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US 6,271,255 B1Granted
Erythromycins and process for their preparation
AssigneesBiotica Technology Limited, Pfizer Inc.
InventorsPeter Francis Leadlay, James Staunton, Jesus Cortes, Michael Stephen Pacey
Life of this patent
Estimating the term…
Abstract
Erythromycins, particularly with C-13 substituents R1 (e.g. C3-C6 cycloalkyl or cycloalkenyl groups) are prepared by fermenting suitable organisms in the presence of R1CO2H. A preferred organism is Saccharopolyspora erythraea preferably containing an integrated plasmid capable of directing synthesis of desired compounds.
Claims27
A compound of the formula 1:
- and to pharmaceutically acceptable salts thereof, wherein:
- R1 is an alpha-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may optionally be substituted by one or more hydroxyl groups;
- a C5-C8 cycloalkylalkyl group wherein the alkyl group is an alpha-branched C2-C5 alkyl group;
- a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C1-C4 alkyl groups or halo atoms;
- or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4 alkyl groups or halo atoms;
- or R1 is phenyl which may be optionally substituted with at least one substituent selected from C1-C4 alkyl, C1-C4 alkoxy and C1-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano;
- or R1 may be with a formula (a) as shown below:
- wherein X is O, S or —CH2—, a, b, c, and d are each independently 0-2 and a+b+c+d≦5.
- R2 is H or OH;
- R3-R5 are each independently H, CH3, or CH2CH3;
- R6 is H or OH;
- and R7 is H, CH3, or CH2CH3;
- R8 is H or desosamine;
- R9 is H, CH3, or CH2CH3;
- R10 is OH, mycarose (R13 is H), or cladinose (R13 is CH3), R11 is H;
- or R10=R11=O;
- and R12 is H, CH3, or CH2CH3;
- or any of the above defined compounds modified by replacing one or more —CHOH or —CHOR groups by a keto group, except that R1 in formula 1 does not represent —CH(—CH3H7)—CH3 or —CH(C3H6OH) —CH3.
15 more elements
A compound of the formula 2:
- and to pharmaceutically acceptable salts thereof, wherein:
- R1 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl containing from 1 to 6 carbon atoms in each alkyl or alkoxy group wherein any of said alkyl, alkoxy, alkenyl or alkynyl groups may be substituted by one or more hydroxyl groups or by one or more halo atoms;
- or a C3-C8 cycloalkyl or C5-C8 cycloalkenyl either of which may be optionally substituted by methyl or one or more C1-C4 alkyl groups or halo atoms;
- or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4 alkyl groups or halo atoms;
- or a group of the formula SR14 wherein R14 is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C1-C4 alkyl, C1-C4 alkoxy or halo, or a 3 to 6 membered oxygen or sulphur-containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more C1-C4 alkyl groups or halo atoms;
- and
- R2 is H or OH;
- R3-R5 are each independently H, CH3, or CH2CH3;
- R6, is H or OH;
- and R7 is H, CH3, or CH2CH3;
- R8 is H or desosamine;
- R9 is H, CH3, or CH2CH3;
- R10, is OH, mycarose (R13 is H), or cladinose (R13 is CH3), R11 is H;
- or R10=R11=O;
- and R12 is H, CH3, or CH2CH3, with the proviso that when R3-R5 are CH3, R7 is CH3, R9 is CH3, and R12 is CH3 or H, then R1 is not C1 alkyl;
- when R3-R5 are CH3, R6 is OH, R7 is CH3, R9 is CH3, and R12 is CH3, then R1 is not H;
- when R3-R5 are CH3, R7 is CH3, R9 is CH3, R12 is CH3, and R13 is H, then R1 is not H;
- or any of the above defined compounds modified by replacing one or more —CHOH or —CHOR groups by a keto group except that R1 in formula 2 does not represent —CH(—CH3H7) —CH3 or —CH(C3H6OH)—CH3.
15 more elements
A compound of the formula 1:
- and to pharmaceutically acceptable salts thereof, wherein:
- R1 is a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, either of which may optionally be substituted by one or more hydrozyl or one or more C1-C4 alkyl groups;
- R2 is H or OH;
- R3-R5 are each independently H, CH3, or CH2CH3;
- R6is H or OH;
- and R7 is H, CH3, or CH2 CH3;
- R8 is H or desosamine;
- R9 is H, CH3, or CH2CH3;
- R10 is OH, mycarose (R13 is H), or cladinose (R13 is CH3), R11 is H;
- or R10=R11=O;
- and R12 is H, CH3, or CH2CH3;
- or any of the above defined compounds modified by replacing one or more —CHOH or —CHOR groups by a keto group.
9 more elements
A compound of the formula 1:
- and to pharmaceutically acceptable salts thereof, wherein:
- R1 is a 5 or 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may optionally be substituted by one or more hydroxyl groups, C1-C4 alkyl groups or halogen atoms;
- R2 is H or OH;
- R3-R5 are each independently H, CH3, or CH2CH3;
- R6 is H or OH;
- and R7 is H, CH3, or CH2CH3;
- R8 is H or desosamine;
- R9 is H, CH3, or CH2CH3;
- R10 is OH, mycarose (R13 is H), or cladinose (R13 is CH3), R11 is H;
- or R10=R10=O;
- and R12 is H, CH3, or CH2CH3;
- or any of the above defined compounds modified by replacing one or more —CHOH or —CHOR groups by a keto group.
9 more elements
A compound of the formula 1:
- and to pharmaceutically acceptable salts thereof, wherein:
- R1 is phenyl which may be optionally substituted with at least one substituent selected from a C1-C4 alkyl, C1-C4 alkoxy and C1-C4 alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano;
- R2 is H or OH;
- R3-R5 are each independently H, CH3, or CH2CH3;
- R6 is H or OH;
- and R7 is H, CH3, or CH2CH3;
- R8 is H or desosamine;
- R9 is H, CH3, or CH2CH3;
- R10 is OH, mycarose (R13 is H), or cladinose (R13 is CH3), R11 is H;
- or R10=R11=O;
- and R12 is H, CH3, or CH2CH3;
- or any of the above defined compounds modified by replacing one or more —CHOH or —CHOR groups by a keto group.
9 more elements
A compound of the formula 1:
- and to pharmaceutically acceptable salts thereof, wherein:
- R1 may be with a formula (a) as shown below:
- wherein X is O1S1 or —CH2—, a, b, c and d are each independently 0-2 and a+b+c+d≦5;
- R2is H or OH;
- R3-R5 are each independently H, CH3, or CH2CH3;
- R6 is H or OH;
- and R7 is H, CH3, or CH2CH3;
- R8 is H or desosamine;
- R9 is H, CH3, or CH2CH3;
- R10 is OH, mycarose (R13 is H), or cladinose (R13 is CH3), R11 is H;
- or R10=R11=O;
- and R12 is H, CH3, or CH2CH3;
- or any of the above defined compounds modified by replacing one or more —CHOH or —CHOR groups by a keto group.
10 more elements
A compound of the formula 2:
- and to pharmaceutically acceptable salts thereof, wherein:
- R1 is 1-(trifluoromethyl) ethyl or a group of the formula SR14 and R14 is methyl or ethyl;
- R2 is H or OH;
- R3-R5 are each independently H, CH3, or CH2CH3;
- R6 is H or OH;
- and R7 is H, CH3, or CH2CH3;
- R8 is H or desosamine;
- R9 is H, CH3, or CH2CH3;
- R10 is OH, mycarose (R13 is H), or cladinose (R13 is CH3), R11 is H;
- or R10=R11=O;
- and R12 is H, CH3, or CH2CH3, with the proviso that when R3-R5 are CH3, R7 is CH3, R9 is CH3, and R12 is CH3, then R1 is not H or C1 alkyl;
- or any of the above defined compounds modified by replacing one or more —CHOH or —CHOR groups by a keto group.
9 more elements
A compound of the formula 1:
- and to pharmaceutically acceptable salts thereof, wherein:
- R1 is an alpha-branched C3-C8 alkenyl or alkynyl, either of which may optionally be substituted by one or more hydroxyl groups;
- R2 is H or OH;
- R3-R5 are each independently H, CH3, or CH2CH3;
- R6 is H or OH;
- and R7 is H, CH3, or CH2CH3;
- R8 is H or desosamine;
- R9 is H, CH3, or CH2CH3;
- R10 is OH, mycarose (R13 is H), or cladinose (R13 is CH3), R11 is H;
- or R10=R11=O;
- and R12 is H, CH3, or CH2CH3;
- or and of the above defined compounds modified by replacing one or more —CHOH or —CHOR groups by a keto group.
9 more elements
A compound of the formula 1:
- and to pharmaceutically acceptable salts thereof, wherein:
- R1 is sec-butyl or 1-methylthioethyl;
- R2 is H or OH;
- R3-R5 are each independently H, CH3, or CH2CH3;
- R6 is H or OH;
- and R7 is H, CH3, or CH2CH3;
- R8 is H or desosamine;
- R9 is H, CH3, or CH2CH3;
- R10 is OH, mycarose (R13 is H), or cladinose (R13 is CH3), R11 is H;
- or R10=R11=O;
- and R12 is H, CH3, or CH2CH3;
- or any of the above defined compounds modified by replacing one or more —CHOH or —CHOR groups by a keto group.
9 more elements
Dependencies are inferred from the claim text.