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WO1994010185A1 - Derive d'erythromycine - Google Patents

Derive d'erythromycine Download PDF

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Publication number
WO1994010185A1
WO1994010185A1 PCT/JP1993/001594 JP9301594W WO9410185A1 WO 1994010185 A1 WO1994010185 A1 WO 1994010185A1 JP 9301594 W JP9301594 W JP 9301594W WO 9410185 A1 WO9410185 A1 WO 9410185A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
methyl
optionally substituted
added
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/JP1993/001594
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English (en)
Japanese (ja)
Inventor
Hiroshi Koga
Kouichi Tsuzuki
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 AU53763/94A priority Critical patent/AU5376394A/en
Publication of WO1994010185A1 publication Critical patent/WO1994010185A1/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 has an action of promoting the contraction of the digestive tract of mammals and is useful as an agent for promoting the contraction of the gastrointestinal tract.
  • Gastrointestinal motility promoters are considered to be direct acetylcholine agonists (acratonium napadisylate), indirect acetylcholine agonists (cisapride), dopamine blockers (domperidone), and opiate agonists (trimeptin maleate) from the viewpoint of action. It is widely used as a therapeutic drug for gastrointestinal symptoms such as dysfunction of gastrointestinal motility, particularly indefinite complaints of gastrointestinal dysfunction due to hypokinesia. However, these drugs have side effects such as extrapyramidal symptoms and increased lactation due to dopamine blocking action. In addition, the mode of gastrointestinal motility promoted by these drugs is different from the naturally occurring physiologic movement that propagates from the upper gastrointestinal tract to the lower gastrointestinal tract, and is often accompanied by side effects such as diarrhea and vomiting. Is known o
  • motilin is known as a gastrointestinal hormone that stimulates the contractile movement of the gastrointestinal tract, but the supply of motilin by extraction from nature and chemical synthesis has been unsatisfactory, and large-scale supply has been difficult. Since motilin is a peptide consisting of 22 amino acids, it was difficult to develop it as an oral preparation.
  • EM-523 is acid-labile and is expected to be degraded by gastric acid when used orally, resulting in diminished effects. Therefore, the present inventors have conducted intensive studies to find an erythromycin derivative which is acid-resistant and orally administrable, and as a result, the following novel erythromycin derivative not described in the literature has such properties and effects. And found the present invention based on this finding.
  • the compound of the present invention is represented by the following general formula (I).
  • R 5 represents a lower alkyl group, and Y represents one NR 6 R 7 or —N + R 8 R 9 R 1 () X—.
  • R 6 and R 7 are the same or different and each have a hydrogen atom, an acyl group, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
  • R 8 , R 9, and R 10 may be the same or different and are a hydrogen atom and a lower alkyl optionally substituted with a lower alkenyl group which may be substituted or a lower alkynyl group which may be substituted.
  • acyl group refers to a formyl group, an acetyl group, a propionyl group, a butyryl group, a bivaloyl group, a benzoyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, and the like. What is meant by formyloxy, acetyloxy, propionyloxy, butyryloxy, bivaloyloxy, benzoyloxy, ethoxycarbonyloxy, t-butoxycarbonyloxy, benzyloxycarbonyloxy, etc.
  • a lower alkyl group refers to an 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, a sec-butyl group, a t-butyl group.
  • a cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms.
  • a lower alkenyl group refers to an alkenyl group having 2 to 6 carbon atoms, preferably a vinyl group, an aryl group, an n-butenyl group, an i-butenyl group
  • a lower alkynyl group refers to an alkynyl group having 2 to 6 carbon atoms, preferably an ethynyl group, a propargyl group, a butynyl group, and the like, and a lower group which may have a substituent
  • substituent in the alkyl group, cycloalkyl group, lower alkenyl group or lower alkynyl group include a hydroxyl group, an amino group, a halogen atom, a nitrile group, an alkyloxy group, a mercapto group, a formyl group, and the
  • chlorine ion bromine ion”, “iodine ion”, “carboxylate ion”, “sulfonate ion” and the like are used.
  • the salt-forming acid include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid, and organic acids such as acetic acid, silicic acid, maleic acid, fumaric acid, and methanesulfonic acid. .
  • the compound (I) of the present invention can be produced by reacting the compound (II) with an alkylating agent in an inert solvent in the presence of a base, followed by deprotection alkylation if necessary. .
  • alkylating agent used in the alkylation reaction examples include alkyl halide dialkyl sulfonates.
  • the base examples include metal bases such as sodium hydride, sodium alkoxide, potassium alkoxide, alkyl lithium, lithium carbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, and triethylamine, trimethylamine, and the like. Amines are used.
  • the inert solvent examples include methanol, ethanol, propanol, porcine form, methylene chloride, ether, tetrahydrofuran, and ⁇ , ⁇ -dimethylformamide.
  • the compound (I) of the present invention can also be obtained by applying the specific production methods described in Examples.
  • the compound (I) of the present invention did not show a decrease in activity under acidic conditions, unlike II-523.
  • it showed a strong gastrointestinal motility-promoting effect upon oral administration, and is particularly useful as an oral agent as a constriction motility promoter for the digestive tract of mammals.
  • Compound 2 N, 2,10-bis (benzyloxycarbonyl) -de (N-methyl) -18,9-anhydrohydroerythromycin A 6,9-hemiketal (Compound 2) white powder 37.9 g (Yield) 99%).
  • Compound 1 was synthesized according to the method described in the literature (EH F lynn, HW Mrp hy, R. E. McMahon; Journal of American Chem. 1 Society 77 3104 (1955)).
  • Compound 2 37.9 g and 4-dimethylaminopyridine
  • Table 1 the NMR spectrum data, the MS spectrum value and the optical rotation for 6, 7, 9, 11, and 13 are shown in Table 1.
  • the NMR spectra for compounds 15, 17, 19, 20, 22, and 24 are shown in Table 1.
  • Table 2 shows the spectrum data, MS spectrum value, and optical rotation.
  • the duodenum was excised from the slaughtered egret, and the mucous membrane was detached from the muscular layer, and then homogenized in a 5 OmM Tris solution ( ⁇ 7.4) to obtain a protein solution.
  • the concentration of the drug reduced to% was expressed as IC 5 o (M).
  • the protein was dissolved in DMSO solution and added to the protein solution (final DMSO concentration. It was dissolved in an acid solution (pH 2.5), left at room temperature for 120 minutes, added to the protein solution, and used for the experiment.
  • the gastrointestinal contractile movement was measured by the following method [Satoru Ito, Journal of the Japanese Society of Smooth Muscle, 13, 33 (1976)].
  • a beagle dog weighing about 10 kg is laparotomized under general anesthesia in advance, and a force 'transducer is chronically applied to the gastric antrum, duodenum and jejunum in a direction in which the contraction of each cricoid muscle can be measured. did.
  • a medical silicone tube was placed in the stomach to directly administer the drug into the stomach. The lead wire of the Force 'transducer and the silicone tube were pulled out from the back and fixed to the skin. Reared in individual laboratory cages, feed once daily Was.
  • the principle of the transducer is that when the gasket at the abutted part shrinks and the transducer is bent, a waveform proportional to the force is recorded on a pen-written oscillograph. By connecting the lead from the transducer to the oscillograph, the contraction waveform can be recorded immediately. Gastrointestinal contractile movements can be broadly divided into two phases, the postprandial period and the fasting period, based on their contraction patterns.
  • the experiment was started two weeks after the operation, and was performed in the fasting period, during the rest period in which no gastric fasting contraction occurred. That is, the sample was directly injected into the stomach for about 10 seconds through a silicon tube placed in the stomach. The drug was dissolved in ethanol beforehand and diluted with saline to make a total volume of 3 ml.
  • MI Motor Index
  • EM-523 and Compound 13 Each showed a gastrointestinal motility-promoting action, and the respective MI 15 () was 14.6 t / gZkg and 2.3 / gZkg. Compound 13 showed a gastrointestinal motility-promoting effect about 6 times stronger than that of EM-523 by intragastric administration.
  • the erythromycin derivative of the present invention having a gastrointestinal motility-promoting action is remarkably superior to the conventionally known erythromycin derivative such as EM-523 in terms of acid stability.
  • the erythromycin derivative of the present invention unlike the conventional erythromycin derivative which is unstable to acid, has a very low degree of decomposition by stomach acid, and thus shows a strong gastrointestinal motility promoting action even when used orally.

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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)
  • Saccharide Compounds (AREA)

Abstract

Composé représenté par la formule générale (I), ou sel de ce composé, étant l'un et l'autre administrables par voie orale du fait de leur excellente aptitude à stimuler l'activité gastrointestinale et à leur très faible décomposition par réaction du suc gastrique, comparés aux dérivés d'érythromcyne connus. Dans ladite formule R1 représente hydrogène ou acyle; R2 et R3, pouvant être identiques ou différents l'un de l'autre, représentent individuellement hydrogène, hydroxy ou acyoxy, ou peuvent être combinés ensemble pour représenter = O; R4 représente hydrogène ou un alkyle inférieur; R5 représente alkyle inférieur; Y représente -NR6R7 ou -N+R8R9R10X-; R6 et R7, qui peuvent être identiques ou différents l'un de l'autre, représentent chacun hydrogène, acyle ou alkyle inférieur facultativement substitué, cycloalkyle facultativement substitué, alcényle inférieur facultativement substitué ou alkynyle inférieur facultativement substitué; R8, R9 et R10 qui peuvent être identiques ou différents l'un de l'autre représentent chacun hydrogène alkyle inférieur facultativement substitué, cycloalkyle facultativement substitué, alcényle inférieur facultativement substitué ou alkynyle inférieur facultativement substitué; et X représente un anion.
PCT/JP1993/001594 1992-11-04 1993-11-04 Derive d'erythromycine Ceased WO1994010185A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53763/94A AU5376394A (en) 1992-11-04 1993-11-04 Erythromycin derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4/295196 1992-11-04
JP29519692 1992-11-04

Publications (1)

Publication Number Publication Date
WO1994010185A1 true WO1994010185A1 (fr) 1994-05-11

Family

ID=17817444

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001594 Ceased WO1994010185A1 (fr) 1992-11-04 1993-11-04 Derive d'erythromycine

Country Status (4)

Country Link
CN (1) CN1091431A (fr)
AU (1) AU5376394A (fr)
TW (1) TW355711B (fr)
WO (1) WO1994010185A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6077943A (en) * 1996-03-01 2000-06-20 Takeda Chemical Industries, Ltd. Method of producing erythromycin derivative
WO2002102818A1 (fr) * 2001-06-13 2002-12-27 Ube Industries, Ltd. Procede pour preparer des composes d'erythromycine
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
WO2007007018A1 (fr) 2005-07-12 2007-01-18 Glaxo Group Limited Derivés d’hétéroaryle pipérazine en tant qu’agonistes gpr38
US7700599B2 (en) 2006-06-28 2010-04-20 Glaxo Group Limited Gpr38 Receptor Agonists
WO2010098145A1 (fr) 2009-02-27 2010-09-02 Raqualia Pharma Inc. Dérivés d'oxyindole ayant une activité agoniste au récepteur de la motiline
US8012981B2 (en) 2006-06-15 2011-09-06 Glaxo Group Limited Benzylpiperazine derivatives as motilin receptor agonists
EP2441763A1 (fr) 2005-07-26 2012-04-18 Glaxo Group Limited Dérivés de benzylpipérazine utiles pour le traitement de troubles gastro-intestinaux
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6399092A (ja) * 1985-08-31 1988-04-30 Kitasato Inst:The エリスロマイシン誘導体およびその製造法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6399092A (ja) * 1985-08-31 1988-04-30 Kitasato Inst:The エリスロマイシン誘導体およびその製造法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL & PHARMACEUTICAL BULLETIN, Vol. 37, No. 10, pp. 2687-2700, (1989), K. TSUZUKI et al., "Motilides, Macrolides with Gastroin-Testinal Motor Stimulating Activity I". *
CHEMICAL & PHARMACEUTICAL BULLETIN, Vol. 37, No. 10, pp. 2701-2709, (1989), K. TSUZUKI et al., "Motilides, Macrolides with Gastroin-Testinal Motor Stimulating Activity II". *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6077943A (en) * 1996-03-01 2000-06-20 Takeda Chemical Industries, Ltd. Method of producing erythromycin derivative
WO2002102818A1 (fr) * 2001-06-13 2002-12-27 Ube Industries, Ltd. Procede pour preparer des composes d'erythromycine
US6906039B2 (en) 2001-06-13 2005-06-14 Ube Industries, Ltd. Process for preparation of erythromycin compounds
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US7335753B2 (en) 2002-09-26 2008-02-26 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US8841263B2 (en) 2004-02-27 2014-09-23 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8236953B2 (en) 2004-12-29 2012-08-07 Glaxo Group Limited Process for preparing piper azine derivatives
WO2007007018A1 (fr) 2005-07-12 2007-01-18 Glaxo Group Limited Derivés d’hétéroaryle pipérazine en tant qu’agonistes gpr38
EP2441763A1 (fr) 2005-07-26 2012-04-18 Glaxo Group Limited Dérivés de benzylpipérazine utiles pour le traitement de troubles gastro-intestinaux
US8536182B2 (en) 2005-07-26 2013-09-17 Glaxo Group Limited Benzylpiperazine derivatives and their medical use
US8012981B2 (en) 2006-06-15 2011-09-06 Glaxo Group Limited Benzylpiperazine derivatives as motilin receptor agonists
US7700599B2 (en) 2006-06-28 2010-04-20 Glaxo Group Limited Gpr38 Receptor Agonists
US8853218B2 (en) 2006-06-28 2014-10-07 Glaxo Group Limited Compounds
WO2010098145A1 (fr) 2009-02-27 2010-09-02 Raqualia Pharma Inc. Dérivés d'oxyindole ayant une activité agoniste au récepteur de la motiline

Also Published As

Publication number Publication date
TW355711B (en) 1999-04-11
AU5376394A (en) 1994-05-24
CN1091431A (zh) 1994-08-31

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