” includes 6 to 10 carbon atoms, such as phenyl, 1-naphthyl and 2-naphthyl. In particular, phenyl is preferred.
　本発明における「アリールアルキル」及び「アリールオキシ」のアリール部分としては、前記のアリールと同じものを挙げることができる。 As the aryl moiety of “arylalkyl” and “aryloxy” in the present invention, the same aryl as the above aryl can be exemplified.
　本発明における「アルキレン」としては、直鎖状又は分枝鎖状の炭素数１～８のもの、例えば、メチレン、エチレン、１－メチルエチレン、２－メチルエチレン、トリメチレン、テトラメチレン、ペンタメチレン、ヘキサメチレン、ヘプタメチレン、オクタメチレンを挙げることができる。とりわけ、炭素数３～６のものが好ましく、炭素数４のものが特に好ましい。 As the “alkylene” in the present invention, linear or branched ones having 1 to 8 carbon atoms such as methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, tetramethylene, pentamethylene, Examples include hexamethylene, heptamethylene, and octamethylene. In particular, those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are particularly preferred.
　本発明における「アルケニレン」としては、直鎖状又は分枝鎖状の炭素数２～８のもの、例えば、エテニレン、１－プロペニレン、２－プロペニレン、１－ブテニレン、２－ブテニレン、３－ブテニレン、１－ペンテニレン、２－ペンテニレン、３－ペンテニレン、４－ペンテニレン、４－メチル－３－ペンテニレン、１－ヘキセニレン、２－ヘキセニレン、３－ヘキセニレン、４－ヘキセニレン、５－ヘキセニレン、１－ヘプテニレン、２－ヘプテニレン、３－ヘプテニレン、４－ヘプテニレン、５－ヘプテニレン、６－ヘプテニレン、１－オクテニレン、２－オクテニレン、３－オクテニレン、４－オクテニレン、５－オクテニレン、６－オクテニレン、７－オクテニレンを挙げることができる。とりわけ、炭素数３～６のものが好ましく、炭素数４のものが特に好ましい。 As the “alkenylene” in the present invention, linear or branched ones having 2 to 8 carbon atoms such as ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 4-methyl-3-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene, 5-hexenylene, 1-heptenylene, 2- Examples include heptenylene, 3-heptenylene, 4-heptenylene, 5-heptenylene, 6-heptenylene, 1-octenylene, 2-octenylene, 3-octenylene, 4-octenylene, 5-octenylene, 6-octenylene and 7-octenylene. . In particular, those having 3 to 6 carbon atoms are preferred, and those having 4 carbon atoms are particularly preferred.
　本発明における「複素環基」としては、次の（１）又は（２）を挙げることができる。
（１）窒素原子、酸素原子及び硫黄原子から選択される１～４個までのヘテロ原子を有する５又は６員の芳香環基、又はそれらのベンゼン縮合環であって、かかる環構成原子が窒素原子又は硫黄原子の場合、かかる窒素原子、硫黄原子はオキシドを形成していてもよい。例えば、１－ピロリル、２－ピロリル、３－ピロリル、３－インドリル、２－フラニル、３－フラニル、３－ベンゾフラニル、２－チエニル、３－チエニル、３－ベンゾチエニル、１，３－オキサゾール－２－イル、４－イソオキサゾリル、２－チアゾリル、５－チアゾリル、２－ベンゾチアゾリル、１－イミダゾリル、２－イミダゾリル、４－イミダゾリル、２－ベンズイミダゾリル、１Ｈ－１，２，４－トリアゾール－１－イル、１Ｈ－テトラゾール－５－イル、２Ｈ－テトラゾール－５－イル、２－ピリジル、３－ピリジル、４－ピリジル、３－ピラゾリル、２－ピリミジニル、４－ピリミジニル、２－ピラジニル、１，３，５－トリアジン－２－イルを挙げることができる。
（２）環構成原子として、窒素原子、酸素原子又は硫黄原子を、同一又は異なって、１～４個含んでいてもよい、４～８員環の飽和環基、又はそれらのベンゼン縮合環基であって、環構成原子が窒素原子又は硫黄原子の場合、かかる窒素原子、硫黄原子はオキシドを形成していてもよい。例えば、ピペリジノ、ピペラジニル、３－メチルピペラジン－１－イル、ホモピペラジニル、モノホリノ、チオモノホリノ、１－ピロリジニル、２－ピロリジニル、２－テトラヒドロフラニルを挙げることができる。 Examples of the “heterocyclic group” in the present invention include the following (1) or (2).
(1) a 5- or 6-membered aromatic ring group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a benzene condensed ring thereof, wherein the ring-constituting atom is nitrogen In the case of an atom or a sulfur atom, such a nitrogen atom or sulfur atom may form an oxide. For example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-indolyl, 2-furanyl, 3-furanyl, 3-benzofuranyl, 2-thienyl, 3-thienyl, 3-benzothienyl, 1,3-oxazole-2 -Yl, 4-isoxazolyl, 2-thiazolyl, 5-thiazolyl, 2-benzothiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 2-benzimidazolyl, 1H-1,2,4-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 1,3,5- Mention may be made of triazin-2-yl.
(2) A 4- to 8-membered saturated ring group, or a benzene condensed ring group thereof, which may contain 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms which are the same or different as ring constituent atoms And when a ring member atom is a nitrogen atom or a sulfur atom, this nitrogen atom and sulfur atom may form the oxide. For example, piperidino, piperazinyl, 3-methylpiperazin-1-yl, homopiperazinyl, monophorino, thiomonophorino, 1-pyrrolidinyl, 2-pyrrolidinyl, 2-tetrahydrofuranyl can be mentioned.
　本複素環誘導体（１）は、前記特許文献１（国際公開第０２／０８８０８４号パンフレット）に記載の方法により合成することができる。 The present heterocyclic derivative (1) can be synthesized by the method described in Patent Document 1 (International Publication No. 02/088084 pamphlet).
　本複素環誘導体（１）は、遊離の塩基又は酸のまま医薬として用いることができるが、公知の方法により医学上許容される塩の形にして用いることもできる。
　本複素環誘導体（１）が塩基性を示す場合の「塩」としては、例えば、塩酸、硫酸、硝酸、リン酸、フッ化水素酸、若しくは臭化水素酸の無機酸の塩、又は酢酸、酒石酸、乳酸、クエン酸、フマール酸、マレイン酸、コハク酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、ナフタレンスルホン酸、若しくはカンファースルホン酸の有機酸の塩を挙げることができる。
　本複素環誘導体（１）が酸性を示す場合の「塩」としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、又はカルシウム塩等のアルカリ土類金属塩を挙げることができる。 The present heterocyclic derivative (1) can be used as a medicine as a free base or acid, but can also be used in the form of a medically acceptable salt by a known method.
As the “salt” when the present heterocyclic derivative (1) is basic, for example, a salt of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, or hydrobromic acid, or acetic acid, List organic acid salts of tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, or camphorsulfonic acid Can do.
Examples of the “salt” when the present heterocyclic derivative (1) is acidic include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt.
　本複素環誘導体（１）には、幾何異性体（Ｚ体及びＥ体）が存在するが、各幾何異性体及びそれらの混合物も本複素環誘導体（１）に含まれる。また、本複素環誘導体（１）には、不斉炭素を有するものも存在するが、各光学異性体及びこれらのラセミ体も本複素環誘導体（１）に含まれる。光学異性体は、上記のようにして得られたラセミ体より、その塩基性を利用して、光学活性な酸（例えば、酒石酸、ジベンゾイル酒石酸、マンデル酸、１０－カンファースルホン酸）を用いて、公知の方法により光学分割するか、或いは予め調製した光学活性な化合物を原料に用いて製造することができる。 The present heterocyclic derivative (1) has geometric isomers (Z-form and E-form), and each geometric isomer and a mixture thereof are also included in the present heterocyclic derivative (1). In addition, some of the heterocyclic derivatives (1) have asymmetric carbons, but each optical isomer and their racemates are also included in the heterocyclic derivatives (1). The optical isomer is obtained from the racemate obtained as described above using its basicity and using an optically active acid (for example, tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid), It can be optically resolved by a known method, or can be produced using a previously prepared optically active compound as a raw material.
　本発明に係るＮＳＡＩＤｓとしては、特に制限されないが、例えば、ジクロフェナック、メロキシカム、オキサプロジン、ナブメトン、インドメタシン、イブプロフェン、ケトプロフェン、ナプロキセン、セレコキシブなどを挙げることができる。 The NSAIDs according to the present invention are not particularly limited, and examples thereof include diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib and the like.
　本発明に係る腸管傷害としては、十二指腸、小腸、大腸で発症する傷害であれば特に制限されないが、例えば、十二指腸、小腸、大腸に生じるびらん等の粘膜傷害や潰瘍を挙げることができる。 The intestinal tract injury according to the present invention is not particularly limited as long as it occurs in the duodenum, small intestine, and large intestine, and examples thereof include mucosal injury such as erosion that occurs in the duodenum, small intestine, and large intestine, and ulcers.
　本発明組成物は、本複素環誘導体（１）を、そのまま又は医薬上許容される無毒性かつ不活性な担体中に、０．０１～９９．５％の範囲内で、好ましくは０．５～９０％の範囲内で含有するものである。 The composition of the present invention comprises the present heterocyclic derivative (1) in a range of 0.01 to 99.5%, preferably 0.5%, as it is or in a pharmaceutically acceptable non-toxic and inert carrier. It is contained within the range of ~ 90%.
　上記担体としては、固形、半固形又は液状の希釈剤、充填剤、その他の処方用の助剤を挙げることができる。これらを一種又は二種以上用いることができる。 Examples of the carrier include solid, semi-solid or liquid diluents, fillers, and other formulation aids. One or more of these can be used.
　本発明組成物は、固形又は液状の用量単位で、末剤、カプセル剤、錠剤、糖衣剤、顆粒剤、散剤、懸濁剤、液剤、シロップ剤、エリキシル剤、トローチ剤等の経口投与製剤、注射剤、坐剤等の非経口投与製剤のいずれの形態をもとることができる。徐放性製剤であってもよい。それらの中で、特に錠剤等の経口投与製剤が好ましい。 The composition of the present invention is a solid or liquid dosage unit, and is a powder, capsule, tablet, dragee, granule, powder, suspension, liquid, syrup, elixir, troche, etc. Any form of parenteral preparations such as injections and suppositories can be used. It may be a sustained-release preparation. Among these, oral preparations such as tablets are particularly preferable.
　末剤は、本複素環誘導体（１）を適当な細かさにすることにより製造することができる。 The powder can be produced by making the present heterocyclic derivative (1) fine.
　散剤は、本複素環誘導体（１）を適当な細かさにし、次いで同様に細かくした医薬用担体、例えば、澱粉、マンニトールのような可食性炭水化物と混合することにより製造することができる。任意に風味剤、保存剤、分散剤、着色剤、香料等を添加することができる。 The powder can be produced by making the present heterocyclic derivative (1) fine and then mixing it with a finely divided pharmaceutical carrier such as edible carbohydrates such as starch and mannitol. A flavoring agent, a preservative, a dispersing agent, a coloring agent, a fragrance | flavor, etc. can be added arbitrarily.
　カプセル剤は、まず上述のようにして粉末状となった末剤や散剤あるいは錠剤の項で述べるように顆粒化したものを、例えば、ゼラチンカプセルのようなカプセル外皮の中へ充填することにより製造することができる。滑沢剤や流動化剤、例えば、コロイド状のシリカ、タルク、ステアリン酸マグネシウム、ステアリン酸カルシウム、固形のポリエチレングリコールを粉末状となった末剤や散剤と混合し、その後、充填操作を行うことにより製造することもできる。崩壊剤や可溶化剤、例えば、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、炭酸カルシウム、炭酸ナトリウムを添加すれば、カプセル剤が摂取されたときの医薬の有効性を改善することができる。また、本複素環誘導体（１）の微粉末を植物油、ポリエチレングリコール、グリセリン、界面活性剤中に懸濁分散し、これをゼラチンシートで包んで軟カプセル剤とすることもできる。 Capsules are manufactured by first filling the powdered powdered powder or powder as described above into granules as described in the section of tablets, for example, into capsule shells such as gelatin capsules. can do. Lubricants and fluidizers such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol are mixed with powdered powder and powder, and then filled. It can also be manufactured. When disintegrators and solubilizers are added, such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, calcium carbonate, sodium carbonate The effectiveness of the medicine can be improved. Alternatively, the fine powder of the present heterocyclic derivative (1) can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant and wrapped in a gelatin sheet to form a soft capsule.
　錠剤は、粉末化された本複素環誘導体（１）に賦形剤を加えて粉末混合物を作り、顆粒化もしくはスラグ化し、次いで崩壊剤又は滑沢剤を加えた後、打錠することにより製造することができる。
　粉末混合物は、適当に粉末化された本複素環誘導体（１）を希釈剤や基剤と混合することにより製造することができる。必要に応じて、結合剤（例えば、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシプロピルメチルセルロース、ゼラチン、ポリビニルピロリドン、ポリビニルアルコール）、溶解遅延化剤（例えば、パラフィン）、再吸収剤（例えば、四級塩）、吸着剤（例えばベントナイト、カオリン）等を添加することができる。
　粉末混合物は、まず結合剤、例えば、シロップ、澱粉糊、アラビアゴム、セルロース溶液又は高分子物質溶液で湿らせ、攪拌混合し、これを乾燥、粉砕して顆粒とすることができる。このように粉末を顆粒化する代わりに、まず打錠機にかけた後、得られる不完全な形態のスラグを破砕して顆粒にすることも可能である。このようにして作られる顆粒に、滑沢剤としてステアリン酸、ステアリン酸塩、タルク、ミネラルオイル等を添加することにより、互いに付着することを防ぐことができる。
　また、錠剤は、上述のように顆粒化やスラグ化の工程を経ることなく、本複素環誘導体（１）を流動性の不活性担体と混合した後に直接打錠することによっても製造することができる。
　こうして製造された錠剤にフィルムコーティングや糖衣を施すことができる。シェラックの密閉被膜からなる透明又は半透明の保護被覆、糖や高分子材料の被覆及びワックスよりなる磨上被覆をも用いることができる。 Tablets are manufactured by adding excipients to the powdered heterocyclic derivative (1) to form a powder mixture, granulating or slugging, then adding a disintegrant or lubricant, and then tableting. can do.
The powder mixture can be produced by mixing the present heterocyclic derivative (1), which has been appropriately pulverized, with a diluent or a base. If necessary, a binder (for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol), a dissolution retardant (for example, paraffin), a resorbent (for example, a quaternary salt), An adsorbent (for example, bentonite, kaolin) or the like can be added.
The powder mixture can first be moistened with a binder such as syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and pulverized into granules. Instead of granulating the powder in this way, it is also possible to first crush the tablet and then crush the resulting incomplete form of slag into granules. By adding stearic acid, stearate, talc, mineral oil or the like as a lubricant to the granules thus produced, it is possible to prevent them from adhering to each other.
Moreover, a tablet can also be manufactured by directly compressing after mixing this heterocyclic derivative (1) with a fluid inert carrier, without going through the granulation and slagging steps as described above. it can.
Film tablets and sugar coatings can be applied to the tablets thus produced. A transparent or translucent protective coating made of a shellac hermetic coating, a coating of sugar or polymer material and a polishing coating made of wax can also be used.
　他の経口投与製剤、例えば、液剤、シロップ剤、トローチ剤、エリキシル剤もまたその一定量が本複素環誘導体（１）の一定量を含有するように用量単位形態にすることができる。 Other oral dosage forms such as solutions, syrups, troches, and elixirs may also be in dosage unit form so that a given amount contains a certain amount of the heterocyclic derivative (1).
　シロップ剤は、本複素環誘導体（１）を適当な香味水溶液に溶解して製造することができる。エリキシル剤は、非毒性のアルコール性担体を用いることにより製造することができる。 The syrup can be produced by dissolving the present heterocyclic derivative (1) in a suitable flavor aqueous solution. An elixir can be produced by using a non-toxic alcoholic carrier.
　懸濁剤は、本複素環誘導体（１）を非毒性担体中に分散させることにより製造することができる。必要に応じて、可溶化剤や乳化剤（例えば、エトキシ化されたイソステアリルアルコール類、ポリオキシエチレンソルビトールエステル類）、保存剤、風味付与剤（例えば、ペパーミント油、サッカリン）等を添加することができる。 The suspending agent can be produced by dispersing the present heterocyclic derivative (1) in a non-toxic carrier. If necessary, solubilizers and emulsifiers (for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavoring agents (for example, peppermint oil, saccharin), etc. may be added. it can.
　必要であれば、経口投与のための用量単位処方をマイクロカプセル化することができる。当該処方はまた、被覆をしたり、高分子・ワックス等中に埋め込んだりすることにより作用時間の延長や持続放出をもたらすこともできる。 If necessary, a dosage unit formulation for oral administration can be microencapsulated. The formulation can also be extended in action time or sustained release by being coated or embedded in a polymer, wax or the like.
　非経口投与製剤は、皮下・筋肉又は静脈内注射用とした液状用量単位形態、例えば、溶液や懸濁液の形態をとることができる。当該非経口投与製剤は、本複素環誘導体（１）の一定量を、注射の目的に適合する非毒性の液状担体、例えば、水性や油性の媒体に懸濁し又は溶解し、次いで当該懸濁液又は溶液を滅菌することにより製造することができる。注射液を等張にするために非毒性の塩や塩溶液を添加することができる。また、安定剤、保存剤、乳化剤等を添加することもできる。 The parenteral preparation can take the form of a liquid dose unit for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension. The parenteral preparation is prepared by suspending or dissolving a certain amount of the heterocyclic derivative (1) in a non-toxic liquid carrier suitable for injection purposes, for example, an aqueous or oily medium, and then suspending the suspension. Or it can manufacture by sterilizing a solution. Non-toxic salts and salt solutions can be added to make the injection solution isotonic. In addition, stabilizers, preservatives, emulsifiers, and the like can be added.
　坐剤は、本複素環誘導体（１）を低融点の水に可溶又は不溶の固体、例えば、ポリエチレングリコール、カカオ脂、半合成の油脂[例えば、ウイテプゾール（登録商標）]、高級エステル類（例えば、パルミチン酸ミリスチルエステル）又はそれらの混合物に溶解又は懸濁させて製造することができる。 The suppository is obtained by dissolving the heterocyclic derivative (1) in a low-melting water-soluble or insoluble solid such as polyethylene glycol, cacao butter, semi-synthetic oil [for example, Witepsol (registered trademark)], higher esters ( For example, it can be prepared by dissolving or suspending in myristyl palmitate ester) or a mixture thereof.
　本発明組成物の投与量は、体重、年齢等の患者の状態、投与経路、症状の程度等によって異なるが、一般的には成人に対して、本複素環誘導体（１）の量として、１日当たり０．００１ｍｇ～１００ｍｇの範囲内が適当であり、０．０１ｍｇ～１０ｍｇの範囲内がより好ましい。場合によっては、これ以下でも足りるし、また逆にこれ以上の用量を必要とする場合もある。また、１日１回から数回の投与又は１日から数日間の間隔で投与することができる。
  The dose of the composition of the present invention varies depending on the patient's condition such as body weight and age, administration route, degree of symptom, etc., but generally the amount of the present heterocyclic derivative (1) is 1 for adults. The range of 0.001 mg to 100 mg per day is appropriate, and the range of 0.01 mg to 10 mg is more preferable. In some cases, a lower dose may be sufficient, and vice versa. Moreover, it can be administered once to several times a day or at intervals of 1 day to several days.
　以下に、試験例を掲げて、本発明を更に詳しく説明するが、本発明は下記に示される範囲に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to test examples, but the present invention is not limited to the scope shown below.
試験例１
（１）試験方法
　非絶食のＳＤ系ラット（雄性、７週齢）（日本エスエルシー社製）にインドメタシン（シグマ社製）を２０ｍｇ／ｋｇで経口投与した。試験物質は、インドメタシンの投与１時間前と９時間後に投与し、インドメタシン投与の翌日と翌々日は１日２回経口投与した。インドメタシンの投与から３日後に小腸を摘出し、小腸潰瘍の個数を評価した。試験物質としては、化合物Ａ（３ｍｇ又は５ｍｇ／ｋｇ）及び化合物Ｂ（３ｍｇ又は５ｍｇ／ｋｇ）を用いた。試験物質は０．５％メチルセルロース水溶液に懸濁して投与した。対照群には０．５％メチルセルロース水溶液を投与した。１群当たり、５匹又は６匹のラットを用いた。
　なお、対照群に対して、Ｗｉｌｌｉａｍｓ検定により有意差を検定した（＊＊：ｐ＜０．０１）。
（２）結果
　図１及び図２に示すように、化合物Ａ或いは化合物Ｂを投与することにより、小腸潰瘍の形成が有意に抑制された。 Test example 1
(1) Test method Indomethacin (manufactured by Sigma) was orally administered at 20 mg / kg to non-fasting SD rats (male, 7 weeks old) (manufactured by SLC Japan). The test substance was administered 1 hour before and 9 hours after administration of indomethacin, and was orally administered twice a day on the next day and the next day after indomethacin administration. Three days after administration of indomethacin, the small intestine was removed and the number of small intestine ulcers was evaluated. As test substances, compound A (3 mg or 5 mg / kg) and compound B (3 mg or 5 mg / kg) were used. The test substance was administered suspended in a 0.5% methylcellulose aqueous solution. A 0.5% methylcellulose aqueous solution was administered to the control group. Five or six rats were used per group.
In addition, the significant difference was tested with respect to the control group by Williams test (**: p <0.01).
(2) Results As shown in FIGS. 1 and 2, administration of Compound A or Compound B significantly suppressed the formation of small intestinal ulcers.
試験例２
　文献（Ｎｕｔｒ　Ｈｏｓｐ．　２００８；２３（４）：３２６－３３１）に記載の方法に準じて、ＮＳＡＩＤｓをラットに投与し、腸管傷害を起こさせる。ＮＳＡＩＤｓ投与前若しくは投与後から、化合物Ａ又は化合物Ｂを投与し、二糖加水分解酵素の活性の変化や腸の刷子縁膜の組織構造の変化を調べることにより、化合物Ａ、化合物Ｂの薬理学的な効果を評価する。 Test example 2
In accordance with the method described in the literature (Nutr Hosp. 2008; 23 (4): 326-331), NSAIDs are administered to rats to cause intestinal injury. Pharmacology of Compound A and Compound B by administering Compound A or Compound B before or after administration of NSAIDs and examining changes in disaccharide hydrolase activity and tissue structure of the intestinal brush border membrane The effective effect.
試験例３
　文献（Ｊ　Ｐｈａｒｍａｃｏｌ　Ｓｃｉ　２００７；１０３：４０－４７）に記載の方法に準じて、インドメタシンをラットに投与し、小腸傷害を起こさせる。インドメタシン投与前若しくは投与後から、化合物Ａ又は化合物Ｂを投与し、ミエロペルオキシダーゼ活性の変化、チオバルビツール酸反応物の変化、誘導性一酸化窒素合成酵素ｍＲＮＡの発現の変化などを調べることにより、化合物Ａ、化合物Ｂの薬理学的な効果を評価する。 Test example 3
Indomethacin is administered to rats according to the method described in the literature (J Pharmacol Sci 2007; 103: 40-47) to cause intestinal injury. By administering Compound A or Compound B before or after indomethacin administration, and examining changes in myeloperoxidase activity, changes in thiobarbituric acid reactant, changes in expression of inducible nitric oxide synthase mRNA, etc. The pharmacological effects of Compound A and Compound B are evaluated.
試験例４
　文献（Ｉｎｆｌａｍｍｏｐｈａｒｍａｃｏｌｏｇｙ　２００７；１５：２６６－２７２）に記載の方法に準じて、インドメタシンをラットに投与し、小腸傷害を起こさせる。インドメタシン投与前若しくは投与後から、化合物Ａ又は化合物Ｂを投与し、腸内細菌数の変化や小腸の運動性の変化などを調べることにより、化合物Ａ、化合物Ｂの薬理学的な効果を評価する。
  Test example 4
Indomethacin is administered to rats according to the method described in the literature (Inflammopharmacology 2007; 15: 266-272) to cause intestinal injury. The compound A or compound B is administered before or after indomethacin administration, and the pharmacological effects of the compound A and compound B are evaluated by examining changes in the number of intestinal bacteria and motility of the small intestine. .

Claims (7)

  1. 　次の一般式（１）で表される複素環誘導体又はその医薬上許容される塩を有効成分として含有する、非ステロイド性抗炎症剤投与に伴う腸管傷害を治療するための医薬組成物；
    Figure JPOXMLDOC01-appb-C000001
     　式（１）中、Ｒ１、Ｒ２は、同一又は異なって、ハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる１～３個の置換基で置換されていてもよいアリールを表し；
    　Ｒ３、Ｒ４は、同一又は異なって、水素原子又はアルキルを表し；
    　Ｒ５は水素原子、アルキル又はハロゲン原子を表し；
    　ＹはＮ又はＮ→Ｏを表し；
    　ＡはＮＲ６を表し、Ｒ６は水素原子、アルキル、アルケニル又はシクロアルキルを表し；
    　Ｄはヒドロキシで置換されていてもよいアルキレン又はアルケニレンを表すか、又はＡとＤとが一緒になって、次の式（２）で表される二価の基を表し；
    Figure JPOXMLDOC01-appb-C000002
     　［式（２）中、ｒは０～２の整数を表し、ｑは２又は３を表し、ｔは０～４の整数をそれぞれ表す。］
    　Ｅは、フェニレン又は単結合を表すか、又はＤとＥとが一緒になって、次の式（３）で表される二価の基を表し；
    Figure JPOXMLDOC01-appb-C000003
     　［式（３）中、ｕは０～２の整数を表し、ｖは０又は１を表す。］
    　Ｇは、Ｏ、Ｓ、ＳＯ又はＳＯ２を表し；
    　Ｑは、カルボキシ、アルコキシカルボニル、テトラゾリル、カルバモイル、モノアルキルカルバモイル、ジアルキルカルバモイル又は次の式（４）で表される基を表す。
    Figure JPOXMLDOC01-appb-C000004
     　［式（４）中、Ｒ７は、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる１～３個の置換基で置換されていてもよい下記１）～４）のいずれかの基を表す；
    　１）アルキル、
    　２）アリール、
    　３）アリールオキシ、
    　４）複素環基。］     A pharmaceutical composition for treating intestinal injury associated with administration of a nonsteroidal anti-inflammatory agent, comprising as an active ingredient a heterocyclic derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof;
    Figure JPOXMLDOC01-appb-C000001
     In formula (1), R 1 and R 2 are the same or different and are each a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy Represents aryl optionally substituted with 1 to 3 substituents selected from the group consisting of cyano and nitro;
    R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl;
    R 5 represents a hydrogen atom, an alkyl or a halogen atom;
    Y represents N or N → O;
    A represents NR 6 and R 6 represents a hydrogen atom, alkyl, alkenyl or cycloalkyl;
    D represents alkylene or alkenylene optionally substituted with hydroxy, or A and D together represent a divalent group represented by the following formula (2);
    Figure JPOXMLDOC01-appb-C000002
     [In the formula (2), r represents an integer of 0 to 2, q represents 2 or 3, and t represents an integer of 0 to 4, respectively. ]
    E represents phenylene or a single bond, or D and E together represent a divalent group represented by the following formula (3);
    Figure JPOXMLDOC01-appb-C000003
     [In the formula (3), u represents an integer of 0 to 2, and v represents 0 or 1. ]
    G represents O, S, SO or SO 2 ;
    Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl or a group represented by the following formula (4).
    Figure JPOXMLDOC01-appb-C000004
     [In the formula (4), R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkyl Any one of the following 1) to 4) which may be substituted with 1 to 3 substituents selected from the group consisting of amino, dialkylamino, carboxy, cyano and nitro;
    1) alkyl,
    2) aryl,
    3) Aryloxy,
    4) A heterocyclic group. ]
  2. 　複素環誘導体（１）において、Ｒ１、Ｒ２が、同一又は異なって、ハロゲン原子、アルキル及びアルコキシからなる群から選ばれる１～３個の置換基で置換されていてもよいフェニルであり、
    　Ｒ３、Ｒ４が、同一又は異なって、水素原子又はアルキルであり、
    　Ｒ５が水素原子であり、
    　ＹがＮであり、
    　ＡがＮＲ６であり、Ｒ６がアルキルであり、
    　Ｄがアルキレンであり、
    　Ｅが単結合であり、
    　ＧがＯであり、
    　Ｑが、カルボキシ又は式（４）で表される基であり、Ｒ７が、アミノ、モノアルキルアミノ、ジアルキルアミノ、若しくはヒドロキシ、又はハロゲン原子、アルキル、ハロアルキル、アリールアルキル、アルコキシ、アルキルチオ、アルコキシアルキル、アルキルスルホニル、ヒドロキシ、アミノ、モノアルキルアミノ、ジアルキルアミノ、カルボキシ、シアノ及びニトロからなる群から選ばれる１～３個の置換基で置換されていてもよい下記１）～４）のいずれかの基である、請求項１に記載の医薬組成物。
    　１）アルキル、
    　２）アリール、
    　３）アリールオキシ、
    　４）複素環基     In the heterocyclic derivative (1), R 1 and R 2 are the same or different and are phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, alkyl and alkoxy,
    R 3 and R 4 are the same or different and each represents a hydrogen atom or alkyl;
    R 5 is a hydrogen atom,
    Y is N,
    A is NR 6 , R 6 is alkyl,
    D is alkylene,
    E is a single bond,
    G is O,
    Q is carboxy or a group represented by formula (4), R 7 is amino, monoalkylamino, dialkylamino, or hydroxy, or a halogen atom, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl Any one of the following 1) to 4), which may be substituted with 1 to 3 substituents selected from the group consisting of alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro The pharmaceutical composition according to claim 1, which is a group.
    1) alkyl,
    2) aryl,
    3) Aryloxy,
    4) Heterocyclic group
  3. 　腸管傷害が、十二指腸、小腸又は大腸で発症する傷害である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the intestinal tract injury is an injury occurring in the duodenum, small intestine or large intestine.
  4. 　腸管傷害が、十二指腸、小腸又は大腸で発症する粘膜傷害又は潰瘍である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the intestinal tract injury is mucosal injury or ulcer that develops in the duodenum, small intestine or large intestine.
  5. 　２－{４－［Ｎ－（５，６－ジフェニルピラジン－２－イル）－Ｎ－イソプロピルアミノ］ブチルオキシ}酢酸若しくは２－{４－［Ｎ－（５，６－ジフェニルピラジン－２－イル）－Ｎ－イソプロピルアミノ］ブチルオキシ}－Ｎ－（メチルスルホニル）アセトアミド、又はその医薬上許容される塩を有効成分として含有する、非ステロイド性抗炎症剤投与に伴う腸管傷害を治療するための医薬組成物。 2- {4- [N- (5,6-diphenylpyrazin-2-yl) -N-isopropylamino] butyloxy} acetic acid or 2- {4- [N- (5,6-diphenylpyrazin-2-yl) -N-Isopropylamino] butyloxy} -N- (methylsulfonyl) acetamide, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for treating intestinal injury associated with administration of a nonsteroidal anti-inflammatory agent object.
  6. 　腸管傷害が、十二指腸、小腸又は大腸で発症する傷害である、請求項５に記載の医薬組成物。 6. The pharmaceutical composition according to claim 5, wherein the intestinal injury is an injury occurring in the duodenum, small intestine or large intestine.
  7. 　腸管傷害が、十二指腸、小腸又は大腸で発症する粘膜傷害又は潰瘍である、請求項５に記載の医薬組成物。 6. The pharmaceutical composition according to claim 5, wherein the intestinal tract injury is a mucosal injury or ulcer occurring in the duodenum, small intestine or large intestine.
PCT/JP2009/061286 2008-06-23 2009-06-22 Therapeutic agent for intestinal tract injury accompanying administration of a non-steroid anti-inflammatory agent WO2009157397A1 (en)

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