Avilamycin derivatives
AssigneeCombinature Biopharm AG
InventorsGabriele Weitnauer, Agnes Muhlenweg, Axel Trefzer, Andreas Bechthold
Life of this patent
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Abstract
Avilamycin derivatives, gene technology biosynthesis processes for their production, medications containing these compounds, as well as the use of these compounds for the production of a active agent against infectious diseases, as well as nucleic acids, proteins, and gene clusters and corresponding cells that are connected to the production of these avilamycin derivatives are disclosed.
Claims31
Avilamycin derivative according to the general Formula I, also in the form of its diastereomers or enantiomers, its racemic mixtures or other mixtures or pure diastereomers and/or enantiomers,
- 3
- where independently of one another, with the following exception,
- R1 is selected from H, COCH3, COC4H9, COCH(CH3)2 or COCH2CH3,
- R2 is selected from H, CHO, COCH3 or CH(OH)CH3,
- R3 corresponds to OCH3,
- R4 corresponds to Cl,
- R5 corresponds to Cl,
- R6 corresponds to CH3,
- R7 corresponds to H, CH3 or CH2OH,
- R8 corresponds to CH3, and
- R9 corresponds to CH3,
- where the following applies with reference to at least one of the residues R3-R6, R8 or R9 in Formula I, in deviation from the above definition:
- R3 is to be replaced by OH,
- R4 is to be replaced by H,
- R5 is to be replaced by H,
- R6 is to be replaced by H,
- R8 is to be replaced by H, and/or
- R9 is to be replaced by H,
- with the proviso that R1-R9 cannot simultaneously take on the meanings in accordance with the combination, in each instance, in one of the compounds 1-4:
- 11 No. R1 R2 R3 R4 R5 R6 R7 R8 R9 1 COCH(CH3)2 COCH3 OH H Cl CH3 CH3 CH3 CH3 2 COCH(CH3)2 COCH3 OCH3 Cl H CH3 CH3 CH3 CH3 3 COCH(CH3)2 COCH3 OCH3 Cl CI H CH3 CH3 CH3 4 COCH(CH3)2 COCH3 OCH3 Cl CI CH3 CH3 H CH3
Avilamycin derivative according to the general Formula I, also in the form of its diastereomers or enantiomers, its racemic mixtures or other mixtures or pure diastereomers and/or enantiomers, that is selected from among compounds in which R1-R9 are combined as follows:
- 14 No. R1 R2 R3 R4 R5 R6 R7 R8 R9 5 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH3 CH3 CH3 6 COCH2CH3 H OH Cl Cl CH3 CH3 CH3 CH3 7 COCH3 COCH3 OH Cl Cl CH3 CH3 CH3 CH3 8 COCH(CH3)2 CH(OH)CH3 OH Cl Cl CH3 CH3 CH3 CH3 9 H COCH3 OH Cl Cl CH3 CH3 CH3 CH3 10 COCH3 CH(OH)CH3 OH Cl Cl CH3 CH3 CH3 CH3 11 H CH(OH)CH3 OH Cl Cl CH3 CH3 CH3 CH3 12 COC4H9 COCH3 OH Cl Cl CH3 CH3 CH3 CH3 13 COCH(CH3)2 COCH3 OH Cl H CH3 CH3 CH3 CH3 14 COCH3CH3 COCH3 OH Cl Cl CH3 CH3 CH3 CH3 15 COCH(CH3)2 COCH3 OH Cl CL H CH3 CH3 CH3 16 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH2OH CH3 CH3 17 COCH(CH3)2 CHO OH Cl Cl CH3 CH3 CH3 CH3 18 COCH(CH3)2 COCH3 OH Cl Cl CH3 H CH3 CH3 19 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH3 H CH3 20 COCH(CH3)2 COCH3 OH H H CH3 CH3 CH3 CH3 21 COCH2CH3 H OH H H CH3 CH3 CH3 CH3 22 COCH3 COCH3 OH H H CH3 CH3 CH3 CH3 23 COCH(CH3)2 CH(OH)CH3 OH H H CH3 CH3 CH3 CH3 24 H COCH3 OH H H CH3 CH3 CH3 CH3 25 COCH3 CH(OH)CH3 OH H H CH3 CH3 CH3 CH3 26 H CH(OH)CH3 OH H H CH3 CH3 CH3 CH3 27 COCH(CH3)2 COCH3 OH H H CH3 CH3 CH3 CH3 28 COC4H9 COCH3 OH H H CH3 CH3 CH3 CH3 29 COCH(CH3)2 COCH3 OH H H CH3 CH3 CH3 CH3 30 COCH2CH3 COCH3 OH H H CH3 CH3 CH3 CH3 31 COCH(CH3)2 COCH3 OH H H H CH3 CH3 CH3 32 COCH(CH3)2 COCH3 OH H H CH3 CH2OH CH3 CH3 33 COCH(CH3)2 CHO OH H H CH3 CH3 CH3 CH3 34 COCH(CH3)2 COCH3 OH H H CH3 H CH3 CH3 35 COCH(CH3)2 COCH3 OH H H CH3 CH3 H CH3 36 COCH(CH3)2 COCH3 OH Cl Cl H CH3 CH3 CH3 37 COCH2CH3 H OH Cl Cl H CH3 CH3 CH3 38 COCH3 COCH3 OH Cl Cl H CH3 CH3 CH3 39 COCH(CH3)2 CH(OH)CH3 OH Cl Cl H CH3 CH3 CH3 40 H COCH3 OH Cl Cl H CH3 CH3 CH3 41 COCH3 CH(OH)CH3 OH Cl Cl H CH3 CH3 CH3 42 H CH(OH)CH3 OH Cl Cl H CH3 CH3 CH3 43 COCH(CH3)2 COCH3 OH H Cl H CH3 CH3 CH3 44 COC4H9 COCH3 OH Cl Cl H CH3 CH3 CH3 45 COCH(CH3)2 COCH3 OH Cl H H CH3 CH3 CH3 46 COCH2CH3 COCH3 OH Cl Cl H CH3 CH3 CH3 47 COCH(CH3)2 COCH3 OH Cl Cl H CH3 CH3 CH3 48 COCH(CH3)2 COCH3 OH Cl Cl H CH2OH CH3 CH3 49 COCH(CH3)2 CHO OH Cl Cl H CH3 CH3 CH3 50 COCH(CH3)2 COCH3 OH Cl Cl H H CH3 CH3 51 COCH(CH3)2 COCH3 OH Cl Cl H CH3 H CH3 52 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH3 H CH3 53 COCH2CH3 H OH Cl Cl CH3 CH3 H CH3 54 COCH3 COCH3 OH Cl Cl CH3 CH3 H CH3 55 COCH(CH3)2 CH(OH)CH3 OH Cl Cl CH3 CH3 H CH3 56 H COCH3 OH Cl Cl CH3 CH3 H CH3 57 COCH3 CH(OH)CH3 OH Cl Cl CH3 CH3 H CH3 58 H CH(OH)CH3 OH Cl Cl CH3 CH3 H CH3 59 COCH(CH3)2 COCH3 OH H Cl CH3 CH3 H CH3 60 COC4H9 COCH3 OH Cl Cl CH3 CH3 H CH3 61 COCH(CH3)2 COCH3 OH Cl H CH3 CH3 H CH3 62 COCH2CH3 COCH3 OH Cl Cl CH3 CH3 H CH3 63 COCH(CH3)2 COCH3 OH Cl Cl H CH3 H CH3 64 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH2OH H CH3 65 COCH(CH3)2 CHO OH Cl Cl CH3 CH3 H CH3 66 COCH(CH3)2 COCH3 OH Cl Cl CH3 H H CH3 67 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH3 H CH3 68 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH3 CH3 H 69 COCH2CH3 H OH Cl Cl CH3 CH3 CH3 H 70 COCH3 COCH3 OH Cl Cl CH3 CH3 CH3 H 71 COCH(CH3)2 CH(OH)CH3 OH Cl Cl CH3 CH3 CH3 H 72 H COCH3 OH Cl Cl CH3 CH3 CH3 H 73 COCH3 CH(OH)CH3 OH Cl Cl CH3 CH3 CH3 H 74 H CH(OH)CH3 OH Cl Cl CH3 CH3 CH3 H 75 COCH(CH3)2 COCH3 OH H Cl CH3 CH3 CH3 H 76 COC4H9 COCH3 OH Cl Cl CH3 CH3 CH3 H 77 COCH(CH3)2 COCH3 OH Cl H CH3 CH3 CH3 H 78 COCH2CH3 COCH3 OH Cl Cl CH3 CH3 CH3 H 79 COCH(CH3)2 COCH3 OH Cl Cl H CH3 CH3 H 80 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH2OH CH3 H 81 COCH(CH3)2 CHO OH Cl Cl CH3 CH3 CH3 H 82 COCH(CH3)2 COCH3 OH Cl Cl CH3 H CH3 H 83 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH3 H H 84 COCH(CH3)2 COCH3 OH Cl Cl H CH3 H H 85 COCH2CH3 H OH Cl Cl H CH3 H H 86 COCH3 COCH3 OH Cl Cl H CH3 H H 87 COCH(CH3)2 CH(OH)CH3 OH Cl Cl H CH3 H H 88 H COCH3 OH Cl Cl H CH3 H H 89 COCH3 CH(OH)CH3 OH Cl Cl H CH3 H H 90 H CH(OH)CH3 OH Cl Cl H CH3 H H 91 COCH(CH3)2 COCH3 OH H Cl H CH3 H H 92 COC4H9 COCH3 OH Cl Cl H CH3 H H 93 COCH(CH3)2 COCH3 OH Cl H H CH3 H H 94 COCH2CH3 COCH3 OH Cl Cl H CH3 H H 95 COCH(CH3)2 COCH3 OH Cl Cl H CH3 H H 96 COCH(CH3)2 COCH3 OH Cl Cl H CH2OH H H 97 COCH(CH3)2 CHO OH Cl Cl H CH3 H H 98 COCH(CH3)2 COCH3 OH Cl Cl H H H H 99 COCH(CH3)2 COCH3 OH Cl Cl H CH3 H H
- preferably,
- 15 R1 R2 R3 R4 R5 R6 R7 R8 R9 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH3 CH3 CH3 COCH(CH3)2 CH(OH)CH3 OH Cl Cl CH3 CH3 CH3 CH3 COCH(CH3)2 COCH3 OH H H CH3 CH3 CH3 CH3 COCH(CH3)2 CH(OH)CH3 OH H H CH3 CH3 CH3 CH3 COCH(CH3)2 COCH3 OH Cl Cl H CH3 CH3 CH3 COCH(CH3)2 CH(OH)CH3 OH Cl Cl H CH3 CH3 CH3 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH3 H CH3 COCH(CH3)2 CH(OH)CH3 OH Cl Cl CH3 CH3 H CH3 COCH(CH3)2 COCH3 OH Cl Cl CH3 CH3 CH3 H COCH(CH3)2 CH(OH)CH3 OH Cl Cl CH3 CH3 CH3 H
Avilamycin derivative that can be obtained in that in a cell that can be cultivated, which contains the necessary genes and/or enzymes for the synthesis of an orthosomycin basic body consisting of
- a) a terminal dichloroisoeverninic acid moiety (A in Formula I) and
- b) a heptasaccharide esterified with it, linked via normal ester bonds and ortho ester bonds (B to H in Formula I), composed of:
- (i) two D-olivose moieties (B and C),
- (ii) a 2-deoxy-D-evalose moiety (D),
- (iii) a D-fucose moiety (E),
- (iv) a D-mannose moiety (F),
- (v) an L-lyxose moiety (G), and
- (vi) a (methyl) eurekanate moiety (H),
- by modifying with gene technology, deleting, and/or not expressing at least one nucleic acid, the sequence of which corresponds by at least 95%, preferably 97%, and particularly precisely to the nucleic acid sequence in accordance with one of FIGS. 1 to 54, by cultivating the cell modified in this way, by recovering and processing the top portion of the culture, by purifying and isolating the avilamycin derivative(s), and, if applicable, by separating different derivatives from one another,
- with the proviso that R1-R9 cannot simultaneously take on the meanings in accordance with the combination, in each instance, as shown below:
- 16 R1 R2 R3 R4 R5 R6 R7 R8 R9 COCH(CH3)2 COCH3 OH H Cl CH3 CH3 CH3 CH3 COCH(CH3)2 COCH3 OCH3 Cl H CH3 CH3 CH3 CH3 COCH(CH3)2 COCH3 OCH3 Cl Cl H CH3 CH3 CH3 COCH(CH3)2 COCH3 OCH3 Cl Cl CH3 CH3 H CH3 COCH(CH3)2 CHO OCH3 Cl Cl CH3 CH3 CH3 CH3 COCH(CH3)2 COCH3 OCH3 Cl Cl CH3 H CH3 CH3 COCH(CH3)2 COCH3 OCH3 Cl Cl CH3 CH3 CH3 CH3 COCH2CH3 H OCH3 Cl Cl CH3 CH3 CH3 CH3 COCH3 COCH3 OCH3 Cl Cl CH3 CH3 CH3 CH3 COCH(CH3)2 CH(OH)CH3 OCH3 Cl Cl CH3 CH3 CH3 CH3 H COH3 OCH3 Cl Cl CH3 CH3 CH3 CH3 COCH3 CH(OH)CH3 OCH3 Cl Cl CH3 CH3 CH3 CH3 H CH(OH)CH3 OCH3 Cl Cl CH3 CH3 CH3 CH3 COC4H9 COCH3 OCH3 Cl Cl CH3 CH3 CH3 CH3 COCH2CH3 COCH3 OCH3 Cl Cl CH3 CH3 CH3 CH3 COCH(CH3)2 COCH3 OCH3 Cl Cl CH3 CH2OH CH3 CH3
Nucleic acid in its sequence corresponding by at least 95%, preferably 97%, and particularly precisely to the nucleic acid sequence in accordance with one of the sequences with the consecutive number 1 to 51 (in accordance with Table 1 in combination with FIG. 1).
Gene clusters containing “Open reading frames,” preferably 54, which correspond, in their nucleic acid sequence, by at least 95%, preferably 97%, and particularly precisely to the nucleic acid sequences according to the sequences with the consecutive numbers 1 to 54 (in accordance with Table 1 in combination with FIG. 1) and that are arranged on a nucleic acid strand, preferably in accordance with FIG. 109.
Protein or polypeptide corresponding, in its amino acid sequence, by at least 95%, preferably 97%, and particularly precisely to the amino acid sequence in accordance with one of the sequences with the consecutive number 55-105 (in accordance with Table 1 in combination with FIG. 1).
Cell containing at least one nucleic acid modified by gene technology, the sequence of which, before modification, corresponded by at least 95%, preferably 97, and particularly precisely to the nucleic acid sequence in accordance with one of the sequences with the consecutive number 1 to 54 (in accordance with Table 1 in combination with FIG. 1).
Cell of the type Streptomyces viridochromogenes, preferably of the subtype Tü57, characterized in that at least one of the nucleic acids with a sequence in accordance with one of the sequences with consecutive number 1-54 (in accordance with Table 1 in combination with FIG. 1) was modified by gene technology or deleted.
Dependencies are inferred from the claim text.