[go: up one dir, main page]

EP1189914A1 - DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN - Google Patents

DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN

Info

Publication number
EP1189914A1
EP1189914A1 EP00940676A EP00940676A EP1189914A1 EP 1189914 A1 EP1189914 A1 EP 1189914A1 EP 00940676 A EP00940676 A EP 00940676A EP 00940676 A EP00940676 A EP 00940676A EP 1189914 A1 EP1189914 A1 EP 1189914A1
Authority
EP
European Patent Office
Prior art keywords
coch
represent
och
same
formula
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.)
Withdrawn
Application number
EP00940676A
Other languages
German (de)
French (fr)
Inventor
Nevenka; Lopotar
Amalija; Narandja
Stjepan Mutak
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.)
Pliva Farmaceutika dd
Original Assignee
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
Publication of EP1189914A1 publication Critical patent/EP1189914A1/en
Withdrawn legal-status Critical Current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 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).

Landscapes

  • 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)
  • Saccharide Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention relates to derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin of formula (I) wherein R represents CHO, CH(OCH3)2) or CH2N[CH2(C6H5)]2, R1 represents H or C¿1?-C3 acyl, R?2¿ represents OR?6 and R6¿ represents H or C¿1?-C3 acyl, R?3¿ represents H or R?2 and R3¿ together represent =O, R4 represents OH, R5 represents H or R?4 and R5¿ together represent =O, and to a process for the preparation thereof. Novel derivatives show antibacterial action and may also be used as intermediates for preparing novel 17-membered azalide antibiotics.

Description

DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN
Technical Field
IPC: A 61 K 31/70 C 07 H 17/08
Technical Problem
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
I
wherein R represents CHO, CH(OCH3)2 or CH2N[CH2(C6H5)]2,
R1 represents H or Cι-C3 acyl,
R2 represents OR6 and R6 represents H or C C3 acyl,
R3 represents H or R2 and R3 together represent =0,
R4 represents OH,
R5 represents H or R4 and R5 together represent =0, and to a process for the preparation thereof.
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. March: "Advanced Organic Chemistry", third ed. 6-15 p. 799 Wiley, New York, 1985) there was prepared 4'- demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (N. Lopotar, HR Patent Application P940962A, 30.11.1994).
Cι-C3 acyl esters of 4'-demycarosyl-8a-aza-8a-homotylosin and of 4'-demycarosyl- 20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin as well as 4"-deoxy-4"-oxo- and 3-deoxy-3-oxo derivatives of 4'-demycarosyl-8a-aza-8a-homotylosin and of 4'- demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin, CpC3 acyl esters thereof and a process for the preparation thereof have hitherto not been disclosed in Prior Art.
Detailed Description of the Invention
According to the present invention derivatives of 4'-demycarosyl-8a-aza-8a- homotylosin of the formula I
I
wherein R represents CHO, CH(OCH3)2 or CH2N[CH2(C6H5)]2,
R1 represents H or C C3 acyl,
R2 represents OR6 and R6 represents H or C C3 acyl,
R3 represents H or R2 and R3 together represent =0,
R4 represents OH,
R5 represents H or R4 and R5 together represent =0, may be prepared in such a way that
4'-demycarosyl-8a-aza-8a-homotylosin 20-dimethylacetal of the formula Ila and 4' demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin of the formula lib
Ila R = CH(OCH3)2 lib R = CH2N[CH2(C6H5)]2 are subjected to
A) an O-acylation with anhydrides of C C3 carboxylic acids, preferably with acetic acid anhydride in methyl ene chloride during 15 minutes to 1 hour at room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6, wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH,
are optionally subjected to
Al) an O-acylation with anhydrides of C C3 carboxylic acids, preferably with acetic acid anhydride in methylene chloride in the presence of an organic base, preferably tri ethyl amine and 4-dimethylaminopyridine as a catalyst during 30 hours at room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH,
are optionally subjected to
B) an oxidation reaction with N(3-dimethylamino-propyl)-N' ethyl carbodiimide hydrochloride in the presence of dimethylsulfoxide and pyridine trifluoroacetate as a catalyst in an inert solvent, preferably methylene chloride, during 2 to 6 hours at a temperature from 10°C to room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 represents H and R4 and R5 together represent =0,
are optionally subjected to
C) methanolysis at room temperature for 2 days and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 and R3 are the same and represent H, R2 represents OR6, wherein R6 represents COCH3, and R4 and R5 together represent =0, are optionally subjected to
Cl) an alkaline methanolysis in a mixture of methanol and 25% ammonia (4: 1) at a temperature from 5°C to room temperature during 20 to 60 hours to obtain compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 and R3 are the same and represent H, R2 represents OR6, wherein R6 represents H, and R4 and R5 together represent =0;
or the compound obtained according to process Cl of the formula I, wherein R represents CH(OCH3)2, R and R are the same and represent H, R2 represents OR6, wherein R6 represents H, and R4 and R~ together represent =0,
is optionally subjected to
D) a hydrolysis of the acetal in a mixture of acetonitrile and 0.1 N hydrochloric acid (1: 1) for 2 hours at room temperature to obtain the compound of the formula I, wherein R represents a CHO group, R1 and R3 are the same and represent H, R2 represents OR6, wherein R6 represents H, and R4 and R5 together represent =0;
or compounds obtained according to process A of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6, wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH,
are optionally subjected to oxidation in the manner disclosed in B, and the obtained compounds of the formula I, wherein R represents CH(OCH3) or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 and R3 together represent =0, R4 represents OH and R5 represents H,
are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 and R5 are the same and represent H, R2 and R3 together represent =0 and R4 represents OH;
or the compound obtained according to process B of the formula I, wherein R represents a CH(OCH3)2 group, R1 represents COCH3, R2 and R3 together represent =0, R4 represents OH and R5 represents H,
is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, and the obtained compound of the formula I, wherein R represents a CHO group, R1 represents COCH3, R2 and R3 together represent =0, R4 represents OH and R5 represents H,
is optionally subjected to methanolysis in the manner disclosed in C, to obtain the compound of the formula I, wherein R represents a CHO group, R1 and
R5 are the same and represent H, R2 and R together represent =0 and R4 represents
OH;
or the compound obtained according to process A of the formula I, wherein R represents CH(OCH3)2, R1 represents COCH3, R2 represents OR , wherein R represents H, R and R are the same and represent H and R4 represents OH,
is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, to obtain a compound of the formula I wherein R represents CHO, R1 represents COCH3, R2 represents OR6, wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH;
or compounds obtained according to process Al of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH, are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1, R3 and R5 are the same and represent H, R2 represents OR6, wherein R6 represents COCH3, and R4 represents OH;
or the compound obtained according to process Al of the formula I, wherein R represents CH(OCH3)2, R1 represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH,
is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, and the obtained compound of the formula I, wherein R represents CHO, R1 represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH,
is optionally subjected to methanolysis in the manner disclosed in C, to obtain the compound of the formula I, wherein R represents CHO, R , R and R are the same and represent H, R represents OR , wherein R represents COCH3, and R4 represents OH.
According to the present invention 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. Optionally, 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 sistem: CH2Cl2-CH3OH-conc. NH4OH (90:9: 1.5, system A), CH2C12-CH30H (90:9, system B) or CHC13-CH3C0CH3 (7:3, system C).
The structure of the novel compounds was confirmed by spectrometric methods and mass analysis. The novel compounds show antibacterial action and may be also used as intermediates for preparing novel 17-membered azalide antibiotics.
The invention is illustrated and in no way limited by the following Examples.
Example 1
4'-Demycarosyl-2',4'-di-0-acetyl-8a-aza-8a-homotylosin 20-dimethylacetal (1)
4'-Demycarosyl-8a-aza-8a-homotylosin 20-dimethylacetal (5.0 g, 6.02 mmol) was dissolved in dry methylene chloride (50 ml), acetic anhydride (2.0 ml) was added and it was stirred for 15 minutes at room temperature. The reaction mixture was poured into a water/ice mixture (500 ml) and extracted twice with methylene chloride at pH 8.5. The combined organic extracts were washed with a saturated NaHC03 solution and water, dried (K2C03) and evaporated at reduced pressure to give a TLC homogeneous product (1) (5.38 g; 97.8 %).
TLC: Rf (B) 0.44; Rf (C) 0.22.
IR KBr m"1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.
1H NMR (CDC13) δ ppm 7J6 (H-l l), 5.69 (H-10), 5.66 (H-13), 4.96 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.76 (H-4'), 4.63 (H-20), 4.58 (H-l"), 4.33 (H-l'), 4.17 (H-8), 3.61 (3"-OCH3), 3.47 (2"-OCH3), 3.56 (2x20-OCH3), 2.33 /3'-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.17 (H-21).
13C NMR (CDC13) δ ppm 179J (C-l), 169.8, 169.4 (2xCOCH3), 166.2 (9-CONH), 144.7 (C-l l), 138.2 (C-13), 134.9 (C-12), 119.2 (C-10), 103.5 (C-20), 102.0 (C-l '), 100.9 (C-l"), 72.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.5 (3"-OCH3), 59.4 (2"-OCH3), 50.4 (2x20-OCH3), 42.7 (C-8), 42.5 (C-4), 41.0 /3'-N(CH3)2/, 40.5 (C-2), 34.3 (C-19), 21.8, 20.9 (2xCOCH3), 21.9 (C-21), 12.6 (C-22), 8.3 (C-18).
FAB (MH+) 917.
Example 2
4'-Demycarosyl-2',4'-di-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8a- homotylosin (2) 4'-Demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (2.8 g, 2.90 mmol) was dissolved in dry methylene chloride (30 ml), acetic anhydride (1.3 ml, 13.76 mmol) was added and it was stirred for 15 minutes at room temperature. The reaction mixture was poured into a water/ice mixture (300 ml) and extracted twice with methylene chloride at pH 6.5. The combined organic extracts were washed with a saturated NaHC03 solution and water, dried (K2C03) and evaporated at reduced pressure to give a TLC homogeneous product (2) (3.02 g; 98.9 %).
TLC: Rf (B) 0.38; Rf (C) 0.23.
IR (KBr) cm_1 1749, 1651, 1633, 1548, 1454, 1374, 1231, 1169, 1059.
1H NMR (CDC13) δ ppm 7.25 ~ 7.41 (phenyl), 7.10 (H-l l), 5.70 (H-l 3), 5.65 (H-10), 4.89 (8a-NH) exchangeable with D20, 4.84 (H-2'), 4.74 (H-4'), 4.60 (H-l"), 4.15 (H-l'), 3.62 (3"-OCH3), 3.61 (20-N-CH2-phenyl), 3.58 (20-CH2-phenyl), 3.51 (2"-OCH3), 2.32 /3 '-N(CH3)2/, 2.06 (COCH3), 2.00 (COCH3), 1.72 (H- 22), 1.12 (H-21).
13C NMR (CDCI3) δ ppm 173.4 (C-l), 169.9, 169.5 (2xCOCH3), 166.1 (9-CONH), 144.8 (C-l l), 137.9 (C-13), 135.2 (C-12), 119.3 (C-10), 102.3 (C-L), 101.0 (C-l"), 72.5 (C-4"), 71.4 (C-4'), 70.4 (C-2'), 66.0 (C-3), 61.5 (3"-OCH3), 59.5 (2"-OCH3), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 41.0 /3 '-N(CH3)2/, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0 (2xCOCH3), 12.7 (C-22), 8.4 (C-l 8), 20-N(CH2C6H5)2, 139.8, 129.1, 128.0, 126.6, 57.9.
FAB (MH+) 1052.
Example 3
4'-Demycarosyl-2',4',4"-tri-0-acetyl-8a-aza-8a-homotylosin 20-dimethylacetal
(3)
Compound 1 (4.0 g, 4.37 mmol) was dissolved in dry methylene chloride (100 ml), triethyl amine (7.0 ml), 4-dimethylaminopyridine (0J2 g) and acetic anhydride (0.42 ml, 4.45 mmol) were added and then the reaction solution was left to stand for 26 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 1 to give a TLC homogeneous product (3) (4.08 g; 97.7 %).
TLC: Rf (A) 0.65; Rf (C) 0.54.
IR KBrJ cm"1 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, 1052.
1H NMR (CDC13) δ ppm 7.16 (H-l l), 5.69 (H-10), 5.65 (H-l 3), 4.89 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.76 (H-4'), 4.64 (H-l"), 4.59 (H-20), 4.33 (H-l '), 4.18 (H-8), 3.52 (3"-OCH3), 3.46 (2"0CH3), 3.36 (20-OCH3), 3.35 (2O-OCH3), 2.33 /3'-N(CH3)2/, 2.12 (COCH3), 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.16 (H-21).
13C NMR (CDCI3) δ ppm 173.1 (C-l), 170.1, 169.8, 169.4 (3xCOCH3), 166.1 (9-CONH), 144.7 (C-l l), 138.0 (C-13), 134.9 (C-12), 119.2 (C-10), 103.7 (C-20), 102.1 (C-l'), 100.9 (C-l"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'),. 65.6 (C-3), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 53.7 (20-OCH3), 50.6 (20-OCH3), 42.7 (C-8), 42.6 (C-4), 41.0 /3 '-N(CH3)2/, 40.5 (C-2), 34.5 (C-19), 21.9, (C- 21), 21.1, 21.0, 20.7 (3xCOCH3), 12.7 (C-22), 8.3 (C-18).
FAB (MH+) 959.
Example 4
4'-Demycarosyl-2',4',4"-tri-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8a- homotylosin (4)
Compound 2 (2.8 g, 2.66 mmol) was dissolved in dry methylene chloride (60 ml), triethyl amine (3.7 ml), 4-dimethylaminopyridine (0.07 g) and acetic anhydride (0.25 ml, 1.64 mmol) were added and then the reaction solution was left to stand for 26 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 1 to give a TLC homogeneous product (4) (2.7 g; 92.9 %).
TLC: Rf (B) 0.55; Rf (C) 0.47.
IR (KBr) cm"! 1747, 1651, 1632, 1538, 1453, 1372, 1233, 1170, 1051.
1H NMR (CDCI3) δ ppm 7.22 ~ 7.41 (phenyl), 7.10 (H-l l), 5.70 (H-13), 5.65 (H-10), 4.91 (8a-NH) exchangeable with D20, 4.86 (H-2'), 4.74 (H-4'), 4.66 (H-l"), 4.46 (H-4"), 4.15 (H-l '), 3.61 (2x20-N-CH2-phenyl), 3.53 (3"-OCH3), 3.50 (2"-OCH3), 2.32 /3'-N(CH3)2/, 2.12 (COCH3), 2.06 (COCH3), 2.00 (COCH3), 1.72 (H-22), 1.12 (H-21), 0.78 (H-l 8).
13C NMR (CDC13) δ ppm 173.3 (C-l), 170.1, 169.9, 169.5 (3xCOCH3), 166.1 (9-CONH), 144.8 (C-l l), 137.9 (C-13), 135.2 (C-12), 119.3 (C-10), 102.3 (C-l '), 101.0 (C-l"), 74.6 (C-4"), 71.4 (C-4'), 70.4 (C-2'), 66.0 (C-3), 61.5 (3"-OCH3), 59.3 (2"-OCH3), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 41.0 /3 '-N(CH3)2/, 38.7 (C-2), 29.4 (C-19), 21.8 (C-21), 21.1, 21.0, 20.7 (3xCOCH3), 12.7 (C-22), 8.4 (C-18), 20-N(CH2C6H5)2, 139.8, 129.1, 128.0, 126.6, 57.9.
FAB (MH+) 1094.
Example 5
4'-Demycarosyl-2',4'-di-0-acetyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin 20- dimethylacetal (5)
A solution of pyridine trifluoroacetate (1.0 g, 5.24 mmol) in methylene chloride (10 ml) was added drop by drop at 15°C to a solution of the compound 1 (1.0 g, 1.09 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g, 5.22 mmol) and dimethyl sulfoxide (1.0 ml, 14.10 mmol) in methylene chloride (20 ml). The reaction mixture was stirred for 3 hours at room temperature, then poured into water (150 ml) and after separating the organic layer, it was extracted two more times with methylene chloride. The combined organic extracts were washed with a saturated NaHC03 solution and water, dried (K2COs) and evaporated at reduced pressure to a dry residue. The obtained crude product (0.95 g) was purified by flash chromatography on a silica gel column using the solvent system B to give a TLC homogeneous product (5) (0.45 g).
TLC: Rf(B) 0.52.
IR^B^cm"11749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, 1060. 1H NMR (CDCI3) δ ppm 7.16 (H-l l), 5.71 (H-10), 5.64 (H-13), 4.97 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.76 (H-4'), 4.60 (H-20), 4.63 (H-l"), 4.33 (H-l'), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.52 (2"-OCH3), 3.36 (2O-OCH3), 3.35 (20-OCH3), 3.30 (H-2"), 2.33 /3 '-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.76 (H-22), 1.34 (H-6"), 1.17 (H-21).
13C NMR (CDCI3) δ ppm 202.4 (C-4"), 173.1 (C-l), 169.9, 169.5 (2xCOCH3), 166.1 (9-CONH), 144.6 (C-l l), 137.6 (C-13), 135.3 (C-12), 119.5 (C-10), 103.6 (C-20), 103.0 (C-l"), 102.1 (C-l '), 85.3 (C-3"), 84.2 (C-2"), 73.3 (C-5"), 71.3 (C-4'), 70.3 (C-2'), 65.6 (C-3), 60.2 (3"-OCH3), 59.1 (2"-OCH3), 53.7 (20-OCH3), 50.5 (2O-OCH3), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH3)2/, 40.7 (C-2) 34.4 (C-19), 21.9 (C-21), 21J, 21.0 (2xCOCH3), 14.0 (C-6"), C-12.7 (C-22), 8.3 (C-18).
FAB (MH+) 915.
Example 6
4'-Demycarosyl-2',4'-di-O-acetyl-4"-deoxy-4"-oxo-20-deoxo-20-dibenzylamino- 8a-aza-8a-homotylosin (6)
A solution of pyridine trifluoroacetate (0.6 g, 3.11 mmol) in methylene chloride (6 ml) was added drop by drop at 15°C to a solution of the compound 2 (0.6 g, 0.57 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.14 mmol) and dimethyl sulfoxide (0.45 ml, 6.35 mmol) in methylene chloride (20 ml). The reaction mixture was stirred for 5 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 5. The obtained crude product (0.54 g) was purified by flash chromatography on a silica gel column using the solvent system B to give a TLC homogeneous product (6) (0.28 g).
TLC: Rf (B) 0.48; Rf (C) 0.33.
IR (KBr) cm_1 1747, 1651, 1633, 1548, 1454, 1372, 1231, 1058. 1H NMR (CDCI3) δ ppm 7.25 ~ 7.41 (phenyl), 7.12 (H-l l), 5.70 (H-13), 5.65 (H-10), 4.94 (8a-NH) exchangeable with D20, 4.82 (H-2'), 4.74 (H-4'), 4.65 (H-l"), 4.15 (H-l '), 3.98 (H-5"), 3.78 (H-3"), 3.62 (20-N-CH2-phenyl), 3.58 (20-CH2-phenyl), 3.55 (3"-OCH3), 3.49 (2"-OCH3), 2.32 /3 '-N(CH3)2/, 2.06 (COCH3), 2.00 (COCH3), 1.74 (H-22), 1.36 (H-6"), 1.12 (H-21).
I3C NMR (CDCI3) δ ppm 202.4 (C-4"), 173.4 (C-l), 169.8, 169.3 (2xCOCH3), 166.1 (9-CONH), 144.6 (C-l l), 137.0 (C-13), 135.6 (C-12), 119.6 (C-10), 103.0 (C-l"), 102.2 (C-l'), 85.3 (C-3"), 84.8 (C-2"), 73.3 (C-5"), 71.4 (C-4'), 70.4 (C-2'), 65.9 (C-3), 60.3 (3"-OCH3), 59.1 (2"-OCH3), 52.2 (C-20), 42.9 (C-8), 42.4 (C-4), 40.9 /3 '-N(CH3)2/, 38.7 (C-2), 29.4 (C-l 9), 21.8 (C-21), 21.1, 21.0 (2xCOCH3), 14.0 (C-6"), 12.8 (C-22), 8.4 (C-18), 20-N(CH2C6H5)2 139.6, 129.9, 128.0, 126.6, 57.8.
FAB (MH+) 1050.
Example 7
4'-Demycarosyl-2',4',4"-tri-0-acetyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20- dimethylacetal (7)
A solution of pyridine trifluoroacetate (3.0 g, 15.72 mmol) in methylene chloride (30 ml) was added drop by drop at 15°C to a solution of the compound 3 (2.0 g, 2.09 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0 g, 15.66 mmol) and dimethyl sulfoxide (2.9 ml, 40.89 mmol) in methylene chloride (50 ml). The reaction mixture was stirred for 3 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 5. The obtained crude product (1.95 g) was purified by flash chromatography on a silica gel column using the solvent system C to give a TLC homogeneous product (7) (1.3 g).
TLC: Rf (C) 0.58.
IR cm"1 1749, 1655, 1618, 1546, 1454, 1374, 1233, 1171, 1052.
1H NMR (CDCI3) δ ppm 6.90 (H-l l), 5.76 (H-10), 5.43 (H-13), 4.96 (8a-NH) exchangeable with D20, 4.89 (H-2'), 4.79 (H-4'), 4.66 (H-l"), 4.40 (H-l '), 4.18 (H-8), 3.55, 3.32 (H-2), 3.52 (3"-OCH3), 3.49 (2"-OCH3), 3.30 (20-OCH3), 3.29 (20-OCH3), 2.34 /3'-N(CH3)2/, 2.12 (COCH3), 2.06 (COCH3), 2.03 (COCH3), 1.75 (H-22), 1.10 (H-21), 1.07 (H-l 8).
13C NMR (CDCI3) δ ppm 205.6 (C-3), 172.9 (C-l), 170.1, 169.8, 169.4 (3xCOCH3), 166.1 (9-CONH), 144.1 (C-l l), 138.0 (C-13), 134.9 (C-12), 119.6 (C-10), 103.7 (C-20), 102.1 (C-l'), 100.9 (C-l"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 53.7 (20-OCH3), 50.6 (20-OCH3), 46.5 (C-2), 44.2 (C-4), 42.0 (C-8), 41.0 /3 '-N(CH3)2/, 34.5 (C-19), 21.9, (C-21), 21.1, 21.0, 20.7 (3xCOCH3), 17.6 (C-18), 12.7 (C-22).
FAB (MH+) 957.
Example 8
4'-Demycarosyl-2',4',4"-tri-O-acetyI-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino- 8a-aza-8a-homotylosin (8)
A solution of pyridine trifluoroacetate (2.0 g, 10.36 mmol) in methylene chloride (10 ml) was added drop by drop at 15°C to a solution of the compound 4 (1.0 g, 1.09 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.04 g, 10.44 mmol) and dimethyl sulfoxide (1.6 ml, 22.56 mmol) in methylene chloride (20 ml). The reaction mixture was stirred for 6 hours at room temperature. The isolation of the product was carried out in the manner disclosed in Example 5. The obtained crude product (0.96 g) was purified by flash chromatography on a silica gel column using the solvent system B to give a TLC homogeneous product (8) (0.62 g).
TLC: Rf (B) 0.60.
IR KBiO cm"1 1748, 1633, 1538, 1454, 1373, 1231, 1052.
1H NMR (CDC13) δ ppm 7.22 ~ 7.40 (phenyl), 6.89 (H-l l), 5.66 (H-10), 5.49 (H-13), 4.96 (8a-NH) exchangeable with D20, 4.81 (H-2'), 4.74 (H-4'), 4.66 (H-l"), 4.42 (H-4"), 4.15 (H-l '), 4.12 (H-8), 3.78, 3.38 (H-2), 3.51 (2x20-N-CH2- phenyl, 3"-OCH3), 3.48 (2"-OCH3), 2.32 /3'-N(CH3)2/, 2.22 (H-4), 2.09 (COCH3), 2.06 (COCH3), 2.00 (COCH3), 1.72 (H-22), 1.10 (H-21), 1.08 (H-18). 13C NMR (CDCI3) δ ppm 206.7 (C-3), 172.7 (C-l), 170.1, 169.9, 169.5 (3xCOCH3), 166.1 (9-CONH), 144.0 (C-l l),. 136.5 (C-12), 135.0 (C-13), 119.9 (C-10), 102.7 (C-l '), 100.9 (C-l"), 74.6 (C-4"), 71.3 (C-4'), 70.3 (C-2'), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 51.7 (C-20), 47.7 (C-2), 44.5 (C-4)), 42.0 (C-8), 41.0 /3 '-N(CH3)2/, 28.6 (C-l 9), 22.0 (C-21), 21.0, 20.7 (3xCOCH3), 17.8 (C-l 8), 13.1 (C-22), 20-N(CH2C6H2), 140.1, 128.9, 128.0, 126.4, 57.9.
FAB (MH+) 1092.
Example 9
4'-Demycarosyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin 20-dimethylacetal (9)
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 NaHC03 solution was added and it was extracted twice with chloroform. The combined organic extracts were dried (K2C03) 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).
TLC: Rf (A) 0.27.
IR CKBrJ cm"1 1749, 1657, 1620, 1542, 1455, 1375, 1230, 1172, 1060.
1H NMR (CDCI3) δ ppm 7.16 (H-l l), 5.72 (H-10), 5.67 (H-13), 4.99 (8a-NH) exchangeable with D20, 4.60 (H-20), 4.63 (H-l"), 4.33 (H-l '), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.52 (2"-OCH3), 3.46 (H-2'), 3.36, 3.35 (2x20-OCH3), 3.30 (H-2"), 3.06 (H-4'), 2.33 /3'-N(CH3)2/, 1.76 (H-22), 1.34 (H-6"), 1.17 (H-21).
13C NMR (CDCI3) δ ppm 202.4 (C-4"), 173.1 (C-l), 166.1 (9-CONH), 144.6 (C-l l), 137.6 (C-13), 135.3 (C-12), 119.5 (C-10), 103.6 (C-20), 103.0 (C-l"), 102.1 (C-l '), 85.3 (C-3"), 84.2 (C-2"), 73.3 (C-5"), 65.6 (C-3), 60.2 (3"-OCH3), 59.1 (2"-OCH3), 53.7 (2O-OCH3), 50.5 (20-OCH3), 42.7 (C-8), 42.6 (C-4), 41.0 /3 '-N(CH3)2/, 40.7 (C-2), 34.4 (C-19), 21.9 (C-21), 14.0 (C-6"), 12.7 (C-22), 8.3 (C-18). FAB (MH+) 831.
Example 10
4'-Demycarosyl-4"-deoxy-4"-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a- homotylosin (10)
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 (K2C03) 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).
TLC: Rf (A) 0.49.
IR (KBr) cm"' 1715, 1655, 1619, 1542, 1454, 1377, 1168, 1082.
1H NMR (CDC13) δ ppm 7.25 ~ 7.41 (phenyl), 7.12 (H-l l), 5.70 (H-13), 5.65 (H-10), 4.94 (8a-NH) exchangeable with D20, 4.84 (H-2'), 4.74 (H-4'), 4.60 (H-l"), 4J5 (H-l'), 3.98 (H-5"), 3.78 (H-3"), 3.62 (3"-OCH3), 3.61 (20-N-CH2- phenyl), 3.58 (20-CH2-phenyl), 3.51 (2"-OCH3), 3.46 (H-2'), 3.01 (H-4'), 2.32 /3'-N(CH3)2/, 1.72 (H-22), 1.12 (H-21).
13C NMR (CDC13) δ ppm 202.4 (C-4"), 173.4 (C-l), 166J (9-CONH), 144.7 (C-l l), 137J (C-13), 135.6 (C-12), 119.7 (C-10), 104.2 (C-l '), 103.0 (C-l"), 85.4 (C-3"), 84.9 (C-2"), 73.3 (C-5"), 66.4 (C-3), 59.8 (3"-OCH3), 58.6 (2"-OCH3), 52.2 (C-20), 43.3 (C-8), 42.3 (C-4), 41.5 /3'-N(CH3)2/, 38.7 (C-2), 29.4 (C-19), 22.0 (C-21), 14.1 (C-6"), 12.8 (C-22), 9.1 (C-18), 20-N(CH2C6H5)2 139.8, 129.1, 128.0, 126.6, 58.0.
FAB (MH+) 967. Example 11
4'-Demycarosyl-4"-0-acetyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20- dimethylacetal (11)
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).
TLC: Rf (A) 0.44.
IR KBiO cm"1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.
1H NMR (CDC13) δ ppm 6.87 (H-l l), 5.77 (H-10), 5.44 (H-13), 5.18 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.64 (H-l"), 4.44 (H-4"), 4.30 (H-l'), 4.17 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH3), 3.50, 3.26 (H-2), 3.48 (2"-OCH3), 3.30 (20-OCH3), 3.29 (20-OCH3), 2.53 /3 '-N(CH3)2/, 2.12 (COCH3), 1.75 (H-22), 1.25 (H-18).
13C NMR (CDCI3) δ ppm 205.4 (C-3), 172.9 (C-l), 170.1 (COCH3), 167.4 (9- CONH), 143.4 (C-l l), 136.2 (C-12), 134.6 (C-13), 120.7 (C-10), 104.2 ,(C-1 '), 103.9 (C-20), 100.8 (C-l"), 74.5 (C-4"), 70.9 (C-2'), 70.5 (C-2'), 61.3 (3"- OCH3), 59.0 (2"-OCH3), 52.6 (20-OCH3), 52.1 (20-OCH3), 45.9 (C-2), 44.4 (C-4), 42.5 (C-8), 41.4 /3 '-N(CH3)2/, 33.8 (C-19), 22.0 (C-21), 20.7 (COCH3), 17.5 (C-18), 12.9 (C-22).
FAB (MH+) 873.
Example 12
4'-Demycarosyl-4"-O-acetyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza- 8a-homotylosin (12) The compound 8 (1.20 g, 10.99 mmol) was dissolved in methanol (100 ml) and left to stand at room temperature for 24 hours. To the reaction solution water (100 ml) was added and it was extracted with methylene chloride at pH 6.5. The combined organic extracts were dried (K2C03) and evaporated at reduced pressure and the obtained crude product (1.0 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (12) (0.52 g).
TLC: Rf (A) 0.65.
IR (KBr) cm_1 1745, 1650, 1622, 1537, 1454, 1373, 1233, 1166, 1058.
1H NMR (CDC13) δ ppm 7.25 ~ 7.41 (phenyl), 6.90 (H-l l), 5.67 (H-10), 5.52 (H-13), 4.98 (8a-NH) exchangeable with D20, 4.67 (H-l"), 4.45 (H-4"), 4.17 (H-l '), 4.02 (H-8), 3.61 (20-CH2-phenyl), 3.53 (3"-OCH3), 3.52 (20-CH2-phenyl), 3.50 (2"-OCH3), 3.76, 3.32 (H-2), 2.52 /3'-N(CH3)2/, 2.12 (COCH3), 1.73 (H- 22), 1.21 (H-l 8), 1.08 (H-21).
13C NMR (CDCI3) δ ppm 205.3 (C-3), 172.5 (C-l), 170.1 (COCH3), 167.2 (9- CONH), 143.9 (C-l l), 135.9 (C-12), 135.4 (C-13), 120.0 (C-10), 103.9 (C-l '), 100.9 (C-l"), 74.6 (C-4"), 70.7 (C-4'), 70.4 (C-2'), 61.3 (3"-OCH3), 59.3 (2"- OCH3), 51.6 (C-20), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3 '-N(CH3)2/, 28.8 (C-19), 22.0 (C-21), 20.7 (COCH3), 17.8 (C-18), 12.9 (C-22), 20- N(CH2C6H)2 139.9, 128.8, 128.0, 126.5, 58.0.
FAB (MH+) 1008.
Example 13
4'-Demycarosyl-4"-0-acetyl-8a-aza-8a-homotylosin 20-dimethylacetal (13)
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). TLC: Rf (A) 0.32.
IR (KBr) cm"1 1739, 1656, 1616, 1541, 1455, 1376, 1237, 1170, 1062.
1H NMR (CDC13) δ ppm 7J5 (H-l l), 5.71 (H-10), 5.66 (H-13), 4.97 (8a-NH) exchangeable with D20, 4.64 (H-l"), 4.62 (H-20), 4.44 (H-4"), 4.24 (H-l '), 4J8 (H-8), 3.53 (3"-OCH3), 3.47 (2"-OCH3), 3.37 (20-OCH3), 3.36 (20- OCH3), 2.50 /3'-N(CH3)2/, 2.12 (COCH3), 1.75 (H-22), 1.17 (H-21).
FAB (MH+) 875.
Example 14
4'-Demycarosyl-4"-O-acetyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin (14)
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) 0.50.
IR (KBr) cm_1 1740, 1657, 1621, 1538, 1454, 1373, 1236, 1169, 1054.
Η NMR (CDCI3) δ ppm 7.25 ~ 7.41 (phenyl), 7.10 (H-l l), 5.69 (H-13), 5.65 (H-10), 4.96 (8a-NH) exchangeable with D20, 4.66 (H-l"), 4.45 (H-4"), 4.14 (H-8), 4.07 (H-l '), 3.59 (20-N-CH2-phenyl), 3.56 (20-CH2-phenyl), 3.53 (3"-OCH3), 3.50 (2"-OCH3), 2.49 /3 '-N(CH3)2/, 2.12 (COCH3), 1.73 (H-22), 1.11 (H-21), 0.94 (H-18).
FAB (MH+) 1010.
Example 15
4'-Demycarosyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin 20-dimethylacetal (15) The compound 11 (0.40 g, 0.46 mmol) was dissolved in a methanol/conc. NH4OH mixture (4: 1, 50 ml) and left to stand for 60 hours at the temperature of 5°C. The reaction solution was evaporated to an oily residue and then a product was isolated in the manner disclosed in Example 9. 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 (15) (0J5 g).
TLC: Rf (A) 0.39. πt KB- cm"1 1739, 1714, 1650, 1620, 1544, 1455, 1375, 1170, 1063.
1H NMR (CDC13) δ ppm 6.87 (H-l l), 5.77 (H-10), 5.44 (H-13), 5.18 (8a-NH) exchangeable with D20, 4.60 (H-20), 4.64 (H-l"), 4.33 (H-l '), 4.17 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH3), 3.50, 3.26 (H-2), 3.48 (2"-OCH3), 3.30 (20-OCH3), 3.29 (20-OCH3), 2.33 /3 '-N(CH3)2/, 1.75 (H-22), 1.25 (H-l 8).
FAB (MH+) 831.
Example 16
4'-Demycarosyl-3-deoxy-3-oxo-20-deoxo-20-dibenzylamino-8a-aza-8a- homotylosin (16)
The compound 12 (0.78 g, 0.77 mmol) was dissolved in a methanol/conc. NH4OH 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 (K2C03) 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).
TLC: Rf (A) 0.55.
IR CKBrJ cm"1 1739, 1714, 1650, 1622, 1538, 1454, 1376, 1167, 1082. 1H NMR (CDCI3) δ ppm 7.25 ~ 7.41 (phenyl), 6.90 (H-l l), 5.66 (H-13), 5.53 (H-10), 5.28 (8a-NH) exchangeable with D20, 4.61 (H-l"), 4.16 (H-l'), 4.03 (H-8), 3.62 (20-N-CH2-phenyl), 3.61 (20-CH2-phenyl, 3"-OCH3), 3.51 (2"-OCH3), 3.78, 3.38 (H-2), 2.5 /3'-N(CH3)2/, 2.38 (H-4), 1.72 (H-22), 1.21 (H-l 8), 1.08 (H-21).
13C NMR (CDC13) δ ppm 205.3 (C-3), 172.5 (C-l), 167.2 (9-CONH), 143.9 (C-l l), 135.9 (C-12), 135.6 (C-13), 120.0 (C-10), 103.9 (C-l '), 101.0 (C-l '), 72.5 (C-4"), 70.7 (C-4'), 70.4 (C-2'), 61.5 (3"-OCH3), 59.5 (2"-OCH3), 51.7 (C-20), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N(CH3)2/, 28.8 (C-19), 22.0 (C-21), 17.8 (C-18), 12.9 (C-22), 20-N(CH2C6H)2 140.0, 128.8, 128.0, 126.5, 58.0.
FAB (MH+) 967.
Example 17
4'-Demycarosyl-3-deoxy-3-oxo-8a-aza-8a-homotylosin (17)
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 NaHC03 solution was added and it was extracted twice with methylene chloride. The combined organic extracts were dried (K C03) 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).
TLC: Rf (A) 0.35.
IR (KBr) cm_I 1739, 1719, 1657, 1620, 1545, 1455, 1376, 1169, 1082.
1H NMR (CDCI3) δ ppm 9.78 (H-20), 7.19 (H-l l), 5.72 (H-10), 5.70 (H-13), 5.06 (8a-NH) exchangeable with D20, 4.58 (H-l"), 4.18 (H-l '), 4.23 (H-8), 3.68, 3.32 (H-2), 3.62 (3"-OCH3), 3.49 (2"-OCH3), 2.49 /3 '-N(CH3)2/, 1.75 (H-22), 1.25 (H-l 8), 1.18 (H-21).
13C NMR (CDCI3) δ ppm 205.3 (C-3), 203.8 (C-20), 173.5 (C-l), 166.9 (9-CONH), 145.1 (C-l l), 138.2 (C-13), 135.1 (C-12), 129.3 (C-10), 103.7 (C-l '), 101.1 (C-l '), 72.8 (C-4"), 71.0 (C-4'), 70.4 (C-2'), 61.5 (3"-OCH3), 59.5 (2"-OCH3), 46.6 (C-19), 46.1 (C-2), 44.5 (C-4), 43.3 (C-8), 41.5 /3'-N(CH3)2/, 22.4 (C-21), 17.8 (C-18), 12.9 (C-22). FAB (MH+) 785.
Example 18
4'-Demycarosyl-2',4'-di-0-acetyl-8a-aza-8a-homotylosin (18)
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).
TLC: Rf (B) 0.35.
IR B^ cm"1 1749, 1657, 1620, 1548, 1455, 1375, 1231, 1170, 1059.
1H NMR (CDC13) δ ppm 9.75 (H-20), 7.21 (H-l l), 5.72 (H-10), 5.71 (H-13), 5.08 (8a-NH) exchangeable with D20, 4.89 (H-2'), 4.74 (H-4'), 4.58 (H-l"), 4.26 (H-l '), 3.61 (3"-OCH3), 3.49 (2"-OCH3), 2.33 /3'-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.18 (H-21).
13C NMR (CDCI3) δ ppm 203.6 (C-20), 173.3 (C-l), 169.9, 169.5 (2xCOCH3), 166.5 (9-CONH), 145.2 (C-l l), 138.3 (C-13), 135.0 (C-12), 119.0 (C-10), 101.6 (C-l '), 100.9 (C-l"), 72.5 (C-4"), 70.6 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.5 (3"-OCH3), 59.5 (2"-OCH3), 46.3 (C-19), 42.5 (C-8), 41.0 /3'-N(CH3)2/, 38.5 (C-2), 21.6 (C-21), 21.1, 21.0 (2xCOCH3), 12.7 (C-22), 8.1 (C-18).
FAB (MH+) 871.
Example 19
4'-Demycarosyl-2',4',4"-tri-0-acetyl-8a-aza-8a-homotylosin (19)
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.
IR - Br m'1 1748, 1659, 1621, 1538, 1455, 1373, 1232, 1171, 1052.
1H NMR (CDC13) δ ppm 9.74 (H-20), 7J6 (H-l l), 5.69 (H-10), 5.65 (H-13), 4.89 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.76 (H-4'), 4.64 (H-l"), 4.44 (H-4"), 4.33 (H-l '), 4J8 (H-8), 3.52 (3"-OCH3), 3.46 (2"-OCH3), 2.33 /3'-N(CH3)2/, 2.12 (COCH3), 2.05 (COCH3), 2.03 (COCH3), 1.74 (H-22), 1.16 (H-21).
13C NMR (CDCI3) δ ppm 203.6 (C-20), 173J (C-l), 170J, 169.8, 169.4 (3xCOCH3), 166J (9-CONH), 144.7 (C-l l), 138.0 (C-13), 134.9 (C-12), 119.2 (C-10), 103.7 (C-20), 102J (C-l '), 100.9 (C-l"), 74.5 (C-4"), 71.4 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.3 (3"-OCH3), 59.3 (2"-OCH3), 46J (C-19), 42.7 (C-8), 42.6 (C-4), 41.0 /3'-N(CH3)2/, 40.5 (C-2), 34.5 (C-19), 21.9 (C-21), 21.1, 21.0, 20.7 (3xCOCH3), 12.7 (C-22), 8.3 (C-18).
FAB (MH+) 913.
Example 20
4'-Demycarosyl-2',4'-di-0-acetyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin (20)
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).
TLC: Rf (B) 0.48.
IR KBrJ cm"1 1749, 1656, 1619, 1543, 1458, 1375, 1230, 1172, 1058.
1H NMR (CDCI3) δ ppm 9.75 (H-20), 7.21 (H-l l), 5.72 (H-10), 5.70 (H-13), 5.08 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.74 (H-4'), 4.58 (H-l"), 4.30 (H-L), 4.17 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.48 (2"-OCH3), 3.30 (H-2"), 2.33 /3 '-N(CH3)2/, 2.05 (COCH3), 2.03 (COCH3), 1.76 (H-22), 1.34 (H-6"), 1J7 (H-21).
13C NMR (CDC13) δ ppm 203.0 (C-20), 202.4 (C-4"), 173.1 (C-l), 169.9, 169.5 (2xCOCH3), 166.5 (9-CONH), 145.0 (C-l l), 138.1 (C-13), 135.1 (C-12), 119.0 (C-10), 102.1 (C-l"), 100.9 (C-l '), 85.3 (C-3"), 84.2 (C-2"), 73.3 (C-5"), 71.3 (C-4'), 70.3 (C-2'), 65.6 (C-3), 61.5 (3"-OCH3), 59.4 (2"-OCH3), 46.3 (C-19), 42.5 (C-8), 41.0 /3 '-N(CH3)2/, 38.5 (C-2), 21.9 (C-21), 21.1, 21.0 (2xCOCH3), 14.0 (C-6"), 12.7 (C-22), 8.3 (C-l).
FAB (MH+) 869.
Example 21
4'-Demycarosyl-4"-0-acetyl-8a-aza-8a-homotylosin (21)
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).
TLC: Rf (A) 0.28.
IR KBiO cm"1 1749, 1657, 1620, 1544, 1455, 1375, 1229, 1170, 1063.
1H NMR (CDCI3) δ ppm 9.78 (H-20), 7.20 (H-l l), 5.72 (H-10), 5.70 (H-13), 5.12 (8a-NH) exchangeable with D20, 4.88 (H-2'), 4.64 (H-l"), 4.44 (H-4"), 4.18 (H-l '), 4.12 (H-8), 3.93 (H-5"), 3.89 (H-3"), 3.53 (3"-OCH3), 3.48 (2"-OCH3), 2.49 /3'-N(CH3)2/, 2.12 (COCH3), 1.75 (H-22).
FAB (MH+) 829.
Example 22
4'-Demycarosyl-4"-deoxy-4"-oxo-8a-aza-8a-homotylosin (22) The compound 20 (0.23 g, 0.27 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 (0J4 g) was purified by flash chromatography on a silica gel column using the solvent system A to give a TLC homogeneous product (22) (0.095 g).
TLC: Rf (A) 0.30.
IR (KBr) cm_1 1717, 1655, 1625, 1542, 1454, 1378, 1170, 1062.
1H NMR (CDC13) δ ppm 9.76 (H-20), 7.20 (H-l l), 5.72 (H-10), 5.70 (H-13), 5J2 (8a-NH) exchangeable with D20, 4.64 (H-l"), 4.33 (H-l '), 4J8 (H-8), 3.98 (H-5"), 3.78 (H-3"), 3.58 (3"-OCH3), 3.46 (2"-OCH3), 3.30 (H-2"), 3.06 (H-4'), 2.33 /3'-N(CH3)2/, 1.74 (H-22), 1.34 (H-6"), 1.16 (H-21).
13C NMR (CDC13) δ ppm 203.7 (C-20), 202.5 (C-4"), 173.4 (C-l), 166.6 (9-CONH), 144.9 (C-l l), 137.6 (C-13), 135.4 (C-12), 119.4 (C-10), 102.1 (C-l'), 100.9 (C-l"), 71.4 (C-4'), 70.3 (C-2'), 66.3 (C-3), 61.5 (3"-OCH3), 59.7 (2"-OCH3), 46.2 (C-19), 42.7 (C-8), 42.1 (C-4), 41.5 /3'-N(CH3)2/, 39.8 (C-2), 21.7 (C-21), 14.0 (C-6"), 12.7 (C-22), 8.7 (C-18).
FAB (MH+) 785.

Claims

1. Compounds of the general formula I
wherein R represents CHO, CH(OCH3)2 or CH2N[CH2(C6H5)]2,
R1 represents H or C C3 acyl,
R represents OR and R represents H or C1-C3 acyl,
R3 represents H or R and R together represent =0,
R4 represents OH,
R5 represents H or R4 and R5 together represent =0.
2. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 represents COCH3, R2 represents OR6 wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH.
3. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6 wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH.
4. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH.
5. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH.
6. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 represents COCH3, R2 and R3 together represent =0, R4 represents OH and R5 represents H.
7. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 and R3 together represent =0, R4 represents OH and R5 represents H.
8. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 represents H and R4 and R5 together represent =0.
9. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 represents H and R4 and R3 together represent =0.
10. A compound according to claim 1, characterized in that R represents
I *
CH(OCH3)2, R and R are the same and represent H, R and R together represent =0 and R4 represents OH.
11. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 and R5 are the same and represent H, R2 and R3 together represent =0 and R4 represents OH.
12. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 and R3 are the same and represent H, R2 represents OR6 wherein R6 represents COCH3, and R4 and R5 together represent =0.
13. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 and R3 are the same and represent H, R2 represents OR6 wherein R6 represents COCH3, and R and R5 together represent =0.
14. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1, R3 and R5 are the same and represent H, R2 represents OR6 wherein R6 represents COCH3, and R4 represents OH.
15. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1, R3 and R5 are the same and represent H, R2 represents OR6 wherein R6 represents COCH3, and R represents OH.
16. A compound according to claim 1, characterized in that R represents CH(OCH3)2, R1 and R3 are the same and represent H, R2 represents OR6 wherein R6 represents H, and R4 and R5 together represent =0.
17. A compound according to claim 1, characterized in that R represents CH2N[CH2(C6H5)]2, R1 and R3 are the same and represent H, R2 represents OR6 wherein R6 represents H, and R4 and R5 together represent =0.
18. A compound according to claim 1, characterized in that R represents CHO, R1 and R3 are the same and represent H, R represents OR6 wherein R6 represents H, and R4 and R5 together represent =0.
19. A compound according to claim 1, characterized in that R represents CHO, R1 represents COCH3, R2 represents OR wherein R6 represents H, R3 and R5 are the same and represent H and R4 represents OH.
20. A compound according to claim 1, characterized in that R represents CHO, R1 represents COCH3, R2 represents OR6 wherein R6 represents COCH3, R3 and R5 are the same and represent H and R represents OH.
21. A compound according to claim 1, characterized in that R represents CHO, R1 represents COCH3, R2 and R3 together represent =0, R4 represents OH and R5 represents H.
22. A compound according to claim 1, characterized in that R represents CHO, R1, R3 and R5 are the same and represent H, R2 represents OR6 wherein R6 represents COCH3, and R4 represents OH.
23. A compound according to claim 1, characterized in that R represents CHO, R1 and R3 are the same and represent H, R2 and R3 together represent =0 and R4 represents OH.
24. Process for the preparation of the compounds of the general formula I
wherein R represents CHO, CH(OCH3)2 or CH2N[CH2(C6H5)]2,
R1 represents H or - acyl,
R represents OR and R represents H or Cj-C3 acyl,
R3 represents H or R2 and R3 together represent =0,
R4 represents OH,
R5 represents H or R4 and R5 together represent =0, characterized in that 4'-demycarosyl-8a-aza-8a-homotylosin 20-dimethylacetal of the formula Ila and 4'- demycarosyl-20-deoxo-20-dibenzylamino-8a-aza-8a-homotylosin of the formula lib
Ila R = CH(OCH3)2 lib R = CH2N[CH2(C6H5)]2 are subjected to
A) an O-acylation with anhydrides of C C3 carboxylic acids, preferably with acetic acid anhydride in methylene chloride during 15 minutes to 1 hour at room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6, wherein R6 represents H, R and R are the same and represent H and R4 represents OH,
are optionally subjected to
Al) an O-acylation with anhydrides of -C3 carboxylic acids, preferably with acetic acid anhydride in methylene chloride in the presence of an organic base, preferably triethyl amine and 4-dimethylaminopyridine as a catalyst during 30 hours at room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH, are optionally subjected to
B) an oxidation reaction with N(3-dimethylamino-propyl)-N' ethyl carbodiimide hydrochloride in the presence of dimethylsulfoxide and pyridine trifluoroacetate as a catalyst in an inert solvent, preferably methylene chloride, during 2 to 6 hours at a temperature from 10°C to room temperature, and the obtained compounds of the formula I, wherein R represents CH(OCH3) or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR , wherein R6 represents COCH3, R3 represents H and R4 and R5 together represent =0,
are optionally subjected to
C) methanolysis at room temperature for 2 days and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 and R3 are the same and represent H, R2 represents OR6, wherein R6 represents COCH3, and R4 and R5 together represent =0,
are optionally subjected to
Cl) an alkaline methanolysis in a mixture of methanol and 25% ammonia (4: 1) at a temperature from 5°C to room temperature during 20 to 60 hours to obtain compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 and R3 are the same and represent H, R2 represents OR , wherein R6 represents H, and R4 and R5 together represent =0;
or the compound obtained according to process Cl
1 " of the formula I, wherem R represents CH(OCH3)2, R and R are the same and represent H, R2 represents OR6, wherein R6 represents H, and R4 and R5 together represent =0,
is optionally subjected to
D) a hydrolysis of the acetal in a mixture of acetonitrile and 0.1 N hydrochloric acid (1: 1) for 2 hours at room temperature to obtain the compound of the formula I, wherein R represents a CHO group, R and R are the same and represent H, R represents OR6, wherein R represents H, and R4 and R5 together represent =0; or compounds obtained according to process A of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 represents OR , wherein R represents H, R3 and R5 are the same and represent H and R4 represents OH,
are optionally subjected to oxidation in the manner disclosed in B, and the obtained compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 represents COCH3, R2 and R3 together represent =0, R4 represents OH and R5 represents H,
are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1 and R5 are the same and represent H, R2 and R3 together represent =0 and R4 represents OH;
or the compound obtained according to process B of the formula I, wherein R represents a CH(OCH3)2 group, R1 represents COCH3, R2 and R3 together represent =0, R4 represents OH and R5 represents H,
is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, and the obtained compound of the formula I, wherein R represents a CHO group, R1 represents COCH3, R2 and R3 together represent =0, R4 represents OH and R5 represents H,
is optionally subjected to methanolysis in the manner disclosed in C, to obtain the compound of the formula I, wherein R represents a CHO group, R1 and
R5 are the same and represent H, R2 and R3 together represent =0 and R4 represents
OH;
or the compound obtained according to process A of die formula I, wherein R represents CH(OCH3)2, R1 represents COCH3, R2 represents OR6, wherein R represents H, R3 and R5 are the same and represent H and R4 represents OH,
is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, to obtain a compound of the formula I wherein R represents CHO, R1 represents COCH3, R2 represents OR6, wherein R6 represents H, R3 and RΛ are the same and represent H and R4 represents OH;
or compounds obtained according to process Al of the formula I, wherein R represents CH(OCH3):. or CH2N[CH2(C6H5)k R1 represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH,
are optionally subjected to methanolysis in the manner disclosed in C, to obtain compounds of the formula I, wherein R represents CH(OCH3)2 or CH2N[CH2(C6H5)]2, R1, R3 and R5 are the same and represent H, R2 represents OR°3 wherein R represents COCH3, and R represents OH;
or the compound obtained according to process Al of the formula J, wherein R represents CH(OCH3)2] R1 represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH,
is optionally subjected to a hydrolysis of acetal in the manner disclosed in D, and the obtained compound of the formula I, wherein R represents CHO, R1 represents COCH3, R2 represents OR6, wherein R6 represents COCH3, R3 and R5 are the same and represent H and R4 represents OH,
is optionally subjected to methanolysis in the manner disclosed in C, to obtain the compound of the foπnula I, wherein R represents CHO, R1, R3 and R5 are the same and represent H, R2 represents OR6, wherein R6 represents COCH3, and
R4 represents OH.
EP00940676A 1999-06-11 2000-06-06 DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN Withdrawn EP1189914A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
HR990192 1999-06-11
HR990192A HRP990192A2 (en) 1999-06-11 1999-06-11 4'-DEMICAROZYL-8a-AZA-8a-HOMOTHILOSINE DERIVATIVES
PCT/HR2000/000018 WO2000077016A1 (en) 1999-06-11 2000-06-06 DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN

Publications (1)

Publication Number Publication Date
EP1189914A1 true EP1189914A1 (en) 2002-03-27

Family

ID=10946940

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00940676A Withdrawn EP1189914A1 (en) 1999-06-11 2000-06-06 DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN

Country Status (13)

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

Families Citing this family (4)

* 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
AU2004217919A1 (en) * 2003-03-05 2004-09-16 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using the same
JPWO2005019238A1 (en) 2003-08-22 2006-10-19 明治製菓株式会社 Novel azalides and azalactam derivatives and their production
EP1723159B1 (en) 2004-02-27 2019-06-12 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI8710674B (en) * 1987-04-14 1998-06-30 Pliva Process for preparation of 10,11,12,13-tetrahydro derivatives of tylosin
YU149889A (en) * 1989-07-26 1991-02-28 Pliva Zagreb Process for preparing biologically active derivatives of tylozine
CZ211798A3 (en) * 1997-07-16 1999-02-17 Pliva, Farmaceutska, Kemijska, Prehrambena I Kozmetička Industrije, Dioničko Društvo Linear 8a-sekoazalides and method of their production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0077016A1 *

Also Published As

Publication number Publication date
CZ20014362A3 (en) 2002-04-17
NO322424B1 (en) 2006-10-02
YU87401A (en) 2004-07-15
HUP0201610A2 (en) 2002-10-28
CA2375812A1 (en) 2000-12-21
HUP0201610A3 (en) 2003-03-28
NO20016030D0 (en) 2001-12-10
EA200200026A1 (en) 2002-06-27
AU767543B2 (en) 2003-11-13
HRP990192A2 (en) 2001-04-30
SK17572001A3 (en) 2002-04-04
NO20016030L (en) 2002-01-30
JP2003502338A (en) 2003-01-21
UA66930C2 (en) 2004-06-15
WO2000077016A1 (en) 2000-12-21
AU5558300A (en) 2001-01-02

Similar Documents

Publication Publication Date Title
EP0827965A2 (en) Synthesis of 9-deoxo- 9a-aza 11,12-deoxy- 9a-methyl-9a-homoerythromycin A 11,12- hydrogenorthoborate dihydrate
HRP980189A2 (en) Novel 15-membered lactams ketolides
EP0287082B1 (en) Derivatives of tylosin and 10,11,12,13-tetrahydro tylosin, methods of manufacture thereof and their use in pharmaceuticals and in the manufacture thereof
EP0606062B1 (en) 9-Deoxo-9a-aza-11-deoxy-9a-homoerythromycin A 9a,11-cyclic carbamates
US4833236A (en) Erythromycin derivatives
WO2000077016A1 (en) DERIVATIVES OF 4'-DEMYCAROSYL-8a-AZA-8a-HOMOTYLOSIN
EP1181298B1 (en) Novel 8a- and 9a-15-membered lactams
DE602004003054T2 (en) NEW 3-DECLADINOSYL-9A-N-CARBAMOYL AND 9A-N-THIOCARBAMOYL DERIVATIVES OF 9-DEOXO-9-DIHYDRO-9A-AZA-9A-HOMOERYTHROMYCIN A
EP1399458B1 (en) An arylation method for the functionalization of o-allyl erythromycin derivatives
JPS6360033B2 (en)
DK152133B (en) METHOD OF ANALOGUE FOR THE PREPARATION OF OLEANDOMYCIN DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS.
RU2234510C2 (en) Derivatives of oleandomycin class and method for their preparing
HRP950145A2 (en) New compounds of the secomacrolide and secoazalide class and a process for the preparation thereof
Heggelund et al. Preparation of cyclic 2′, 3′-carbamate derivatives of erythromycin macrolide antibiotics
RU2158268C2 (en) Secomacrolides of erythromycin class and method of their synthesis
CH661513A5 (en) 14-DE (HYDROXYMETHYL) -MYCAMINOSYLTYLONOLIDE COMPOUNDS.
Ku et al. An efficient synthesis of des-N-methyl-N-acetyl erythromycin derivatives via the N-oxide
EP0490311B1 (en) Derivatives of 10,11,12,13-tetra-hydrodesmycosin, processes for preparation, and use thereof in obtaining pharmaceuticals
DE3403656A1 (en) 3-0-ACYL-4 "-DEOXYDESMYCOSINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
Lazarevski et al. Acid catalyzed ring opening reactions of 6-deoxy-9-deoxo-9a-aza-9a-homoerythromycin A 6, 9-cyclic imino ether
HK1016989A (en) New secomacrolides from class of erythromycins and process for their preparation
JPS6155920B2 (en)
JPH10251291A (en) New mycaminosyltylonolide derivatives
HK1064390B (en) An arylation method for the functionalization of o-allyl erythromycin derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20011217

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI PAYMENT 20011217

17Q First examination report despatched

Effective date: 20030731

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20031211