Patent EA-001744-B1 (EA)
Title: Novel erythromycins and process for their preparation
Inventor: LEADLAY PETER FRANCIS
IPC: C07D498/18
Filed: 1997-07-04
Abstract: 1. A compound of the formula 1:   and pharmaceutically acceptable salts thereof wherein: R1 is an α-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 α-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, each of which may optionally be substituted by methyl or one or more hydroxyl groups or one or more C1-C1 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 a group of formula (_a_):   wherein X is O, S or -CH2-; and 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=0; 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. 2. A compound of the formula _2_:   and a pharmaceutically acceptable salts thereof, wherein: R1 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl group 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 group, each 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, C7-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C1-C4alkyl, 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; 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=0; 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 nnodified by replacing one or more -CHOH or -CHOR groups by a keto group. 3. A compound of the formula _1_ as claimed in Claim 1 wherein R1 is a C3-C6 cycloalkyl or cycloalkenyl group which may be optionally substituted by one or more hydroxyl groups or one or more C1-C4 alkyl groups. 4. A compound of Claim 3 wherein R1 is cyclopropyl. 5. A compound of Claim 3 wherein R1 is cyclobutyl. 6. A compound of Claim 3 wherein R1 is cyclopentyl. 7. A compound of Claim 3 wherein R1 is cyclohexyl. 8. A compound of Claim 1 wherein R1 is an α-branched C3-C8 alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group. 9. A compound of Claim 8 wherein R1 is isopropyl. 10. A compound of Claim 8 wherein R1 is sec-butyl. 11. A compound of Claim 8 wherein R1 is 2-buten-2-yl, 2-penten-2-yl, or 4-methyl-2-penten-2-yl. 12. A compound of Claim 8 wherein R1 is 1-methylthioethyl. 13. A compound of Claim 1 wherein R1 is a 5 or 6 membered oxygen- or sulphur-containing heterocyclic ring which may be optionally substituted by one or more hydroxyl groups or C1-C4 alkyl groups or halogen atoms. 14. A compound of Claim 13 wherein R1 is 3-thienyl. 15. A compound of Claim 13 wherein R1 is 3-furanyl. 16. A compound of Claim 1 wherein R1 is phenyl. 17. A compound of Claim 1 wherein R1 is a group of formula (_a_) wherein a and b are 0, c and d are 1 and X is -CH2-. 18. A compound of Claim 1 wherein R1 is a group of formula (_a_) wherein a and b are 0, c is 1, d is 2 and X is -CH2-. 19. A compound of Claim 1 wherein R1 is a group of formula (_a_) wherein a and b are 0, c and d are 1 and X is 0. 20. A compound of Claim 2 wherein R1 is SR14 and R14 is methyl or ethyl. 21. A compound of Claim 2 wherein R1 is ethyl, propyl, butyl, isopropyl or sec-butyl. 22. A compound of Claim 2 wherein R1 is 1-(trifluoromethyl)ethyl. 23. A process for preparing a compound of formula _1_ as claimed in Claim 1 or formula _2_ as claimed in Claim 2 which comprises fermenting an organism capable of producing erythromycin in the presence of a carboxylic acid of the formula R1CO2H wherein R1 is as defined in Claim 1 or Claim 2, or a salt, ester or amide thereof or oxidative precursor thereof, and isolating the compound of formulae _1_ or _2_. 24. A process of Claim 23 wherein the organism is Saccharopolyspora erythraea and which may optionally contain an effectively integrated plasmid capable of directing the biosynthesis of compounds of formula 1. Said plasmid may optionally contain a Type II PKS promoter/activator gene. 25. A process of Claim 24 wherein the organism Saccharopolyspora erythraea is selected from strains NRRL 2338, 18643 or 21484 which may optionally contain an effectively integrated plasmid capable of directing the biosynthesis of compounds of formula _1_. Said plasmid may optionally contain the actI promoter and its cognate activator gene actII-orf4. 26. A process of Claim 25 wherein the optionally effectively integrated plasmid is pAVLD, pIG1, pND30, pCJR26, pCJR49, pc-AT12, pc-ATX or other similar constructions. 27. A process of Claim 25 wherein the organism is S. erythraea ERMD1, S. erythraea NRRL 2338/pIG1, S. erythraea NRRL 2338/pND30, or other similar transformants. 28. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 or Claim 2 in combination with a pharmaceutically acceptable carrier. 29. A method of treating a bacterial infection, or a disorder related to a bacterial infection, or a protozoal infection in a mammal, fish, or bird which comprises administering to said mammal, fish, or bird a therapeutically effective amount of a compound of Claim 1 or Claim 2. 30. Use of compound of Claim 1 or Claim 2 in the manufacture of a medicament for treating a bacterial infection in a mammal, fish or bird. 31. Use of a compound of Claim 1 or Claim 2 for improving performance effects (such as weight gains, feed efficiency utilisation, milk yield, etc,) in a mammal, fish, or bird.