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WO2001010880A1 - Derives d'erythromycine a - Google Patents

Derives d'erythromycine a Download PDF

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Publication number
WO2001010880A1
WO2001010880A1 PCT/JP2000/005146 JP0005146W WO0110880A1 WO 2001010880 A1 WO2001010880 A1 WO 2001010880A1 JP 0005146 W JP0005146 W JP 0005146W WO 0110880 A1 WO0110880 A1 WO 0110880A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
acetyl
pyridyl
desosaminyl
acid
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/JP2000/005146
Other languages
English (en)
Japanese (ja)
Inventor
Toshifumi Asaka
Masato Kashimura
Akira Manaka
Tetsuya Tanikawa
Tomohiro Sugimoto
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.)
Taisho Pharmaceutical Co Ltd
Original Assignee
Taisho 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 Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Priority to AU61838/00A priority Critical patent/AU6183800A/en
Publication of WO2001010880A1 publication Critical patent/WO2001010880A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to novel erythromycin A derivatives of antibiotics. More specifically, the present invention relates to a novel erythromycin A derivative having antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin-resistant bacteria (eg, resistant pneumococci and streptococci).
  • erythromycin-resistant bacteria eg, resistant pneumococci and streptococci.
  • Erythromycin is a macrolide antibiotic that is widely used as a treatment for infectious diseases caused by gram-positive bacteria, mycoplasma, and the like.
  • erythromycin has the drawback that it is easily decomposed by acid in the stomach because it is unstable to acid, and its pharmacokinetics is not constant.
  • Many derivatives have been investigated for the purpose of improving the instability to this acid.
  • a 6- ⁇ _methylerythromycin A derivative (US Pat. No. 4,331,803) has increased acid stability. It has been reported that its antibacterial activity in vivo upon oral administration is superior to that of erythromycin. I have.
  • an erythromycin 3-position acyl derivative aimed at expanding the antibacterial spectrum in addition to acid stability (US Pat. No. 5,631,354; W098 / 23628). Disclosure of the invention
  • the present inventors have introduced a certain type of acyl group at the 3-position of erythromycin.
  • the 11- and 12-positions are cyclic carbamates and have a nitrogen atom.
  • a novel erythromycin derivative in which one of the nitrogen atoms of a condensed ring of a 5-membered ring and a 5-membered ring is bonded to the nitrogen atom of a cyclic bamate group through an alkyl group having 2 to 6 carbon atoms.
  • the present inventors have found that they have strong antibacterial activity against erythromycin-resistant bacteria and influenza bacteria, and completed the present invention.
  • the present invention relates to the formula (1)
  • ⁇ represents an integer of 2 to 6
  • R 1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • R 2 represents a pyridyl group, a virazyl group, or a thiazolyl group.
  • X 4 , X 5 or X 6 is at least one of the formula (5)
  • R 3 is a hydrogen atom, a hydroxyl group, a nitro group, an alkyl group having 13 carbon atoms, a ureido group, a guanidyl group, a dimethylamino group, a trifluoromethyl group, a halogen atom, an amino group, a carbon atom number.
  • Upsilon 4 or Upsilon 5 represents an oxygen atom or a sulfur atom, and the other nitrogen atom or the formula (9)
  • n is 4, R 1 is a methyl group, and a group represented by an aromatic ring of the formulas (3) to (6) is, for example, indoleyl Group, benzopyrazolyl group, benzimidazolyl group, benzotriazolyl group, pyrrolopyridyl group, pyrazolyl pyridyl group, imidazopyridyl group, triazopyridyl group, pyrrolylic pyrimidyl group, pyrazolyl pyrimidyl group, imidazopyrimidyl group, triazopyrimidyl group
  • the alkyl group having 1 to 3 carbon atoms means a methyl group, an ethyl group, an n-propyl group or an iso-propyl group.
  • the alkoxy group having 13 carbon atoms means a methoxy group, an ethoxy group, or a propoxy group.
  • Pharmaceutically acceptable salts are used in chemotherapy and prevention of bacterial infections which means They include, for example, acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethyl succinic acid, lactobionic acid, dalconic acid, dalcoheptonic acid, benzoic acid, methanesulfone Acid, ethanesulfonic acid, 2-hydroxyxetanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, malic acid, aspartic acid, glutamic acid, adipic acid, cysteine, N-acetyl cysteine, hydrochloric acid , Hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid
  • the compounds of the present invention can be administered orally or parenterally.
  • the dosage forms are tablets, capsules, powders, troches, ointments, suspensions, suppositories, injections, etc., which can be produced by conventional formulation techniques.
  • the dosage is 100-l OOOmg / day for treating adults, which can be administered 2-3 times a day. This dose can be adjusted appropriately according to the age, weight and condition of the patient.
  • the compound of the present invention can be produced, for example, as follows.
  • the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the yellow oily substance obtained as a crude product was dissolved in 10 ml of methanol and heated under reflux for 5 hours.
  • Example 10 10, 11-anhydro-2 '-0-acetyl- 12-0-imidazolylcarbo 2 3-O-(2-pyridyl) acetyl-5-1-desosaminyl 6--1-methylerythronolide A 500mg (0.605mmol ) And synthesized in the same manner as in Reference Example 1. The same procedure as in Example 1 was carried out using 579 mg (3.03 mmol) of 4- (9 H-purin-9-yl) butylamine to obtain 320 mg of the title compound.
  • Example 1 10, 11-anhydro- 1 2'- ⁇ -acetyl-5- 0_desosaminyl 12- O-imidazolylcarbonyl 3-- ⁇ - (2-pyridyl) acetyl-6-O-methyl erythronolide A 1.80 g (2.18mmoI ) And Reference Example 1 were synthesized in the same manner as in Example 1 using 2.60 g (ll. 1 mmol) of 4- (5-nitro-2H-indazo-2-yl) butylamine. 1.32 g of the compound was obtained.
  • the compounds of the present invention showed stronger antibacterial activity than the comparative drugs 1 and 2. Therefore, it was shown to be useful as a new antibiotic. Industrial applicability
  • the compound of the present invention has antibacterial activity not only against erythromycin-sensitive bacteria but also against erythromycin-resistant bacteria. Accordingly, the compounds of the present invention are useful as new antibiotics for the treatment of bacterial infections in humans and animals (including farm animals).

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux dérivés d'érythromycine représentés par la formule générale (1), caractérisés par un groupe acyle introduit à la position 3, une structure de carbamate cyclique condensée aux positions 11 et 12, et un cycle condensé composé d'un hétérocycle azoté à cinq chaînons et un cycle à 5 ou 6 chaînons, dont un des atomes d'azote est lié à l'atome d'azote carbamate par un groupe alkyle C2-C6, ces nouveaux dérivés présentant des effets antimicrobiens puissants sur les bactéries résistant à l'érythromycine et sur l'Haemophilus influen zae.
PCT/JP2000/005146 1999-08-06 2000-07-31 Derives d'erythromycine a Ceased WO2001010880A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61838/00A AU6183800A (en) 1999-08-06 2000-07-31 Erythromycin a derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP22355699 1999-08-06
JP11/223556 1999-08-06

Publications (1)

Publication Number Publication Date
WO2001010880A1 true WO2001010880A1 (fr) 2001-02-15

Family

ID=16800020

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/005146 Ceased WO2001010880A1 (fr) 1999-08-06 2000-07-31 Derives d'erythromycine a

Country Status (2)

Country Link
AU (1) AU6183800A (fr)
WO (1) WO2001010880A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6825172B2 (en) 2002-05-31 2004-11-30 Janssen Pharmaceutica, Nv 3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide antibacterial agents
US6849608B2 (en) 2000-08-07 2005-02-01 Pfizer, Inc. Macrolide antibiotics
WO2006035301A3 (fr) * 2004-09-27 2007-04-19 Ranbaxy Lab Ltd Agents antibactériens
JP2007531794A (ja) * 2004-04-05 2007-11-08 アルニラム ファーマスーティカルズ インコーポレイテッド オリゴヌクレオチドの合成および精製に使用する方法および反応試薬
CN103797013A (zh) * 2011-07-21 2014-05-14 埃斯蒂维实验室股份有限公司 吡唑并[3,4-d]嘧啶化合物、它们的制备及作为西格玛配体的用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997031929A1 (fr) * 1996-02-28 1997-09-04 Hoechst Marion Roussel Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments
US5786339A (en) * 1994-12-09 1998-07-28 Roussel Uclaf Erythromycins
AU6421398A (en) * 1997-03-24 1998-10-20 Taisho Pharmaceutical Co., Ltd. Erythromycin a derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5786339A (en) * 1994-12-09 1998-07-28 Roussel Uclaf Erythromycins
WO1997031929A1 (fr) * 1996-02-28 1997-09-04 Hoechst Marion Roussel Nouveaux derives de l'erythromycine, leur procede de preparation et leur application comme medicaments
AU6421398A (en) * 1997-03-24 1998-10-20 Taisho Pharmaceutical Co., Ltd. Erythromycin a derivatives

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6849608B2 (en) 2000-08-07 2005-02-01 Pfizer, Inc. Macrolide antibiotics
US6825172B2 (en) 2002-05-31 2004-11-30 Janssen Pharmaceutica, Nv 3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide antibacterial agents
JP2007531794A (ja) * 2004-04-05 2007-11-08 アルニラム ファーマスーティカルズ インコーポレイテッド オリゴヌクレオチドの合成および精製に使用する方法および反応試薬
US8431693B2 (en) 2004-04-05 2013-04-30 Alnylam Pharmaceuticals, Inc. Process for desilylation of oligonucleotides
WO2006035301A3 (fr) * 2004-09-27 2007-04-19 Ranbaxy Lab Ltd Agents antibactériens
CN103797013A (zh) * 2011-07-21 2014-05-14 埃斯蒂维实验室股份有限公司 吡唑并[3,4-d]嘧啶化合物、它们的制备及作为西格玛配体的用途
JP2014520872A (ja) * 2011-07-21 2014-08-25 ラボラトリオス・デル・デエレ・エステベ・エセ・ア ピラゾロ［３，４−ｄ］ピリミジン化合物、その製造およびシグマリガンドとしての使用
US9567338B2 (en) 2011-07-21 2017-02-14 Laboratorios Del Dr. Esteve S.A. Pyrazolo[3,4-d]pyrimidine compounds, their preparation and use as sigma ligands

Also Published As

Publication number Publication date
AU6183800A (en) 2001-03-05

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