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WO1998003531A1 - Derives d'erythromycine - Google Patents

Derives d'erythromycine Download PDF

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Publication number
WO1998003531A1
WO1998003531A1 PCT/JP1997/002554 JP9702554W WO9803531A1 WO 1998003531 A1 WO1998003531 A1 WO 1998003531A1 JP 9702554 W JP9702554 W JP 9702554W WO 9803531 A1 WO9803531 A1 WO 9803531A1
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WO
WIPO (PCT)
Prior art keywords
group
atom
hydrogen atom
compound
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1997/002554
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English (en)
Japanese (ja)
Inventor
Yoshihiko Ishitani
Shotaro Takata
Masaki Ishigai
Yoshiko Nishigoori
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chugai Pharmaceutical Co Ltd
Original Assignee
Chugai Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Pharmaceutical Co Ltd filed Critical Chugai Pharmaceutical Co Ltd
Priority to AU36343/97A priority Critical patent/AU3634397A/en
Publication of WO1998003531A1 publication Critical patent/WO1998003531A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the present invention relates to an erythromycin derivative or a salt thereof, which exhibits an action of promoting contraction of the digestive tract of a mammal and is useful as an agent for promoting contractile movement of the digestive tract.
  • gastrointestinal motility enhancers include direct acetylcholine agonists such as acratonium napadisylate, indirect acetylcholine agonists such as cisapride, dopamine blockers such as domberidon, and obiate agonists such as trimebutine maleate.
  • gastrointestinal motility enhancers include direct acetylcholine agonists such as acratonium napadisylate, indirect acetylcholine agonists such as cisapride, dopamine blockers such as domberidon, and obiate agonists such as trimebutine maleate.
  • gastrointestinal symptoms such as dysfunction of gastrointestinal motility, particularly complaints of indefinite complaints due to hypokinesia.
  • these drugs are accompanied by side effects such as extrapyramidal symptoms and enhanced lactation due to dopamine blocking action.
  • the mode of gastrointestinal motility promoted by these drugs is different from the naturally occurring physiologic movement that propagates from the
  • motilin is known as a gastrointestinal hormone that stimulates the contractile movement of the gastrointestinal tract.
  • erythromycin and its derivatives have been found to have a motilin-like gastrointestinal contraction-promoting action.
  • An erythromycin derivative which is acid-resistant, orally administrable, and has a strong gastrointestinal motility-promoting action has been found (JP-A-6-56873). Disclosure of the invention
  • the present inventors have conducted intensive studies from a new viewpoint, and as a result, have found that the acid-resistant erythromycin derivative disclosed in Japanese Patent Application Laid-Open No. 6-56873 is disclosed.
  • a novel erythromycin derivative having a hydroxyl group at position 15 was found as a metabolite in plasma and urine.
  • the compound has a gastrointestinal motility-promoting action equal to or better than that of the starting compound,
  • the present invention has been completed on the basis of the findings described above.
  • R> represents a hydrogen atom or an acyl group
  • R 12 represents a hydrogen atom or a lower alkyl group
  • R 4 represents a hydrogen atom or a lower alkyl group
  • R 5 and R 6 represent a hydrogen atom or a hydroxyl group, at least one of which represents a hydroxyl group
  • Y represents —NR.
  • R 7 , R 8 , R E , R 10 and RH may be the same or different and may have a hydrogen atom or a substituent, A lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a 3- to 7-membered heterocyclic group containing an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom, and an anion, respectively.
  • R 7 and R E, R 9 and R 10 Waso Together with the nitrogen atom adjacent respectively together may form a ⁇ The cycloalkyl group.
  • FIG. 1 shows the LC (APC I) mass spectrum of compound (3).
  • FIG. 2 is a 1 H—ID—NMR spectrum of compound (3).
  • Figure 3 is a 'H- 1 H- DQF- COS Y spectrum of the compound (3).
  • FIG. 4 is a HOHOHA spectrum of the compound (3).
  • the acetyl group means a formyl group, an acetyl group, a propionyl group, a butyryl group, a bivaloyl group, a benzoyl group, an ethoxyquincarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group or the like.
  • the acyloxy group means a formyloxy group, an acetyloxy group, a propionyloxy group, a petyryloxy group, a bivaloyloxy group, a benzoyloxy group, an ethoxycarbonyloxy group, a t-butoxycarbonyloxy group, a benzyloxycarbonyloxy group, or the like.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i- Shows butyl group, sec-butyl group, t-butyl group, neopentyl group, etc.
  • the lower alkenyl group refers to a linear or branched alkenyl group having 2 to 6 carbon atoms, preferably a vinyl group, an aryl group, an n-butenyl group, an i-butenyl group, a sec-butenyl group, or the like.
  • the lower alkynyl group refers to a linear or branched alkynyl group having 2 to 6 carbon atoms, preferably an ethynyl group, a propargyl group, a petynyl group and the like.
  • the cycloalkyl group refers to a cycloalkyl group having 3 to 8 carbon atoms, preferably a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like.
  • Examples of the 3- to 7-membered heterocyclic group containing an oxygen atom, a nitrogen atom or a sulfur atom as a hetero atom include aziridine, azetidine, pyrrolidine, piperidine, oxirane, oxetane, oxolane, tetrahydrovirane, thiirane, Thietane, thiolane, thiane and the like can be mentioned.
  • R 7 and R 8 , R 9 and R 10 may be taken together to form an azacycloalkyl group together with an adjacent nitrogen atom.
  • a group in which one or more carbon violet atoms of the group are replaced with a nitrogen atom such as an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, and a hexamethyleneimino group.
  • An oxygen atom as a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group or a hetero atom, which may have a substituent at R 7 , R 8 , R 9 , R 10 and R tl ;
  • substituent for a 3- to 7-membered heterocyclic group containing a nitrogen atom or a sulfur atom include a hydroxyl group, an amino group, a halogen atom, a nitrile group, an alkyloxy group, a mercapto group, an acyl group, and a carbamoyl group.
  • a substituent in a 3- to 7-membered heterocyclic group containing an acid or nitrogen atom or a sulfur atom as a cycloalkyl group or a hetero atom a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group And hydrocarbon groups such as aralkyl groups.
  • the anion in X- indicates a chloride ion, a bromide ion, an iodide ion, a carboxylate ion, a sulfonate ion, or the like.
  • Examples of the acid that forms a salt include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid, and organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, and methanesulfonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, and methanesulfonic acid.
  • R 5 is a hydrogen atom and Re is a hydroxyl group
  • R 2 and R 3 are either a hydrogen atom, the other is a hydroxyl group
  • R 4 is a methyl group
  • R 5 is a hydrogen atom
  • Re is a hydroxyl group
  • R 7 and R in Y Compounds in which one of e is a methyl group and the other is an isopropyl group are more preferred.
  • de (N-methyl) 1-11-dexoxy15-hydroxy-N-isopropyl pill-12-2-0-methyl-11-oxo-1,8,9-anhydroerythromycin A 6.91 Miquetals are particularly preferred.
  • the compound of the present invention may be a possible stereoisomer or optical isomer of the compound represented by the general formula (1), or a salt thereof.
  • the compound of the present invention can be obtained, for example, as follows.
  • the compound of the present invention may be obtained by administering a known erythromycin derivative, for example, the compound described in the above-mentioned JP-A-6-56873 as a starting compound, for example, administering the starting compound to a mammal, It can be obtained by isolating and purifying from. That is, the raw material compound is dissolved or suspended in water or a buffer, the raw material compound is encapsulated, the raw material compound itself is orally administered to mammals such as rats, dogs and monkeys. It is administered by intravenous, intramuscular, intraperitoneal administration and the like. Biological samples collected to purify the target compound are preferably urine, bile, and feces, but may be organs such as liver, kidney, and lung, and blood.
  • plasma or serum is separated by a general technique in biochemistry, and this plasma or blood slip is used for purification.
  • these are pulverized with a scissor homogenizer or the like, and then extracted with water, a buffer solution, or an organic solvent such as methanol, ethanol, ethyl acetate or the like. If necessary, solids may be removed by filtration, centrifugation or the like.
  • Purification of the target compound from extracts of urine, bile, plasma, serum, feces or organs is performed by general methods of natural product chemistry, such as liquid-liquid extraction, solid-phase extraction, column chromatography, high-performance liquid chromatography, It is performed by a method such as recrystallization.
  • the erythromycin derivative or a salt thereof as a starting compound of the compound of the present invention can be obtained by known means, for example, the method described in the above-mentioned JP-A-6-56873.
  • Compound (2) was dissolved in a solution of 90% 10 OmM lactobionic acid—10% polyethylene glycol 400 to prepare 25 mg Z4 ml, which was used as an administration solution.
  • the administration solution was orally administered by gavage to a rat at a ratio of lm 1 Zhead once a day for 2 days using an oral probe.
  • Urine from each rat excreted between the first dose and 24 hours after the last dose was collected in its entirety.
  • Urine obtained from all rats was combined and filtered using diatomaceous earth. The filtrate was adjusted to pH about 9 with sodium hydrogen carbonate, extracted three times with ethyl acetate, and the obtained ethyl acetate layers were combined and concentrated under reduced pressure.
  • the motilin receptor binding test was performed by the following method [V. Bormans et al., Regul, Peptides s. 15. 143 (1986)].
  • the upper small intestine was removed from the slaughtered egret, and the mucous membrane was detached from the muscular layer, and then homogenized in a 50 mM Tris-HCl buffer (pH 7.4) to obtain a protein solution.
  • 125 1-label motilin purchased from PEN I NSUL A
  • the radioactivity in the protein was measured with a counter, and the radioactivity was measured without any addition.
  • Test example 2 ⁇ contraction activity test on excised specimen of ⁇ heron duodenal longitudinal muscle
  • the erythromycin derivative or a salt thereof in which at least one of the 14-position and the 15-position of the present invention is a hydroxyl group has a strong gastrointestinal motility-promoting activity and is useful as a gastrointestinal motility-promoting agent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des composés correspondant à la formule générale (1) où R1 représente hydrogène ou acyle, tandis que R2 et R3 représentent chacun hydrogène, hydroxy, acyloxy ou amino. R2 et R3 peuvent encore former tous les deux =O ou =NOR12 où R12 représente hydrogène ou alkyle inférieur. R4 représente quant à lui hydrogène ou alkyle inférieur, tandis que R5 et R6 représentent chacun hydrogène ou hydroxy, étant entendu que l'un d'entre eux au moins représente hydroxy. Y représente -NR7R8 ou -N+R9R10R11X1 où les éléments R¿7? à R11 représentent chacun hydrogène, alkyle inférieur, alcényle inférieur, cycloalkyle, etc., R7 et R8 ou, encore, R9 et R10 peuvent chacun former, à l'aide de l'azote adjacent, un azacyclo-alkyle. X?-¿ représente quant à lui un anion. Cette invention concerne également des sels de ces composés acceptables sur le plan pharmaceutique, lesquels peuvent être utilisés en qualité de médicaments aidant aux mouvements digestifs.
PCT/JP1997/002554 1996-07-24 1997-07-24 Derives d'erythromycine Ceased WO1998003531A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU36343/97A AU3634397A (en) 1996-07-24 1997-07-24 Erythromycin derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP22580696 1996-07-24
JP8/225806 1996-07-24

Publications (1)

Publication Number Publication Date
WO1998003531A1 true WO1998003531A1 (fr) 1998-01-29

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Application Number Title Priority Date Filing Date
PCT/JP1997/002554 Ceased WO1998003531A1 (fr) 1996-07-24 1997-07-24 Derives d'erythromycine

Country Status (2)

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AU (1) AU3634397A (fr)
WO (1) WO1998003531A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7635714B2 (en) 2002-10-25 2009-12-22 Chugai Seiyaku Kabushiki Kaisha Methods of treating dyschezia

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0656873A (ja) * 1992-05-26 1994-03-01 Chugai Pharmaceut Co Ltd エリスロマイシン誘導体
JPH0656874A (ja) * 1992-03-19 1994-03-01 Takeda Chem Ind Ltd エリスロマイシン誘導体、その製造法および用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0656874A (ja) * 1992-03-19 1994-03-01 Takeda Chem Ind Ltd エリスロマイシン誘導体、その製造法および用途
JPH0656873A (ja) * 1992-05-26 1994-03-01 Chugai Pharmaceut Co Ltd エリスロマイシン誘導体

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7635714B2 (en) 2002-10-25 2009-12-22 Chugai Seiyaku Kabushiki Kaisha Methods of treating dyschezia

Also Published As

Publication number Publication date
AU3634397A (en) 1998-02-10

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