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WO2000077016A1 - Derives de 4'-demycarosyl-8a-aza-8a-homotylosine - Google Patents

Derives de 4'-demycarosyl-8a-aza-8a-homotylosine Download PDF

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Publication number
WO2000077016A1
WO2000077016A1 PCT/HR2000/000018 HR0000018W WO0077016A1 WO 2000077016 A1 WO2000077016 A1 WO 2000077016A1 HR 0000018 W HR0000018 W HR 0000018W WO 0077016 A1 WO0077016 A1 WO 0077016A1
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WIPO (PCT)
Prior art keywords
coch
represent
och
same
formula
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PCT/HR2000/000018
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English (en)
Inventor
Nevenka Lopotar
Amalija Narandja
Stjepan Mutak
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Pliva Farmaceutika dd
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Pliva Farmaceutika dd
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 Pliva Farmaceutika dd filed Critical Pliva Farmaceutika dd
Priority to CA002375812A priority Critical patent/CA2375812A1/fr
Priority to UA2001129085A priority patent/UA66930C2/uk
Priority to JP2001503873A priority patent/JP2003502338A/ja
Priority to EA200200026A priority patent/EA200200026A1/ru
Priority to AU55583/00A priority patent/AU767543B2/en
Priority to SK1757-2001A priority patent/SK17572001A3/sk
Priority to EP00940676A priority patent/EP1189914A1/fr
Publication of WO2000077016A1 publication Critical patent/WO2000077016A1/fr
Priority to NO20016030A priority patent/NO322424B1/no
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
    • 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 compounds from the class of 17-membered azalides having an antibacterial action. More particularly, the invention relates to derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin of the formula I
  • R represents CHO, CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 ,
  • R 1 represents H or C ⁇ -C 3 acyl
  • R 2 represents OR 6 and R 6 represents H or C C 3 acyl
  • R 4 represents OH
  • Prior Art 4'-Demycarosyl-8a-aza-8a-homotylosin a novel semisynthetic macrolide from the class of 17-membered azalides, was prepared by a double transformation of C-9 ketone of the 16-membered antibiotic 4'-demycarosyl-tylosin (R. L. Hamill, Antibiotics and Chemotherapy 11, 328 (1961); A. Narandja et al, EP 0 287 082 B l; N. Lopotar et al, EP 0 410 433 B l). By reductive amination of C-20 aldehyde group in the presence of formic acid (Wallach reaction, J.
  • R represents CHO, CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2 ,
  • R 1 represents H or C C 3 acyl
  • R 2 represents OR 6 and R 6 represents H or C C 3 acyl
  • R 4 represents OH
  • R represents CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2
  • R 1 represents COCH 3
  • R 2 represents OR 6
  • R 6 represents H
  • R 3 and R 5 are the same and represent H and R 4 represents OH
  • R represents CH(OCH 3 ) or CH 2 N[CH 2 (C 6 H 5 )] 2
  • R 1 represents COCH 3
  • R 4 represents OH
  • R 5 represents H
  • R represents CH(OCH 3 ) 2 or CH 2 N[CH 2 (C 6 H 5 )] 2
  • R 1 and R 5 are the same and represent H
  • R 2 and R 3 together represent 0 and R 4 represents OH;
  • R represents a CH(OCH 3 ) 2 group
  • R 1 represents COCH 3
  • R 2 and R 3 together represent 0
  • R 4 represents OH
  • R 5 represents H
  • R represents CH(OCH 3 ) 2
  • R 1 represents COCH 3
  • R 2 represents OR 6
  • R 6 represents COCH 3
  • R 3 and R 5 are the same and represent H and R 4 represents OH
  • R represents CHO, R , R and R are the same and represent H, R represents OR , wherein R represents COCH 3 , and R 4 represents OH.
  • novel compouds are isolated by conventional processes of extraction from aqueous solutions of halogenated hydrocarbons such as methylene chloride or chloroform and by evaporating the organic solvent to a dry residue.
  • the separation of the reaction products or the purification of the products for spectral analyses is carried out by flash chromatography on a silica gel column (Merck & Co., Silicagel 60, 230-400 mesh/ASTM) in a solvent ist: CH 2 Cl 2 -CH 3 OH-conc. NH 4 OH (90:9: 1.5, system A), CH 2 C1 2 -CH 3 0H (90:9, system B) or CHC1 3 -CH 3 C0CH 3 (7:3, system C).
  • novel compounds show antibacterial action and may be also used as intermediates for preparing novel 17-membered azalide antibiotics.
  • TLC Rf (B) 0.44; Rf (C) 0.22.
  • TLC Rf (B) 0.38; Rf (C) 0.23.
  • TLC Rf (A) 0.65; Rf (C) 0.54.
  • TLC Rf (B) 0.55; Rf (C) 0.47.
  • TLC Rf (B) 0.48; Rf (C) 0.33.
  • the compound 5 (0.65 g, 0.71 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 48 hours. To the reaction solution a saturated NaHC0 3 solution was added and it was extracted twice with chloroform. The combined organic extracts were dried (K 2 C0 3 ) and evaporated at reduced pressure to a dry residue. The obtained crude product (0.45 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (9) (0.20 g).
  • the compound 6 (0.30 g, 0.73 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 30 hours. After addition of water (50 ml) the product was isolated by a gradient extraction with chloroform at pH 4.5 and 7.5. The combined chloroform extracts at pH 7.5 were dried (K 2 C0 3 ) and evaporated at reduced pressure and the obtained product (0J7 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (10) (0.08 g).
  • the compound 7 (0.70 g, 0.73 mmol) was dissolved in methanol (50 ml) and left to stand at room temperature for 24 hours.
  • the isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.62 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (11) (0.40 g).
  • the compound 3 (0.5 g, 0.52 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 24 hours.
  • the isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.43 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (13) (0.32 g).
  • the compound 4 (0.75 g, 0.69 mmol) was dissolved in methanol (20 ml) and left to stand at room temperature for 24 hours.
  • the isolation of the product was carried out in the manner disclosed in Example 12 and the obtained crude product (0.66 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (14) (0.45 g).
  • TLC Rf (A) 0.39. ⁇ t KB- cm "1 1739, 1714, 1650, 1620, 1544, 1455, 1375, 1170, 1063.
  • the compound 12 (0.78 g, 0.77 mmol) was dissolved in a methanol/conc. NH 4 OH mixture (4: 1, 50 ml) and left to stand for 24 hours at room temperature. To the reaction solution water (80 ml) was added and it was extracted twice with methylene chloride at pH 7.5. The combined organic extracts were dried (K 2 C0 3 ) and evaporated at reduced pressure and the obtained product (0.66 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (16) (0.32 g).
  • the compound 15 (0.5 g, 0.60 mmol) was dissolved in an acetonitrile/OJ N HC1 mixture (1 : 1, 35 ml) and stirred for 2 hours at room temperature. To the reaction solution a saturated NaHC0 3 solution was added and it was extracted twice with methylene chloride. The combined organic extracts were dried (K C0 3 ) and evaporated at reduced pressure and the obtained product (0.42 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (17) (0.25 g).
  • the compound 1 (0.5 g, 0.55 mmol) was dissolved in an acetonitrile/OJ N HCl mixture (1 : 1, 35 ml) and stirred for 2 hours at room temperature.
  • the isolation of the product was carried out in the manner disclosed in Example 17 to give a TLC homogeneous product (18) (0.34 g).
  • the compound 3 (0.5 g, 0.52 mmol) was dissolved in an acetonitrile/OJ N HCl mixture (1: 1, 35 ml) and stirred for 2 hours at room temperature.
  • the isolation of the product was carried out in the manner disclosed in Example 17 to give a TLC homogeneous product (19) (0.47 g).
  • TLC Rf (B) 0.60; Rf (C) 0.50.
  • the compound 5 (0.7 g, 0.77 mmol) was dissolved in an acetonitrile/OJ N HCl mixture (1: 1, 50 ml) and stirred for 1 hour at room temperature.
  • the isolation of the product was carried out in the manner disclosed in Example 17 to give a TLC homogeneous product (20) (0.36 g).
  • the compound 19 (0.30 g, 0.33 mmol) was dissolved in methanol (20 ml) and left to stand for 24 hours at room temperature.
  • the isolation of the product was carried out in the manner disclosed in Example 9 and the obtained crude product (0.25 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (21) (0.19 g).

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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)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (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)
  • Cephalosporin Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne des dérivés de 4'-demycarosyl-8a-aza-8a-homotylosine représentés par la formule (I), dans laquelle R représente CHO, CH(OCH3)2 ou CH2N[CH2(C6H5)]2, R1 représente H ou C¿1?-C3 acyle, R?2¿ représente OR6 et R6 représente H ou C¿1?-C3 acyle, R?3¿ représente H ou R2 et R3 représentent ensemble =O, R4 représente OH, R5 représente H ou R4 et R5 représentent ensemble =O, ainsi qu'un procédé de préparation desdits dérivés. Ces nouveaux dérivés, qui ont une action antibactérienne, peuvent également être utilisés comme produits intermédiaires dans la préparation de nouveaux antibiotiques à base d'azalides à 17 éléments.
PCT/HR2000/000018 1999-06-11 2000-06-06 Derives de 4'-demycarosyl-8a-aza-8a-homotylosine Ceased WO2000077016A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CA002375812A CA2375812A1 (fr) 1999-06-11 2000-06-06 Derives de 4'-demycarosyl-8a-aza-8a-homotylosine
UA2001129085A UA66930C2 (uk) 1999-06-11 2000-06-06 Похідні 4'-демікарозил-8а-аза-8а-гомотилозину
JP2001503873A JP2003502338A (ja) 1999-06-11 2000-06-06 ４’−デミカロシル−８ａ−アザ−８ａ−ホモタイロシンの誘導体
EA200200026A EA200200026A1 (ru) 1999-06-11 2000-06-06 ПРОИЗВОДНЫЕ 4'-ДЕМИКАРОЗИЛ-8а-АЗА-8а-ГОМОТИЛОЗИНА
AU55583/00A AU767543B2 (en) 1999-06-11 2000-06-06 Derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin
SK1757-2001A SK17572001A3 (sk) 1999-06-11 2000-06-06 4'-Demykarozyl-8a-aza-8a-homotylozíny a spôsob ich výroby
EP00940676A EP1189914A1 (fr) 1999-06-11 2000-06-06 Derives de 4'-demycarosyl-8a-aza-8a-homotylosine
NO20016030A NO322424B1 (no) 1999-06-11 2001-12-10 Derivater av 4'-demykarosyl-8a-aza-8a-homotylosin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HRP990192A 1999-06-11
HR990192A HRP990192A2 (en) 1999-06-11 1999-06-11 4'-DEMICAROZYL-8a-AZA-8a-HOMOTHILOSINE DERIVATIVES

Publications (1)

Publication Number Publication Date
WO2000077016A1 true WO2000077016A1 (fr) 2000-12-21

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PCT/HR2000/000018 Ceased WO2000077016A1 (fr) 1999-06-11 2000-06-06 Derives de 4'-demycarosyl-8a-aza-8a-homotylosine

Country Status (13)

Country Link
EP (1) EP1189914A1 (fr)
JP (1) JP2003502338A (fr)
AU (1) AU767543B2 (fr)
CA (1) CA2375812A1 (fr)
CZ (1) CZ20014362A3 (fr)
EA (1) EA200200026A1 (fr)
HR (1) HRP990192A2 (fr)
HU (1) HUP0201610A3 (fr)
NO (1) NO322424B1 (fr)
SK (1) SK17572001A3 (fr)
UA (1) UA66930C2 (fr)
WO (1) WO2000077016A1 (fr)
YU (1) YU87401A (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078770A1 (fr) * 2003-03-05 2004-09-16 Rib-X Pharmaceuticals, Inc. Composes heterocycliques bifonctionnels et leurs procedes d'obtention et d'utilisation
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
US7365174B2 (en) 2003-08-22 2008-04-29 Meiji Seika Kaisha, Ltd. Azalide and azalactam derivatives and method for producing the same
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0287082A2 (fr) * 1987-04-14 1988-10-19 SOUR PLIVA farmaceutska, Kemijska prehrambena i kozmeticka industrija, n.sol.o. Dérivés de la tylosine et de la 10,11,12,13-tétrahydrotylosine, leur méthode de préparation et leur utilisation dans des compositions pharmaceutiques et dans la préparation de celles-ci
EP0410433A2 (fr) * 1989-07-26 1991-01-30 Pliva Farmaceutska, Kemijska, Prehrambena I Kozmeticka Industrija S P.O. Dérivés de tylosine
EP0891981A1 (fr) * 1997-07-16 1999-01-20 PLIVA, farmaceutska, kemijska, prehrambena i kozmeticka industrija dionicko drustvo Composés sécomacrolides de tylosin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0287082A2 (fr) * 1987-04-14 1988-10-19 SOUR PLIVA farmaceutska, Kemijska prehrambena i kozmeticka industrija, n.sol.o. Dérivés de la tylosine et de la 10,11,12,13-tétrahydrotylosine, leur méthode de préparation et leur utilisation dans des compositions pharmaceutiques et dans la préparation de celles-ci
EP0410433A2 (fr) * 1989-07-26 1991-01-30 Pliva Farmaceutska, Kemijska, Prehrambena I Kozmeticka Industrija S P.O. Dérivés de tylosine
EP0891981A1 (fr) * 1997-07-16 1999-01-20 PLIVA, farmaceutska, kemijska, prehrambena i kozmeticka industrija dionicko drustvo Composés sécomacrolides de tylosin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GRDISA, MIRA ET AL: "Effect of a 17-member azalide on tumor cell growth", CHEMOTHERAPY (BASEL) (1998), 44(5), 331-336, 1998, XP000940917 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2004078770A1 (fr) * 2003-03-05 2004-09-16 Rib-X Pharmaceuticals, Inc. Composes heterocycliques bifonctionnels et leurs procedes d'obtention et d'utilisation
US7365174B2 (en) 2003-08-22 2008-04-29 Meiji Seika Kaisha, Ltd. Azalide and azalactam derivatives and method for producing the same
US8202843B2 (en) 2004-02-27 2012-06-19 Rib-X Pharmaceuticals, Inc. Macrocyclic compounds and methods of making and using the same
US8841263B2 (en) 2004-02-27 2014-09-23 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same

Also Published As

Publication number Publication date
HRP990192A2 (en) 2001-04-30
CA2375812A1 (fr) 2000-12-21
EA200200026A1 (ru) 2002-06-27
YU87401A (sh) 2004-07-15
NO20016030L (no) 2002-01-30
AU767543B2 (en) 2003-11-13
AU5558300A (en) 2001-01-02
HUP0201610A3 (en) 2003-03-28
NO20016030D0 (no) 2001-12-10
SK17572001A3 (sk) 2002-04-04
HUP0201610A2 (en) 2002-10-28
NO322424B1 (no) 2006-10-02
JP2003502338A (ja) 2003-01-21
EP1189914A1 (fr) 2002-03-27
UA66930C2 (uk) 2004-06-15
CZ20014362A3 (cs) 2002-04-17

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