WO2009157397A1 - Agent thérapeutique pour une lésion au tractus intestinal accompagnant l’administration d’un anti-inflammatoire nonstéroïdien - Google Patents

Agent thérapeutique pour une lésion au tractus intestinal accompagnant l’administration d’un anti-inflammatoire nonstéroïdien Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
injury
pharmaceutical composition
formula
group
Prior art date
Application number
PCT/JP2009/061286
Other languages
English (en)
Japanese (ja)
Inventor
隆 興井
Original Assignee
日本新薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 日本新薬株式会社 filed Critical 日本新薬株式会社
Publication of WO2009157397A1 publication Critical patent/WO2009157397A1/fr

Links

Images

Classifications

    • 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

L’invention concerne une composition pharmaceutique pour le traitement d’une lésion au tractus intestinal qui accompagne l’administration d’un anti-inflammatoire non stéroïdien, laquelle composition contient comme ingrédient actif un dérivé hétérocyclique représenté par la formule générale (1) ou un sel pharmaceutiquement acceptable de celui-ci. [ÉQUATION 1]. Dans la formule (1), R1 et R2, lesquels peuvent être identiques ou différents, représentent un groupe aryle éventuellement substitué, R3 et R4, lesquels peuvent être identiques ou différents, représentent un atome d’hydrogène ou un groupe alkyle, R5 représente un atome d’hydrogène, un groupe alkyle ou un atome halogène, Y représente un atome N ou un N→O, A représente NR6, R6 représente un atome d’hydrogène, un groupe alkyle ou similaire, D représente un groupe alkylène ou alcénylène éventuellement à substitution hydroxy, E représente un groupe phénylène ou une liaison simple, G représente un atome O, un atome S ou similaire, et Q représente un groupe carboxy, un groupe alcoxycarbonyle ou similaire.
PCT/JP2009/061286 2008-06-23 2009-06-22 Agent thérapeutique pour une lésion au tractus intestinal accompagnant l’administration d’un anti-inflammatoire nonstéroïdien WO2009157397A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2008-162639 2008-06-23
JP2008162639 2008-06-23

Publications (1)

Publication Number Publication Date
WO2009157397A1 true WO2009157397A1 (fr) 2009-12-30

Family

ID=41444463

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2009/061286 WO2009157397A1 (fr) 2008-06-23 2009-06-22 Agent thérapeutique pour une lésion au tractus intestinal accompagnant l’administration d’un anti-inflammatoire nonstéroïdien

Country Status (1)

Country Link
WO (1) WO2009157397A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010150865A1 (fr) 2009-06-26 2010-12-29 日本新薬株式会社 Cristaux
WO2011024874A1 (fr) * 2009-08-26 2011-03-03 日本新薬株式会社 Sels d'addition avec une base
WO2018019296A1 (fr) * 2016-07-29 2018-02-01 成都苑东生物制药股份有限公司 Composé d'aminopyrazine, sel ou isomère, son procédé de préparation et son application
WO2018162527A1 (fr) 2017-03-08 2018-09-13 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
WO2019065792A1 (fr) 2017-09-28 2019-04-04 日本新薬株式会社 Cristaux
WO2019098300A1 (fr) 2017-11-16 2019-05-23 日本新薬株式会社 Formulation à libération contrôlée
US10821108B2 (en) 2015-12-02 2020-11-03 Nippon Shinyaku Co., Ltd. Pharmaceutical composition containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide
WO2021078835A1 (fr) 2019-10-23 2021-04-29 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
WO2021152060A1 (fr) 2020-01-31 2021-08-05 Actelion Pharmaceuticals Ltd Composition de sélexipag à libération contrôlée
WO2022162163A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Procédé de fabrication d'un dérivé de diphénylpyrazine
WO2022162158A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant un dérivé de diphénylpyrazine
WO2023131608A1 (fr) 2022-01-04 2023-07-13 Actelion Pharmaceuticals Ltd Compositions à libération contrôlée
WO2023214059A1 (fr) 2022-05-06 2023-11-09 Actelion Pharmaceuticals Ltd Composés de diphénylpyrazine utilisés en tant que promédicaments
WO2024017964A1 (fr) 2022-07-20 2024-01-25 Actelion Pharmaceuticals Ltd Composition pharmaceutique injectable comprenant un dérivé de diphénylpyrazine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002088084A1 (fr) * 2001-04-26 2002-11-07 Nippon Shinyaku Co., Ltd. Derives de composes heterocycliques et medicaments
WO2006109881A1 (fr) * 2005-04-12 2006-10-19 Sucampo Ag Utilisation combinee d'un compose de prostaglandine et d'un inhibiteur de pompe a protons pour le traitement des troubles gastro-intestinaux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002088084A1 (fr) * 2001-04-26 2002-11-07 Nippon Shinyaku Co., Ltd. Derives de composes heterocycliques et medicaments
WO2006109881A1 (fr) * 2005-04-12 2006-10-19 Sucampo Ag Utilisation combinee d'un compose de prostaglandine et d'un inhibiteur de pompe a protons pour le traitement des troubles gastro-intestinaux

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KEISUKE HONDA ET AL.: "Yakuzaisei Daichoen no Chiryo", SHUKAN NIPPON IJI SHINPO, 2002, pages 6 - 7, 33 TO 36 *
NOBUO TOMIYASU ET AL.: "Shokakan no Shukketsusei Shikkan 2005 Shikkan Kakuron 13. Yakuzaisei Shukketsusei Choen", STOMACH AND INTESTINE, vol. 40, no. 4, 2005, pages 611 - 615 *
TOSHIYUKI MATSUI: "Yakuzaisei Choen no Tokucho to Taio", MEDICAL PRACTICE, vol. 17, no. 4, 2000, pages 621 - 624 *

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3689855A1 (fr) 2009-06-26 2020-08-05 Nippon Shinyaku Co., Ltd. Cristaux
US8791122B2 (en) 2009-06-26 2014-07-29 Nippon Shinyaku Co., Ltd. Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and method for producing the same
US9284280B2 (en) 2009-06-26 2016-03-15 Nippon Shinyaku Co., Ltd. Use of form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide
US9340516B2 (en) 2009-06-26 2016-05-17 Nippon Shinyaku Company, Ltd. Form-II crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl) acetamide, method for producing the same, and use thereof
US9440931B2 (en) 2009-06-26 2016-09-13 Nippon Shinyaku Co., Ltd. Form-III crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and use thereof
KR20170024165A (ko) 2009-06-26 2017-03-06 니뽄 신야쿠 가부시키가이샤 결정
EP3275871A1 (fr) 2009-06-26 2018-01-31 Nippon Shinyaku Co., Ltd. Cristaux
WO2010150865A1 (fr) 2009-06-26 2010-12-29 日本新薬株式会社 Cristaux
WO2011024874A1 (fr) * 2009-08-26 2011-03-03 日本新薬株式会社 Sels d'addition avec une base
US10828298B2 (en) 2015-12-02 2020-11-10 Nippon Shinyaku Co., Ltd. Pharmaceutical composition containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy]-N-(methylsulfonyl)acetamide
US10821108B2 (en) 2015-12-02 2020-11-03 Nippon Shinyaku Co., Ltd. Pharmaceutical composition containing 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide
CN109563055B (zh) * 2016-07-29 2021-12-24 成都苑东生物制药股份有限公司 氨基吡嗪类化合物或盐、异构体、其制备方法及用途
CN109563055A (zh) * 2016-07-29 2019-04-02 成都苑东生物制药股份有限公司 氨基吡嗪类化合物或盐、异构体、其制备方法及用途
WO2018019296A1 (fr) * 2016-07-29 2018-02-01 成都苑东生物制药股份有限公司 Composé d'aminopyrazine, sel ou isomère, son procédé de préparation et son application
WO2018162527A1 (fr) 2017-03-08 2018-09-13 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
US11655218B2 (en) 2017-09-28 2023-05-23 Nippon Shinyaku Co., Ltd. Crystalline substituted pyrazines as PGI2 receptor agonists
KR20200060393A (ko) 2017-09-28 2020-05-29 니뽄 신야쿠 가부시키가이샤 결정
WO2019065792A1 (fr) 2017-09-28 2019-04-04 日本新薬株式会社 Cristaux
US10906879B2 (en) 2017-09-28 2021-02-02 Nippon Shinyaku Co., Ltd. Crystalline substituted pyrazines as PGI2 receptor agonists
KR20240042215A (ko) 2017-09-28 2024-04-01 니뽄 신야쿠 가부시키가이샤 결정
KR20200088382A (ko) 2017-11-16 2020-07-22 니뽄 신야쿠 가부시키가이샤 방출 제어 제제
WO2019098300A1 (fr) 2017-11-16 2019-05-23 日本新薬株式会社 Formulation à libération contrôlée
US11382912B2 (en) 2017-11-16 2022-07-12 Nippon Shinyaku Co., Ltd. Controlled-release preparation
WO2021078835A1 (fr) 2019-10-23 2021-04-29 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant du sélexipag
WO2021152060A1 (fr) 2020-01-31 2021-08-05 Actelion Pharmaceuticals Ltd Composition de sélexipag à libération contrôlée
WO2022162158A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Composition pharmaceutique comprenant un dérivé de diphénylpyrazine
WO2022162163A1 (fr) 2021-01-29 2022-08-04 Actelion Pharmaceuticals Ltd Procédé de fabrication d'un dérivé de diphénylpyrazine
WO2023131608A1 (fr) 2022-01-04 2023-07-13 Actelion Pharmaceuticals Ltd Compositions à libération contrôlée
WO2023214059A1 (fr) 2022-05-06 2023-11-09 Actelion Pharmaceuticals Ltd Composés de diphénylpyrazine utilisés en tant que promédicaments
WO2024017964A1 (fr) 2022-07-20 2024-01-25 Actelion Pharmaceuticals Ltd Composition pharmaceutique injectable comprenant un dérivé de diphénylpyrazine

Similar Documents

Publication Publication Date Title
WO2009157397A1 (fr) Agent thérapeutique pour une lésion au tractus intestinal accompagnant l’administration d’un anti-inflammatoire nonstéroïdien
JP5527206B2 (ja) 炎症性腸疾患治療剤
JP5522030B2 (ja) 線維化抑制剤
JP5527205B2 (ja) 脊柱管狭窄症治療剤
WO2009154246A1 (fr) Agent thérapeutique pour un dysfonctionnement érectile
US20210155623A1 (en) Purine diones as wnt pathway modulators
CA2598536A1 (fr) Derives d'oxyindole utilises comme agonistes du recepteur 5ht4
CA2483368A1 (fr) (s)-4-amino-5-chloro-2-methoxy-n-[1-[1-(2-tetrahydrofurylcarbonyl)-4-piperidinylmethyl]-4-piperidinyl]benzamide, son procede de preparation, composition pharmaceutique le contenant et intermediaire pour la preparation dudit compose
US6967211B2 (en) Remedial agent for chronic articular rheumatism
TW200811137A (en) mGluR5 modulators II
JPWO2012161301A1 (ja) ギラン・バレー症候群に伴う神経因性疼痛の予防又は治療剤
TW406083B (en) Novel piperazine derivatives
WO1999064403A1 (fr) Derives 1,5-benzodiazepine
AU2018338856B2 (en) Crystal
JP2012092079A (ja) 育毛剤
ZA200107244B (en) Benzamide derivatives and drugs containing the same
KR20120037035A (ko) 위 음식물 수용능 장해 치료약
WO1999036068A1 (fr) Activateurs des canaux de potassium
JP2013501707A (ja) タウプロテインキナーゼ１阻害剤としてのピリミドン誘導体
WO2022211052A1 (fr) Agent thérapeutique contre un trouble de la marche
JP7010404B1 (ja) 歩行障害治療剤
WO1999061016A1 (fr) Inhibiteurs de cyclo-oxygenase-2

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09770107

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: JP

122 Ep: pct application non-entry in european phase

Ref document number: 09770107

Country of ref document: EP

Kind code of ref document: A1