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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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• 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)

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Cited By (4)

Citations (3)

• 1999
  • 1999-06-11 HR HR990192A patent/HRP990192A2/hr not_active Application Discontinuation
• 2000
  • 2000-06-06 WO PCT/HR2000/000018 patent/WO2000077016A1/en not_active Ceased
  • 2000-06-06 CZ CZ20014362A patent/CZ20014362A3/cs unknown
  • 2000-06-06 JP JP2001503873A patent/JP2003502338A/ja active Pending
  • 2000-06-06 UA UA2001129085A patent/UA66930C2/uk unknown
  • 2000-06-06 HU HU0201610A patent/HUP0201610A3/hu unknown
  • 2000-06-06 YU YU87401A patent/YU87401A/sh unknown
  • 2000-06-06 SK SK1757-2001A patent/SK17572001A3/sk unknown
  • 2000-06-06 EA EA200200026A patent/EA200200026A1/ru unknown
  • 2000-06-06 EP EP00940676A patent/EP1189914A1/en not_active Withdrawn
  • 2000-06-06 AU AU55583/00A patent/AU767543B2/en not_active Ceased
  • 2000-06-06 CA CA002375812A patent/CA2375812A1/en not_active Abandoned
• 2001
  • 2001-12-10 NO NO20016030A patent/NO322424B1/no unknown

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