MXPA00006604A - Novel macrolides - Google Patents

Abstract

The invention relates to novel erythromycin analogs and azalides, particularly ones with novel C-13 substituents, and to pharmaceutically acceptable salts thereof. The compounds of this invention are antibacterial agents that may be used to treat various bacterial and protozoa infections. The invention also relates to pharmaceutical compositions containing such compounds and to methods of treating bacterial protozoa infections by administering such compounds. The invention also relates to methods of preparing such compounds and to intermediates useful in such preparation.

Description

NEW MACROLIDES BACKGROUND OF THE INVENTION This invention relates to novel erythromycins and azalides which are useful as antibacterial agents and antiprotozoal agents and in other applications (eg, against cancer, atherosclerosis, reduction of gastric motility, etc.) in mammals, including humans, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and methods for the treatment of bacterial infections and caused by protozoa in mammals, fish and birds, by administering the new compounds to mammals, fish and birds that need said treatment. It is known that macrolide antibiotics are useful in the treatment of a broad spectrum of bacterial infections and caused by protozoa in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A such as azithromycin, which is commercially available and is cited in U.S. Patents 4.4J4J68 and 4,517,359, which are incorporated herein by reference in their entirety. Additional macrolides are cited in U.S. Patent Application Serial No. 60/063676, filed October 29, 1997 (Yong-Jin Wu), U.S. Patent Application Serial No. 60/063161, filed on October 29, 1997 (Yong-Jin Wu), United States patent application serial number 60/054866, filed August 6, 1997 (Hiroko Masamune, Yong-Jin Wu, Takushi Kaneko and Paul R. McGuirk) , United States patent application serial number 60/049980, filed June 1, 1997 (Brian S. Bronk, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), United States patent application serial number 60/049348, filed on June 1, 1997 (Brian S. Bronk, Hengm.ao Cheng, EA Glaser, Michael A. Letavic, Takushi Kaneko and Bingwei V. Yang), application for international PCT document no. PCT / GB97 / 01810, presented on July 4, 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and M ichael Stephen Pacey), PCT international document application No. PCT / GB97 / 01819, filed July 4, 1997 (Peter Francis Leadlay, James Staunton and Jesus Cortes), United States patent application serial number 60/070343 , filed on January 2, 1998 (Dirlam), United States patent application serial number 60/070358, filed on January 2, 1998 (Yong-Jin Wu) and United States patent application serial number 60/097075, filed August 19, 1998 (Hengmiao Cheng, Michael A. Letavic, Carl B. Ziegler, Jason K, Dutra, Brian S. Bronk), which are incorporated herein by reference in their entirety. Like azithromycin and other macrolide antibiotics, the new macrolide compounds of the present invention possess potent activity against various bacterial infections and caused by protozoa, as described below.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula or a pharmaceutically acceptable salt thereof, wherein: Y is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (C 6 -C 6 aryl), - (CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4 and wherein alkyl, alkenyl, aryl, heteroaryl and alkynyl groups are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R21, -OC (O) R21, -NR21 (O) R22, -C (O) NR21R22, -NR21R22, hydroxy, Ci-Cß alkyl, C alco alkoxy C6, aryl C6-C? 0 and heteroaryl of 5 to 10 links; R1 is a branched C3-C8 alpha alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of which being optionally substituted by one or more hydroxyl groups; a Cs-C8 cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C3 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more C 1 -C 4 alkyl groups or halogen atoms; or R 1 is phenyl which may be optionally substituted by at least one substituent selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and (C 1 -C 4 alkyl) thio groups, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R1 can be a group with a formula (a) as shown below: wherein X is O, S or -CH2-, a, b, c and d are each, independently an integer ranging from 0 to 2 and a + b + d = 5; or R1 is CH2R24, where R24 is H, C2-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and may be any of said alkyl, alkoxy, alkenyl or alkynyl groups substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or Cs-Cs cycloalkenyl, any of which may be optionally substituted by methyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C -C alkyl groups or halogen atoms; or a group of formula SR23 wherein R23 is Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C? -C alkyl, alkoxy CrC.o halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C? -C alkyl groups or halogen atoms; R2 is H or OH; R3 is H, OH or OCH3; R 4 is H, -C (0) R 9, -C (0) OR 9, -C (0) NR 9 R 10 or a hydroxy protecting group; R 5 is -SR 8, - (CH 2) nC (O) R 8, where n is 0 or 1, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (C 6 aryl) C? 0) or - (CH2) m (5-10 membered heteroaryl), where m is an integer ranging from 0 to 4 and where the above R5 groups are optionally substituted by 1 to 3 R16 groups; each R6 and R7 is independently, H, hydroxy, C? -C6 alkoxy, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CH2) m (C6-C? 0 aryl) or - (CH2) m ( 5-10-membered heteroaryl), where m is an integer ranging from 0 to R8 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C20 alkynyl) - (CH2) qCR11R12 (CH2) rNR13R14, where q and r are each independently, an integer that varies from 0 to 3, except that q and r are not both 0, - (CH2) m- (aryl C6-C? 0) or - (CH2) m (heteroaryl of 5-10 links), where m is an integer ranging from 0 to 4, and where the above R8 groups, except H, are optionally substituted by 1 to 3 R16 groups; or when R8 is -CH2NR8R15, R15 and R8 can be taken together to form a saturated mono- or polycyclic ring of 4 to 10 links or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and N (R8) -, in addition to the nitrogen to which R15 and R8 are attached, said saturated ring optionally includes 1 or 2 double or triple carbon-carbon bonds and said saturated and heteroaryl rings are optionally substituted by 1 to 3 groups R16; each of R9 and R10 is, independently, H or C? -C6 alkyl; each of R 11, R 12, R 13 and R 14 is independently selected from H, C 1 -C 10 alkyl, - (CH 2) m (C 1 -C 10 aryl) and - (CH 2) m (5-10 link heteroaryl), where m is an integer ranging from 0 to 4 and where groups R11, R12, R13 and R14 above, except, H are optionally substituted by 1 to 3 R16 groups; or R11 and R13 are taken together to form - (CH2) P-, where p is an integer ranging from 0 to 3, such that a saturated 4-7-membered ring is formed which optionally includes 1 or 2 double or triple carbon bonds -carbon; or R13 and R14 are taken together to form a saturated monocyclic or polycyclic ring of 4-10 links or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and -N (R8) -, in addition to the nitrogen to which R13 and R14 are attached, said saturated ring optionally includes 1 or 2 double or triple carbon-carbon bonds and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R16 groups; R 15 is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, or C 2 -C 0 alkynyl, wherein the above R 15 groups are optionally substituted by 1 to 3 substituents independently selected from halogen and -OR 9; each R16 is independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R17, C (O) OR17, -C (O) OR17, -OC (O) OR17, -NR6C (O) R7, -C (O) NR6R7, -NR6R7, hydroxy, C6 alkyl, Ci-Cd alkoxy, - (CH2) m (Ce-Cio aryl) and - (CH2) m (5-1-membered heteroaryl), where m is an integer ranging from 0 to 4 and wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R17, -C (O) OR 17, -C (O) OR 17, -OC (O) OR 17 -NR 6 C (O) R 7, -C (O) NR 6 R 7, -NR 6 R 7, hydroxy, d-C 6 alkyl and C 1 -C 6 alkoxy; and each R 17 is independently selected from H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m- (C 6 -C 0 aryl) and - (CH 2) m (5-10 membered heteroaryl), where m is an integer ranging from 0 to 4, provided that R8 is not H when R19 is -CH2-S (O) nR8; R18 is OH; R19 is C1-C10 alkyl, C2-C2 alkenyl, C2-C2 alkynyl, cyano, -CH2S (O) nR8, where n is an integer ranging from 0 to 2, -CH2OR8, -CH2N (OR9) R8, -CH2NR8R15, - (CH2) m (C6-C? 0 aryl), or - (CH2) m (heteroaryl of 5-10 links), where m is an integer ranging from 0 to 4, and the groups Previous R19 optionally substituted by 1 to 3 groups R16, or R18 and R19 are taken together to form an oxazolyl ring as shown below Y; each of R21 and R22 is independently H, hydroxy, C? -C6 alkoxy, C? -C6 alkyl, C2-C6 alkenyl, (CH2) m (C6-C? 0 aryl), (CH2) m (heteroaryl), to 10 links), where m is an integer ranging from 0 to 4, or C2-Cι alkynyl- The present invention also relates to compounds of formula or a pharmaceutically acceptable salt thereof, wherein: Y is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl) C 2 -C 8 alkynyl 0 - (CH 2) m (C 6 -C 0 aryl), - (CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4 and wherein alkyl, alkenyl, aryl, heteroaryl and alkynyl groups are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R21, -OC (O) R21, -NR21C (O) R22, -C (O) NR21R22, -NR21R22, hydroxy, Ci-Cß alkyl, Ci-Cβ alkoxy . Ce-Cyl aryl and heteroaryl of 5 to 10 links; R1 is a branched C3-C8 alpha alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of which being optionally substituted by one or more hydroxyl groups; a Cs-Cs cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkenyl C5-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more C 1 -C 4 alkyl groups or halogen atoms; or R1 is phenyl which may be optionally substituted with at least one substituent selected from C? -C alkyl groups, C? -C4 alkoxy and (C? -C alkyl) thio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R1 can be a group with a formula (a) as shown below: wherein X is O, S or -CH2-, a, b, c and d are each, independently 0 to 2 and a + b + c + d < 5; or R1 is CH2R24, where R24 is H, C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing from 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and any of said alkyl, alkoxy, alkenyl or alkynyl groups substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or C5-C8 cycloalkenyl, any of which may be optionally substituted by methyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C?-C4 alkyl groups or halogen atoms; or a group of formula SR23 wherein R23 is d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C? -C alkyl, alkoxy C? -C4 or halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or fully or partially unsaturated and which may be optionally substituted by one or more C? -C4 alkyl groups or halogen; R2 is H or OH; R3 is H, OH or OCH3; R 4 is H, -C (O) R 9, -C (O) OR 9, -C (O) NR 9 R 10 or a hydroxy protec group; each of R9 and R10 is independently, H or Ci-Cß alkyl; R18 is OH; R19 is H; each of R2 and R22 is independently H, hydroxy, C6-C6 alkoxy > C 1 -C 6 alkyl, C 2 -C 6 alkenyl, (CH 2) m (C 6 -C 6 aryl), (CH 2) m (5- to 10-membered heteroaryl), where m is an integer ranging from 0 to 4, or C2-C10 alkynyl. The compounds of formula I are exemplified by the compounds of formulas 5 and 6, described below, where Y = H and CH 3, respectively.

Preferred compounds of formula I include those in which R1 = isopropyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylthioethyl and 3-furyl. The compounds of formula II are exemplified by the compounds of formula 6 and 6a, described below, wherein Y = H and CH3, respectively. Preferred compounds of formula II include those in which R 1 = isopropyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylthioethyl and 3-furyl. Other preferred compounds of formula I and formula II include those in which R20 is R1 is isopropyl, R2 is H and R19 is OH; R1 is isopropyl, R2 is OH and R19 is OH; R1 is cyclopropyl, R2 is H and R19 is OH; R1 is cyclopropyl, R2 is OH and R19 is OH; R1 is sec-butyl, R2 is H and R19 is OH; R1 is sec-butyl, R2 is OH and R9 is OH; R1 is cyclobutyl, R2 is H and R19 is OH; R1 is cyclobutyl, R2 is OH and R9 is OH; R1 is cyclopentyl, R2 is H and R19 is OH; R1 is cyclopentyl, R2 is OH and R19 is OH; R1 is methylthioethyl, R2 is H and R19 is OH; R1 is methylthioethyl, R2 is OH and R19 is OH; R1 is 3-furyl, R2 is H and R19 is OH; R1 is 3-furyl, R2 is OH and R19 is OH. The invention further relates to the compounds of 2, 2a, 3, 3a, 4, 5, 6, 7, 8, 9, 10,, 12, 13, 14, 15, 16, 17, and 18. The invention is also refers to a compound of formula or to a pharmaceutically acceptable salt thereof, wherein: R1 is a branched C3-C8 alpha alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, which may be any of which optionally substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more C 1 -C 4 alkyl groups or halogen atoms; or R1 is phenyl which may be optionally substituted with at least one substituent selected from alkyl groups CrC4, alkoxy C? -C4 and (C 1 -C alkyl) thio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R1 can be a group 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; or R1 is CH2R24, where R24 is H, C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing from 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and any of said alkyl, alkoxy, alkenyl or alkynyl groups substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or C5-C8 cycloalkenyl, any of which may be optionally substituted by methyl or one or more CrC4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C?-C4 alkyl groups or halogen atoms; or a group of formula SR23, wherein R23 is C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C? -C alkyl, alkoxy C? -C or halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or fully or partially unsaturated and which may be optionally substituted by one or more CC alkyl groups or halogen atoms, and R2 is H or OH. The invention also relates to a compound of formula or to a pharmaceutically acceptable salt thereof, wherein: R1 is a branched C3-C8 alpha alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, which may be any of which optionally substituted by one or more hydroxyl groups; a Cs-Cs cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-Cs alkyl group; a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more C? -C alkyl groups or halogen atoms; or R1 is phenyl which may be optionally substituted with at least one substituent selected from C-C4 alkyl groups, C-C4 alkoxy and (C 1 -C 4 alkyl) thio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R1 can be a group 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; or R1 is CH2R24, where R24 is H, C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing from 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and can be any of said alkyl, alkoxy, alkenyl or alkynyl groups substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or Cs-Cs cycloalkenyl, any of which may be optionally substituted by methyl or one or more C -C alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms; or a group of formula SR23 wherein R23 is C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C?-C4 alkyl, C1 alkoxy -C4, or halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C? -C4 alkyl groups or halogen atoms; and R2 is H or OH. The invention further relates to a pharmaceutical composition for the treatment of a bacterial infection or infection caused by protozoa in a mammal, fish or poultry, comprising a therapeutically effective amount of a compound of formula I, II, 8 or 9, or one of its pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier. The invention also relates to a method for treating a bacterial infection or an infection caused by protozoa in a mammal, fish or poultry, which comprises administering to said mammal, fish or birds, a therapeutically effective amount of a compound of formula I, II , 8 or 9, or a pharmaceutically acceptable salt thereof. The invention further relates to a process for preparing a compound of formula wherein R1 and R2 are as defined for the compound of formula I, which comprises treating a compound of formula wherein R1 and R2 are as defined for the compound of formula I, with a reducing agent. The invention also relates to the above process, wherein the reducing agent is NaBH 4 or platinum oxide.

The invention also relates to a process for preparing a compound of formula wherein R1 and R2 are as defined for the compound of formula I, which comprises treating a compound of formula wherein R1 and R2 are as defined for the compound of formula I, with a methylating agent.

The invention also relates to the above process, in which the methylating agent is formaldehyde. The invention also relates to a process for preparing a compound of formula wherein R1 and R2 are as defined for the compound of formula I, which comprises treating a compound of formula wherein R1 and R2 are as defined for the compound of formula I, with a reducing agent.

The invention also relates to the above process, wherein the reducing agent is NaBH 4 or platinum oxide. The invention also relates to a process for preparing a compound of formula wherein R1 and R2 are as defined for the compound of formula I, which comprises treating a compound of formula wherein R1 and R2 are as defined for the compound of formula I, with a methylating agent. The invention also relates to the above process, in which the methylating agent is formaldehyde. The invention relates to a compound of formula or to one of its pharmaceutically acceptable salts, wherein: Y is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (Ce-Cι aryl,), - ( CH2) m (5-10 membered heteroaryl), where m is an ester which varies from 0 to 4 and where the alkyl, alkenyl, aryl, heteroaryl and alkynyl groups are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano , nitro, trifluoromethyl, azido, -C (O) R21, -OC (O) R21, -NR21C (O) R22, -C (O) NR21R22, -NR21R22, hydroxy, Ci-Cß alkyl, Ci-Cβ alkoxy , Ce-C o aryl, and 5- to 10-membered heteroaryl; R1 is a branched C3-C8 alpha alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, any of which being optionally substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group, wherein the alkyl group is a C2-C5 alkyl, alpha-branched group; a C3-C8 cycloalkyl group, or C5-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C? -C alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 bonds which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more C 1 -C 4 alkyl groups or halogen atoms; or R1 is phenyl which may be optionally substituted with at least one substituent selected from C1-C4 alkyl groups, C? -C4 alkoxy, and (C? -C4 alkyl) thio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R1 can be a group with a formula (a) as shown below: wherein X is O, S or -CH2-, a, b, c and d are each, independently an integer ranging from 0 to 2 and a + b + c + d < 5; or R1 is CH2R24, where R24 is H, C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing from 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and any of said alkyl, alkoxy, alkenyl or alkynyl groups substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or C5-C8 cycloalkenyl, any of which may be optionally substituted by methyl or one or more C1-C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms; or a group of formula SR23 wherein R23 is C-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C?-C4 alkyl, alkoxy C? -C4, or halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C? -C4 alkyl groups or halogen; R2 is H or OH; R3 is H, OH or OCH3; R4 is H, -C (0) Rs, -C (0) ORs, -C (0) NR 9SRD1I0U or a hydroxy protecting group; R5 is -SR8, - (CH2) nC (O) R8, where n is 0 or 1, CC? 0 alkyl, C2-C? Alkenyl, C2-C10 alkynyl, - (CH2) m (C6-C aryl? 0) or - (CH2) m (5-10 membered heteroaryl), where m is an integer ranging from 0 to 4 and where the above R5 groups are optionally substituted by 1 to 3 R16 groups; each R 6 and R 7 is independently H, hydroxy, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, - (CH 2) m (C 6 -C 0 aryl) or - (CH 2) m (heteroaryl 5-10 links), where m is an integer that varies from 0 to 4; each R8 is independently H, C1-C10 alkyl, C2C alkenyl or, C2-C0 alkynyl, - (CH2) qCR11R12 (CH2) rNR13R14, where q and r are each independently, an integer ranging from 0 to 3, except that q and y are not both 0, - (CH2) m- (aryl C6-C? 0) or - (CH2) m (heteroaryl of 5-10 links), where m is an integer ranging from 0 to 4, and where previous R8 groups, except H, are optionally substituted by 1 to 3 R16 groups; or when R8 is -CH2NR8R15, and R15 and R8 can be taken together to form a saturated mono- or polycyclic ring of 4 to 10 links or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and -N (R8) -, in addition to the nitrogen to which R15 and R8 are attached, said saturated ring optionally includes 1 or 2 double or triple carbon-carbon bonds and said saturated and heteroaryl rings are optionally substituted by 1 to 3 groups R16; each of R9 and R10 is independently H or C? -C6 alkyl; each of R11, R12, R13 and R14 is independently selected from H, C1-C10 alkyl; - (CH2) m (aryl C6-C? 0) and - (CH2) m (heteroaryl of 5-10 links), where m is an integer that varies from 0 to 4 and where the groups R11, R12, R13 and R14 previous, except H, are optionally substituted by 1 to 3 R16 groups; or R11 and R2 are taken together to form - (CH2) P-, where p is an integer ranging from 0 to 3, such that a 4-7-membered saturated ring is formed which optionally includes 1 or 2 double or triple bonds carbon-carbon; or R13 and R14 are taken together to form a saturated monocyclic or polycyclic ring of 4-10 links or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and -N (R8) - further, of the nitrogen ai which R13 and R14 are attached, said saturated ring optionally includes 1 or 2 double or triple carbon-carbon bonds and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R16 groups; R 15 is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, or C 2 -C 0 alkynyl, wherein the above R 15 groups are optionally substituted by 1 to 3 substituents independently selected from halogen and -OR 9; each R16 is independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R17, -C (O) OR17, -C (O) OR17, -OC (O) OR17, NR6C (O) R 7, -C (O) NR 6 R 7, -NR 6 R 7, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, - (CH 2) m (C 6 -C 0 aryl) and - (CH 2) m (heteroaryl 5 -10 links), wherein m is an integer ranging from 0 to 4 and wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O ) R 17, -C (O) OR 17, -C (O) OR 17, -OC (O) OR 17, -NR 6 C (O) R 7, -C (O) NR 6 R 7, -NR 6 R 7, hydroxy, C 1 -C 6 alkyl and alkoxy CrC6; and each R 17 is independently selected from H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m- (C 6 -C 6 aryl), and - (CH 2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, provided that R8 is not H when R19 is -CH2-S (O) nR8; R18 is OH; R19 is C1-C10 alkyl, C2-C10 alkenyl, C2-C2 alkynyl, cyano, -CH2S (O) nR8, where n is an integer ranging from 0 to 2, -CH2OR8, -CH2N (OR9) R8, -CH2NR8R15. - (CH2) m (C6-C? 0 aryl), or - (CH2) m (5-10-membered heteroaryl), where m is an integer ranging from 0 to 4, and the above R19 groups being optionally substituted by 1 to 3 groups R 6; or R18 and R19 are taken together to form an oxazolyl ring as shown below Y; each of R21 and R22 is independently H, hydroxy, C? -C6 alkoxy, C? -C6 alkyl, C2-C6 alkenyl, (CH2) m (C6-C? 0 aryl), (CH2) m (heteroaryl), to 10 links), where m is an integer ranging from 0 to 4, or C2-Cycloalkynyl- As used herein, the term "treatment", unless otherwise indicated, includes the treatment or prevention of a bacterial infection or infection caused by protozoa, as provided in the method of the present invention. As used herein, unless otherwise indicated, the term "bacterial infection (s)" or "infection (s) caused by protozoa" include bacterial infections and infections caused by protozoa that occur in mammals, fish and birds, as well as disorders related to bacterial infections and infections caused by protozoa that can be treated or prevented by the administration of antibiotics, such as the compounds of the present invention. Said bacterial infections and infections caused by protozoa and disorders related to such infections include the following: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis, related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp .; pharyngitis, rheumatic fever and glomerulonephritis related to infection by Streptococcus pyogenes, streptococci of groups C and G, Clostridium diptheriae or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis and puerperal fever related to Staphylococcus aureus infection, coagulase-positive Staphylococci (ie, S. epidermis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, groups of CF streptococci (minute colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; urinary tract infections if complications related to infection by Staphylococcus saprophyticus or Enterococcus spp .; urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum or Neisseria gonorrheae; diseases caused by toxins related to infection by S. aureus (intoxicated food and toxic shock syndrome) or streptococci of groups A, B and C; ulcers related to Helycobacter pylori infection; systemic febrile syndromes related to Borrelia recurrentis infection; Lyme disease related to Borrelia burgdorferi infection; conjunctivitis, keratitis and dacryocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyrogenes, H. influenzae or Listeria ssp .; Mycobacterium avium disseminated complex (MAC) related to infection by Mycobacterium avium or Mycobacterium intracellulare; gastroenteritis related to Campylobacter jejuni infection; intestinal protozoa related to infection by Cryptosporidium spp .; odontogenic infection related to viridans streptococcal infection; persistent cough related to Bordetella pertussis infection; Gas gangrene related to infection by Clostridium perfringens or Bacteroides spp .; and atherosclerosis related to infection by Helycobacter pylori or Chlamydia pneumoniae. Bacterial infections and infections caused by protozoa and disorders related to such infections that can be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. haem, P. multocida, Mycoplasma bovis or Bordetella spp.; enteric disease of cattle related to infection by E. coli or protozoa (ie, coccidia, cryptosporidia, etc); milk cow mastitis related to Staph infection. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Cornybacterium or Enterococcus spp .; porcine respiratory disease related to infection by A pleuro., P. multocida or Mycoplasma spp .; enteric swine disease related to infection by E. coli, Lawsonia intracellularis, Salmonella or Serpulina hyodysinteriae; Necrosis of the hoof in cows related to infection by Fusobacterium spp .; Metritis vaccine related to E. coli infection; hairy warts in cows related to infection by Fusobacterium necrophorum or Bacteroides nodosus; the red eye of the cows related to the infection by Moraxella bovis; premature bovine abortion related to infection caused by protozoa (ie, neosporium); urinary tract infection in dogs and cats related to E. coli infection; skin and soft tissue infections in dogs and cats related to Staph infection. epidermis, Staph. intermedius, Staph. coagulase negative or P. multocida and dental or oral infections in dogs and cats related to infection by Alcaligenes spp., Bacterioides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and infections caused by protozoa and disorders related to such infections that can be treated or prevented according to the method of the present invention are cited in JP Sanford et al., "The Sanford Guide To Antimicrobial Therapy", 26th edition ( Antimicrobial Therapy, Inc., 1996). The present invention also relates to a process for preparing the compounds of formulas I, II, 8 or 9. The compounds used in the preparation of the compounds of formulas I, II 8 and 9 can be prepared using the methods described in the application of PCT International Document No. PCT / GB97 / 01810, submitted on July 4, 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey) n and PCT International Application No. PCT / GB97 / 01819, filed on July 4, 1997 (Peter Francis Leadlay, James Staunton and Jesus Cortes), which are incorporated herein by reference in their entirety. The present invention also relates to compounds of formulas 2, 2a, 3, 3a, and 4 to 23, which are useful in the preparation of the above compounds of formulas I, II, 8 and 9 and the pharmaceutically acceptable salts of the same.

In term "hydroxy protecting group", as used herein, unless otherwise indicated, includes acetyl, benzyloxycarbonyl, and various hydroxy protecting groups familiar to those skilled in the art, including the groups mentioned in TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis" (J. Wiley &Sons, 1991). The term "halogen", as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The term "alkyl", as used herein, unless otherwise indicated, includes the saturated monovalent hydrocarbon radicals having straight, cyclic and branched moieties or mixtures thereof. It is understood that when speaking of cyclic moieties, at least three carbons must be present in said alkyl. Such cyclic moieties are cyclopropyl, cyclobutyl and cyclopentyl. The term "alkoxy", as used herein, unless otherwise indicated, includes the - (O) -alkyl groups in which, "alkyl" is as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl. The term "5-10 membered heteroaryl", as used herein, unless otherwise indicated, includes aromatic heterocyclic groups containing one or more heteroatoms, each selected from O, S, and N , in which each heterocyclic group has 5-10 atoms in its ring system. Examples of appropriate 5-10 element heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, (1, 2, 3) - and (1, 2,4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl and thiazolyl. The term "pharmaceutically acceptable salt (s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the present invention. . The compounds of the present invention which are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids which can be used to prepare the pharmaceutically acceptable acid addition salts of said basic compounds are those which form the non-toxic acid addition salts, ie the salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide salts , hydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate , benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie, 1, r-methylene-bis- (2-hydroxy-3-naphthoate)]. The compounds of the present invention that include an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. The compounds of the present invention which are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal and alkaline earth metal salts and especially the calcium, magnesium, sodium and potassium salts of the compounds of the present invention. Certain compounds of the present invention can also have asymmetric centers and, therefore, exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention and mixtures thereof and to all pharmaceutical compositions and methods of treatment which may employ or contain them. The present invention includes the compounds of the present invention and pharmaceutically acceptable salts thereof, wherein one or more hydrogens, carbons or other atoms are substituted by their isotopes. Said compounds may be useful as research or diagnostic tools in pharmacokinetic studies of metabolism and in binding assays.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention can be prepared according to the following schemes 1-4 and with the corresponding description. In the following schemes, unless otherwise indicated, the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 , R19, R20 and Y are as defined above.

SCHEME 1 SCHEME 1 (CONTINUED) SCHEME 1 (CONTINUED) SCHEME 2 2a 3a 15 SCHEME 2 (CONTINUED) 5a SCHEME 3A SCHEME 3B SCHEME 4 SCHEME 4 (CONTINUED) The compounds of the present invention are prepared easily. The compounds used in the preparation of the compounds of formulas I, II, 8 and 9 can be prepared using the methods described in PCT International Application No. PCT / GB97 / 01810, filed July 4, 1997 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey) and PCT international document application No. PCT / GB97 / 01819, presented on July 4, 1997 (Peter Francis Leadlay, James Staunton and Jesus Cortes), which are incorporated in the present as a reference in its entirety. The new polyketides and the methods and means for their preparation and, in particular, the new macrolides which are useful in the preparation of the compounds of the present invention are prepared by fermenting suitable organisms in the presence of R? CO2H, where R1 is as defined in claims 1 or 2. A preferred organism is Saccharopolyspora erythraea, which preferably contains an integrated plasmid capable of directing the synthesis of the desired compounds. By producing such polyketides, the biosynthetic genes of polyketide or fragments thereof are manipulated, which can be derived from different biosynthetic gene aggregates of polyketides, allowing the production of new erythromycins. Polyketides are a numerous and structurally varied class of natural products that include compounds that possess antibiotic properties and other pharmacological properties, such as erythromycin, tetracyclines, rapamycin, avermectin, polyether ionophores and FK506. In particular, polyketides are abundantly produced by Streptomyces and related actinomycete bacteria. These are synthesized by the repeated multi-stage condensation of acylthioesters in a manner analogous to fatty acid biosynthesis. The greatest structural diversity found among natural polyketides derives from the selection of acetate (usually) or propionate as the "initiating" or "paver" unit, and of the different degree of processing of the group - scent observed after each condensation. Examples of processing steps include reduction to b-hydroxyacyl-, reduction followed by dehydration to 2-enoyl- and complete reduction to saturated acyl thioester. The stereochemical goal of these processing steps is also specified for each cycle of the chain extension. The biosynthesis of polyketides is initiated by a group of chain-forming enzymes known as polyketide synthetases. Two classes of polyketide synthetases (PKS) have been described in actinomycetes. However, the novel polyketides and the processes used in the preparation of the compounds of the present invention are synthesized by Type I PKS, represented by the PKS for the macrolides erythromycin, avermectin and rapamycin, and which consists of a different group or "module" of enzymes for each cycle of the extension of the polyketide chain (Cortes, J. et al., Nature (1990), 348: 176-178; Donadío, S. et al., Science (1991) 252: 675-679; MacNeil, DJ et al, Gene (1992, 115-1 19-125; Schwecke, T. et al., Proc. Nati, Acad. Sci. USA (1995) 92: 7839-7843). The term "natural modulus" as used herein refers to the group of contiguous domains, from a? -acetoacetyltase ("KS") gene to the following acyl carrier protein ("ACP") gene, which carries out an extension cycle of the polyketide chain. The term "combinatorial module" is used to refer to any group of contiguous domains (and parts of a domain) that extend from a first point in a first natural module, to a second equivalent point in a second natural module. The first and second points will usually be in the domain of the nucleus that is present in all the modules, that is, both in equivalent points of the KS, AT (acyl transferase), ACP domains, or in regions of inter-domain linkage . The organization of erythromycin-producing PKS genes (also known as 6-deoxyerythronolide B synthetase, DEBS) contains three open reading frames that encode the DEBS polypeptides. The genes are organized into six modules that designate repeated units. The first open reading phase encodes the first multi-enzyme or cassette (DEBS1) consisting of three modules: the load module (erv-load) and two extension modules (modules 1 and 2). The charge module comprises an acyl transferase and an acyl carrier protein. This can be contrasted with Figure 1 of WO93 / 13663 (cited below). This shows that ORF1 consists of only two modules, the first of which is in fact the load module and the first extension module.

The phase deletion of the part encoding the DNA of the ketoreductase domain of module 5 in DEBS has been shown to lead to the formation of erythromycin analogues 5,6-dideoxy-3-micarosyl-5-oxoerythronolide B, 5,6-dideoxy -5-oxoerythronolide B and 5,6-dideoxy-6,6-epoxy-5-oxoerythronolide B (Donadío, S. et al., Science, (1991), 252-675-679). Likewise, the alteration of the residues of active sites in the enoylreductase domain of module 4 in DEBS, by genetic engineering of the corresponding DNA encoding PKS and its introduction in Saccharopolyspora erythraea, leads to the production of 6J-anhydroerythromycin C (Donadío S. et al., Proc. Nati, Acad. Sci., USA (1993) 90:71 19-7123). International patent application number WO 93/13663, which is incorporated herein by reference in its entirety, discloses further types of genetic manipulation of DEBS genes that can produce altered polyketheides. However, many of the cited attempts have been described as unproductive (Hutchinson C., R. and Fujii, I, Annu, Rev. Microbiol. (1995) 49: 201-238, on page 231). The complete DNA sequence of the Streptomyces hygroscopicus genes encoding the modular type 1 PKS that directs the biosynthesis of the immunosuppressive macrocyclic polyketide rapamycin (Schwecke, T. et al, (1995) Proc. Nati. Acad. Sci. USA) has been described. 92: 7839-7843). The DNA sequence is deposited in the database EMBL / Genbank Datábase with the access number X86780. The complex polyketides produced by modular type I PKS are particularly valuable because they include compounds with utility known as anthelminthic, insecticidal, immunosuppressive, antifungal and / or antibacterial agents. Due to their structural complexity, such new polyketides can not be easily obtained by total chemical synthesis, or by chemical modifications of known polyketides. As described in the international application PCT / GB97 / 01810, the PKC type I gene assembly encodes a loading module that is followed by extension modules. It is particularly useful to provide a hybrid PKS gene assembly in which the loading module is heterologous to the extension modules and is such as to lead to a polyketide having an altered initial unit. As indicated in the international application PCT / GB97 / 01810, this is a concept that is quite unknown in the prior art since it does not recognize the existence of load modules. WO 93/13663 refers to PKS genes altered by inactivation of a single function (ie, a single enzyme) or by affecting "a complete module" by deletion, insertion or substitution thereof. The load set, in its terms, is not a module. If the loading module is such that it accepts many different carboxylic acid units, then a hybrid gene assembly can be used to produce many different polyketides. For example, a hybrid gene assembly can employ nucleic acid encoding a load module a and r with extension modules erv. A charge module can accept units of non-native acids and derivatives thereof; the avr charge module is particularly useful in this regard (Dutton et al., (1991), J. Antibiot., 44: 357-365). In addition, it is possible to determine the specificity of the native loading module for the non-native initiating units and take advantage of the limited specificity of the loading module to generate new polyketides. Thus, the international application PCT / GB97 / 01810 describes an unexpected ability of the ery charge module to incorporate non-native carboxylic acids and derivatives thereof and produce new erythromycins in erythromycin-producing strains containing only DEBS genes. Of course, alterations in a product polyketide can be made, in particular, by replacing an extension module with one that provides a ceturo unit in a different oxidation state and / or with a different stereochemistry. As usual, it has been assumed that the stereochemistry of the methyl groups in the polyketide chain is determined by the acyltransferase. but in fact, it is a characteristic of other PKS domains and, therefore, subject to variation only by the substitution of these domains, separately or by replacement of the module. Methyl and substituents can be added or removed by substituting the acyltransferase domain or replacing the total module. Accordingly, it is evident to the person skilled in the art that it is possible to combine the use of the limited specificity of the substrate of the erythromycin loading module with the replacement of the extension module and the replacement of the hybrid charge module with the substitution of the extension as a mechanism to produce a wide range of new erythromycins. Thus, the international application PCT / GB97 / 01810 describes the production of new erythromycins by non-transformed organisms and also such assemblies of genes, vectors containing such assemblages of genes and transforming organisms that can express them, producing new erythromycins in transformed organisms. The transformant organisms may host recombinant plasmids or the plasmids may be integrated. A plasmid with a nt sequence will be integrated into a specific binding site (att) of the chromosome of a host. Transforming organisms can modify the initial products, for example, by carrying out all or some of the normal biosynthetic modifications in the production of erythromycins. However, use may be made of mutant organisms such that some of the normal routes are blocked, for example, by producing products without one or more "native" hydroxy groups or sugar groups, for example, as described in WO 91/16334 or in Weber et al., (1985) J. Bacteriol. 164: 425-433, which is incorporated herein by reference in its entirety. Alternatively, use may be made of organisms in which some of the normal routes are overexpressed to overcome the possible limiting steps of speed in the production of the desired product, for example, as described in WO 97/06266, which is it is incorporated herein by reference in its entirety. This aspect of the procedure is closely related to the treatment of the PKS gene modules as building blocks that can be used to build enzyme systems, and thus new erythromycin products of the desired types. This usually involves cutting and assembling the modules and grouping of several modules. The logical positions to make and break intermodular connections are in the regions of union between the modules. However, it may be preferable to make cuts and junctions in the domains (ie, the portions encoding the enzymes), near their edges. DNA is well conserved here among modular PKSs, and so can help build hybrids that can be transcribed. This can help maintain the separation of the active sites from the encoded enzymes, which may be important. For example, by producing a hybrid gene by substituting the ery load module for a load module a and r, the ery module can be removed together with a small amount of the following ketosintetase (KS) domains. The start of the KS domain (quite separate from the active sites) is well conserved and therefore provides a splice site as an alternative to the region of linkage between the loading domain and the beginning of the KS domain. The separated ery module was then replaced by a load module a and r. In fact, when a charge module is replaced, it may be desirable to replace not only the charge module domains (in general acyl transferase (AT) and acyl carrier protein (ACP)) but also the KS at the start of the module. next extension. Typically, the separate charge module would have provided a propionate initiator, and it is intended that the substitution provide one or more different primers. However, the propionate can be fed to the KS of the extension module from an accumulation of propionate in the host cell, leading to the dilution of the desired products. This can be largely avoided by replacing an extended load module that includes all or most of the KS domain. (The splice site may be in the terminal region of the KS gene, or almost in the next AT gene, or the region of linkage between them). When the "modules" are replaced, you are not limited to the "native" modules. For example, a "combinatorial module" to be separated and / or replaced and / or inserted can be extended from the corresponding domain of two corresponding native type modules, for example, from AT of one module to the TA of the next, or from KS to KS. The splice sites will be in corresponding conserved marginal regions or in crimp regions. A combinatorial module can also be a "double" or higher multiple, to add 2 or more modules at a time. The international application PCT / GB97 / 01810 describes new erythromycins that can be obtained by means of the above aspects. These include the following: (i) An erythromycin analogue (which is a macrolide compound with a 14-membered ring) in which a substituent R, at the C-13 position, supports a side chain that is not ethyl, in general a straight chain C3-C6 alkyl group, a branched chain C3-C8 alkyl group, a C3-C8 cycloalkyl or cycloalkenyl group (optionally substituted, for example, with one or more hydroxy, alkyl or CrCalkoxy groups or halogen atoms) ), or a 3 to 6 membered heterocycle containing O, S, saturated or wholly or partially unsaturated, optionally substituted (as for cycloalkyl) or R is phenyl, which may be optionally substituted with at least one substituent selected from alkyl groups C1 -C4, C1-C4 alkoxy and (C alkyl) C4) thio, halogen atoms, trifluoromethyl and cyano; or R can be a group with a formula (a) like the following wherein X is O, S or -CH2-, a, b, c and d are each, independently 0-2 and a + b + c + d < 5. Preferred candidates for the R substituent at the C-13 position are the RCOOR 'carboxylate unit groups, which are used as substrates by an avr initiator module, or starter variants by rapamycin.

The preferred substrates are the carboxylic acids RCOOH. Alternative substrates that can be used effectively are salts of carboxylic acids, ethers of carboxylic acids or amides. Preferred esters are thioesters of N-acetyl-cysteamine which can be easily used as substrates by the avr initiator module as illustrated by Dutton et al., In EP 0350187 which is incorporated herein by reference in its entirety. Preferred amides are N-acyl imidazoles. Other alternative substrates that can be used are derivatives that are oxidative precursors of carboxylic acids; thus, for example, suitable substrates would be amino acids of formula RCH (NH2) COOH, glyoxylic acids of formula RCOCOOH, methylamine derivatives of formula RCH2NH2, methanol derivatives of formula RCH2OH, aldehydes of formula RCHO or substituted alkanoic acids of formula R (CH2) COOH where n is 2, 4 or 6. Thus, examples of preferred substrates include sobutyrate (R is i-Pr) and 2-methylbutyrate (R is 1-methylpropyl). Other possibilities include n-butyrate, cyclopropyl carboxylate, cyclobutyl carboxylate, cyclopentyl carboxylate, cyclohexyl carboxylate, cycloheptanyl carboxylate, cyclohexenyl carboxylates, cycloheptenyl carboxylates and ring methylated variants of the above-mentioned cyclic carboxylates and derivatives thereof. The erythromycin analog may correspond to the initial product of a PKS (6-deoxyerythronolide) or the product after one or more normal biosynthetic steps. These comprise: 6-hydroxylation; 3-0-glycosylation; 5-0-glycosylation; 12-hydroxylation; and specific sugar methylation. Thus, the analogs may include those corresponding to 6-deoxyerythronolide B, erythromycin A, and various intermediates and alternatives thereof. (ii) The erythromycin analogues differ from the corresponding "native" in the oxidation state of one or more of the ceturo units (ie, selection of group alternatives: -CO-, -CH (OH) -, isoCH- and -CH2-). The stereochemistry of any -CH (OH) - can also be selected independently. (iii) Erythromycin analogues that differ from the corresponding "native" compound in the absence of a "native" methyl side chain. (This can be achieved by using an AT variant). Normal extension modules use C2 or C3 units to provide unmethylated and methylated ceturo units. Unmethylated units can be provided when native methylated units exist (and vice versa, in systems where there are native non-methylated units) and also provide larger units, eg, C4 to provide ethyl substituents. (iv) Erythromycin analogs that differ from the corresponding "native" compound in the stereochemistry of "native" methyl and / or ring substituents other than methyl. (v) Erythromycin analogs having the characteristics of two or more of sections (i) to (iv). (vi) Derivatives of any of the foregoing that have undergone additional processing by enzymes other than PKS, for example, one or more hydroxylation, epoxidation, glycosylation and methylation. The international application PCT / GB97 / 01810 describes methods for the production of the new erythromycins useful in the preparation of the compounds of the present invention. In the simplest procedure, non-native initiator units (preferably, but not limited to the carboxylic acid analogues of the non-native initiator units) are introduced into transformed organisms capable of producing erythromycins. A preferred technique involves introducing the starter unit into fermentation broths of the erythromycin producing organism, a technique that is more effective for transformed organisms capable of producing erythromycin. However, the analog of the initiator unit can also be introduced into alternative preparations of the organisms that produce erythromycin, for example, fractionated or fractionated broken cell preparations. Again, this technique is equally effective for transformed organisms capable of producing erythromycins. In another method, one or more segments of DNA encoding individual modules or domains in the heterologous type I PKS (the "donor" PKS) have been used to replace the DNA encoding, respectively, individual modules or individual domains in the genes of DEBS of an organism producing erythromycin. Load modules and extension modules extracted from any native or non-native type I PKS are suitable for this "donor" PKS although, for these purposes, the components of PKS type I for the biosynthesis of erythromycin, rapamycin, avermectin are particularly suitable. , tetronasine, oleandomycin, monensin, amphotericin, and rifamycin, for which the gene and the modular organization are known by at least part of the gene sequence analysis. Particularly favorable examples of the loading modules of the donor PKS are the loading modules that show a limited specificity, for example, the loading module of the avermectin-producing PKS of (avr) Streptomyces avermitilis; or charge modules that have unusual specificity, for example, the loading modules of rapamycin-producing PKS, FK506 and ascomycin, which naturally accept an initiator unit derived from shikimate. Unexpectedly, it has been found that both unprocessed erythromycin producing organisms and those produced by genetic engineering when grown under suitable conditions produce non-native erythromycins, and when appropriate, the products are subjected to the same processing as native erythromycin. International application PCT / GB97 / 01810 further discloses that a plasmid containing a "donor" PKS DNA is introduced into a host cell under conditions in which the plasmid that is integrated into the DEBS genes of the chromosome of the producer strain of erythromycin by homologous recombination, creating a hybrid PKS. A preferred embodiment is when the DNA of the donor PKS includes a segment encoding a loading module such that this loading module binds to the DEBS genes of the chromosome. Said hybrid PKS leads to new and valuable erythromycin products when grown under suitable conditions as described herein. Specifically, when the load module of the DEBS genes is replaced by the loading module of avermectin-producing PKS (avr), the new erythromycin products contain a starter unit typical of those used by the avr PKS. Thus, when the loading module of the PKS ery is replaced by the avr loading module, it is found that strains of Saccharopolyspora erythrae containing said hybrid PKS produce 14-link macrolides containing initiator units typically used by the avr PKS. As indicated in the international application PCT / GB97 / 01810, the 14-link macrolide polyketides produced by said recombinant S. erythraea cells can not be expected to include erythromycin A derivatives, showing that the various processing steps are carried out correctly required for the transformation of the hybrid PKS products into new and therapeutically valuable erythromycin A derivatives. International application PCT / GB97 / 01810 describes the unexpected and surprising discovery that the transcription of any of the hybrid erythromycin genes can specifically increase when the hybrid genes are placed under the control of a promoter for a type II PKS gene linked to a specific activator gene for said promoter. It is particularly remarkable that when a genetically engineered cell containing hybrid erythromycin genes under said control is grown under conditions suitable for the production of erythromycin, significantly improved levels of the new erythromycin are produced. Such specific increases in the yield of a valuable erythromycin product are also anticipated for native erythromycin PKS placed under the control of a PKS type II promoter and an activating gene. In a preferred embodiment, the desired genes present in the plasmid derived from SCP2 * are placed under the control of the bidirectional actl promoter, derived from the biosynthetic actinorhodin gene cluster of Streptomyces coelicolor, and in which the vector also contains the structural gene encoding Act-ll-orf specific activator protein 4. The recombinant plasmid is introduced into Saccharopolyspora erythraea, under conditions in which introduced PKS genes or PKS genes already present in the host strain, are expressed under the control of the active promoter. .

Such strains produce the desired erythromycin product and the activating gene requires only the presence of the specific promoter in order to improve the transcription efficiency of the promoter. This is particularly surprising because activators of the Actll-orf4 family do not belong to a recognized class of DNA binding proteins. Therefore, it would be expected that additional proteins or other control elements were necessary for activation to occur in a heterologous host not known to produce actinorhodin or a related isocromanoquinone pigment. It is also surprising and useful that recombinant strains can produce more than ten times of erythromycin product than when the same PKS genes are under the control of the native promoter, and the specific product erythromycin is also produced rapidly in growing culture, instead of only during the transition from the growth phase to stationary. Such erythromycins are useful as antibiotics and for many other purposes in human and veterinary medicine. Thus, when the genetically engineered cell is Saccharopolyspora erythraea, the activator and promoter are derived from the actinorhodin PKS gene cluster and the PKS ery gene cluster regulated by actl / actll-orf4 is housed in the chromosome, followed by the site-specific integration of a plasmid vector with low copy number, culturing these cells under suitable conditions can produce more than ten times the total 14-link macrolide product than in a comparable strain that is not under heterologous control. When in said engineered cell of S. erythraea, the PKS genes under heterologous control are hybrid PKS type I genes whose construction is described herein, can be obtained more than ten times hybrid polyketide product compared to the same hybrid type I PKS genes that are not under said control. Specifically, when the genes of PKS type I hybrids are PKS ery genes in which the charge module is replaced by the avr charge module, a ten-fold increase in the total amounts of new macrolides of 14 is found. links produced by cells engineered when grown under appropriate conditions such as those described herein. Suitable and preferred growth media of the non-transformed and engineered erythromycin producing cells and the suitable and preferred means for the isolation, identification and practical utility of the new erythromycins are described in more detail in the international PCT / GB97 application. / 01810. The erythromycin analogues described in the international patent application PCT / GB97 / 01810 are produced by fermentation of an untransformed or transformed organism capable of producing erythromycins, including, but not limited to Saccharopolyspora, Streptomyces griseoplanus, Nocardia sp., Micromonospora sp. ., Arthobacter sp., And Streptomyces antibioticus, but excluding S. coelicolor. In this regard, particularly preferred are untransformed and transformed strains of Saccharopolyspora erythraea, for example, NRRL 2338, 18643, 21484. Particularly preferred transformed strains are those in which the erythromycin loading module has been replaced by the loading module of producer of avermectin, Streptomyces avermitilis or the producer of rapamycin, Streptomyces hygroscopicus. The preferred process for producing the compounds of the present invention is by fermentation of the appropriate organism in the presence of the appropriate carboxylic acid of formula RiCOOH, where R1 is as defined above in formulas or 2, of the international document application PCT / BG97 / 01810 or is R1 of the compounds of the present invention, or a salt, ester (the thioester of N-acetylcysteamine being particularly preferred), or its amide or its oxidative precursor. The acid or derivative thereof is added to the fermentation at the time of inoculation or at intervals during fermentation. The production of the compounds of this invention can be controlled by obtaining samples, of the fermentation, extracting with an organic solvent and following the appearance of the compounds of the present invention by chromatography, for example, using high pressure liquid chromatography. The incubation is continued until the yield of the compound of formula 1 or 2 has reached the maximum, generally, during a period of 4 to 10 days. A preferred level of each addition of carboxylic acid or derivative thereof ranges from 0.05 to 4.0 g / l. The best yields of the compounds of formulas 1 or 2 are generally by gradually adding the acid or derivative to the fermentation, for example, by daily addition over a period of several days. The medium used for the fermentation can be a conventional complex medium containing assimilable sources of carbon, nitrogen and trace elements. The wide range of initiating units accepted by the avr load module has been consistently established in previous studies (for example, European patent applications 0214731, 0350187, 0317148, which are incorporated herein in their entirety). Accordingly, it will be understood that the invention is not limited to the specific details of these examples and merely serves to confirm the efficiency of the load module a and r. In addition, the examples using the plG1 pND30 construct clearly demonstrate the ability of the actl promoter and its actll-orf4 analog activator gene to enhance the expression of the novel compounds of this invention when bound to the a and charge module. It is also evident from the examples that the untransformed strains of Saccharopolyspora erythraea are also easily able to absorb substrates supplied exogenously to generate new erythromycin polyketides. Accordingly, it is evident to those skilled in the art that the new specific compounds of this invention can be easily produced by selection of the appropriate erythromycin producing strain (optionally incorporating the plasmid plG1 or pND30 into the desired strain), and by supplementing the fermentation with the appropriate initiating unit. Thus, the 6-deoxyerythromycin and 6,12-dideoxerythromycin derivatives of the present invention can be easily produced using Saccharopolyspora erythraea NRRL 18643 or NRRL 21484 as indicated in U.S. Patent 5,141,926 and in WP97 / 06266. Likewise, the use of strains of Saccharopolyspora erythrae described by Weber et al., In J. Bacteriol., 164: 425-433, 1991 can also be used to obtain new desired analogues of the present invention. For example, strain UW / 24 (optionally transformed by plG1 or pND30) can be used to obtain new analogs of erythronolide B. In step 1 of scheme 1, the carbonyl C-9 of formula 1_ is converted to the corresponding oxime. at the C-9 position by reacting the macrolide with hydroxylamine or preferably, a hydroxylamine salt as the hydrochloride. Under the preferred conditions, at least one molar equivalent, usually an excess, of 5-10 equivalents, is employed in a weakly basic tertiary amine (preferably pyridine) as the solvent; at a temperature range of 20-80 ° C. A protic solvent such as methanol in combination with a base, such as barium carbonate, may also be used to provide a weakly basic solvent. In step 2 of scheme 1, the oxime, of formula 2, undergoes a rearrangement to the corresponding imino ether by a Beckman rearrangement as depicted in J. Chem. Soc. Perkin Trans. I, 1986, 1181. Preferred conditions employ an excess (2-4 molar equivalents) of an organic sulfonyl chloride, preferably p-toluene sulfonyl chloride, which is reacted with the oxime, (as the free base or acid) in a mixture of a lower ketone, such as methyl ethyl ketone or acetone, and water containing a large molar excess of sodium bicarbonate, at a temperature of 0-50 ° C, preferably at 0-30 ° C. In step 3 of scheme 1, the imine ether, of formula 3, is reduced to a mixture of lactam, of formula 4, and of azalide, of formula 5. This can be carried out in different procedures familiar to those skilled in the art. The technique. One such method is catalytic hydrogenation which employs a reducing agent such as an organometallic catalyst such as platinum oxide in an acidic solvent such as glacial acetic acid under a minimum hydrogen pressure of 3.44 x 10 5 Pa. A preferred process for the production of 5 the use of boron reducing agents such as sodium borohydride, generally used in excess, 2-10 equivalents, in protic solvents such as methanol or ethylene glycol, at a temperature range of -5 to 40 ° C, preferably 0-20 ° C. In step 4 of scheme 1, the azalide of formula 5 is converted to formula 6 by reductive methylation using a methylating agent such as formaldehyde in the presence of a reducing agent, preferably formic acid. The preferred process requires at least one molar equivalent of each of formaldehyde and formic acid in an inert solvent such as chloroform at 20-100 ° C, preferably at 30-60 ° C. In step 1 of scheme 2, the carbonyl C-9, of formula 1, is converted to the corresponding oxime at the C-9 position by reacting the macrolide with hydroxylamine or preferably, a hydroxylamine salt as the hydrochloride. Under the preferred conditions, at least one molar equivalent, usually an excess, 5-10 equivalents, is employed in weakly basic tertiary amine (preferably pyridine) as the solvent; at a temperature range of 20-80 ° C. A protic solvent such as methanol in combination with a base, such as barium carbonate, may also be used to provide a weakly basic solvent. In step 2a of scheme 2, the oxime of formula 2, in which the geometry of the olefin is preferably the "E" isomer, is converted to the "Z" isomer in protic solvents such as ethanol, using bases of sufficient strength to substantially deprotonate oxime 9E with small counter ions such as Li + or Na \ as lithium hydroxide. In step 3a of scheme 2, the oxime of formula 2a undergoes a rearrangement to the corresponding imino ether by a Beckman rearrangement as depicted in J. Chem. Soc. Perkin Trans. I, 1986, 1181. Preferred conditions employ an excess (2-4 molar equivalents) of an organic sulfonyl chloride, preferably p-toluene sulfonyl chloride, which is reacted with the oxime, (as the free base or acid) in a mixture of a lower ketone, such as methyl ethyl ketone or acetone, and water containing a large molar excess of sodium bicarbonate, at a temperature of 0-50 ° C, preferably at 0-30 ° C. In step 4a of scheme 2, the imine ether, of formula 3a, is reduced to the azalide, of formula 5a, This can be carried out in different procedures familiar to those skilled in the art. One such method is catalytic hydrogenation which employs a reducing agent such as an organometallic catalyst such as for example platinum oxide., in an acid solvent such as glacial acetic acid under a minimum hydrogen pressure of 3.44 x 105 Pa. A preferred process for the production of 5a incorporates the use of boron reducing agents such as sodium borohydride, generally used in excess, 2-10 eqlents, in protic solvents such as methanol or ethylene glycol, at a temperature range of -5 to 40 ° C, preferably 0-20 ° C. In step 5a of scheme 2, the azalide, of formula 5a, is converted to formula 6a by reductive methylation using a methylating agent such as formaldehyde in the presence of a reducing agent, preferably formic acid. The preferred process requires at least one molar eqlent of each of formaldehyde and formic acid in an inert solvent such as chloroform at 20-100 ° C, preferably at 30-60 ° C. In step 1 of scheme 3A, the C-2 hydroxy group can be selectively protected by treating the compound of formula 0 with one eqlent of acetic anhydride in dichloromethane in the absence of external base, yielding the compound of formula H wherein R is acetyl. The acetyl protecting group can be removed by treating the compound of formula 1 with methanol at 23-65 ° C for about 10 to about 48 hours. The C-2 'hydroxy can also be protected with other protecting groups such as the benzyloxycarbonyl group (Cbz) using procedures familiar to those skilled in the art. The amino group C-9a may also require protection when Y is H before carrying out additional synthetic modifications. Suitable protecting groups for the amino moiety are Cbz and t-butyloxycarbonyl groups (Boc). To protect the amino group C-9a, the macrolide can be treated with t-butyl dicarbonate in anhydrous tetrahydrofuran (THF) or benzyloxycarbonyl ester N-hydroxysuccinimide or benzyl chloroformate to protect the amino group as its t-butyl or benzyl carbamate . Both C-9a and hydroxy C-2 'can be selectively protected with the Cbz group in one step by treating the compound of formula 10 where Y is a hydrogen with benzyl chloroformate in THF and water. The Boc group can be removed by acid treatment and the Cbz group can be removed by conventional catalytic hydrogenation. In the following description, it is assumed that the amino moiety C-9a and the hydroxy group C-2 'are protected and deprotected as deemed appropriate by one skilled in the art. In step 2 of scheme 3A, the C-4 hydroxy group of the compound of formula H is oxidized to the corresponding ketone, formula 12 by procedures familiar to those skilled in the art, The compounds of formula 14 can be generated by treating the compounds of formula 12 with RigMgXi or R19-LÍ and Mg (X?) 2, wherein Xi is a halide such as chlorine or bromine, in a solvent such as THF, ethylene glycol, dimethyl ether (DME), diisopropyl ether, toluene, diethyl ether or tetramethylethylenediamine (TMEDA), or a mixture of the above solvents, preferably an ether solvent, at a temperature ranging from about -78 ° C to about room temperature (20-25 ° C).

Scheme 2B illustrates the preparation of compounds of formula 14 using an epoxide intermediate. In scheme 3B, the compound of formula 13 can be generated by two methods. Treating the compound of formula 12 with (CH 3) 3 S (O) X 2, wherein X is halogen, -BF or PF 6, preferably iodine, in the presence of a base such as potassium tert-butoxide, sodium ethoxide, sodium hydride, 1, 1 3,3-tetramethylguanidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, potassium ethoxide or sodium methoxide, preferably a sodium-containing base as sodium hydride, in a solvent such as THF, an ether solvent, dimethylformamide (DMF) or methyl sulfoxide (DMSO), or a mixture of the above solvents, at a temperature ranging from about 0 ° C to about 60 ° C , the compound of formula 13 is generated, where the following configuration of the epoxide moiety may predominate: Treating the compound of formula 12 with (CH3) 3SX3, wherein X3 is halogen, -BF, -PFβ, preferably -BF, in the presence of a base such as potassium tert-butoxide, sodium ethoxide, sodium hydride, 1, 1, 3, 3-tetramethylguanidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, potassium ethoxide, potassium t-butoxide, KHMDS or sodium methoxide , preferably KHMDS, in a solvent such as THF, an ether solvent, dimethylformamide (DMF) or metio sulfoxide (DMSO) or a mixture of the above solvents, at a temperature ranging from about 0 ° C to about 60 ° C, the compound of formula 13 is generated, where the following configuration of the epoxide moiety may predominate: In step 1 of scheme 3B, the compound of formula 13 can be converted to a compound of formula 14 where R 8 is hydroxy and R 19 is a group that is bonded to carbon C 4 through a methylene group, when R19 is -CH2NR6R8 or -CH2S (0) nR8, where n, R6 and R8 are as defined above To prepare a compound of formula 14, wherein R19 is -CH2NR6R8, the compound of formula 13 can be treated with a compound of formula HNR6R8, wherein R6 and R8 are as defined above, in the absence or presence of a solvent such as water, methanol or THF, or a mixture of the above solvents, at a temperature ranging from about room temperature to about 100 ° C, preferably 60 ° C, optionally in the presence of a metal halide such as potassium iodide, pyridinyl hydrochloride or tetraalkylammonium halide, reactant such as benzene or toluene at a temperature ranging from about room temperature to about 120 ° C. of scheme 4 can be prepared using substantially the same procedures described in U.S. patent no. 3,681,322, issued August 1, 1972 and methods known to those skilled in the art. In step 1 of scheme 4, the C-9 carbonyl of formula 15 is converted to the corresponding oxime at the C-9 position by reacting the macrolide with hydroxylamine or preferably a hydroxylamine salt such as the hydrochloride. Under the preferred conditions, at least one molar equivalent, usually an excess, 5-10 equivalents, is usually employed in a weakly basic tertiary amine (preferably pyridine) as the solvent; at a temperature range of 20-80 ° C. A protic solvent such as methanol, combined with a base, such as barium carbonate, can also be used to provide a weakly basic solvent. In step 2 of scheme 4, the oxime of formula 16 can be reduced to the corresponding mine by treating with a metal halide such as TiCl 3 in a solvent buffered with acetate such as methanol or ethanol, with methanol being preferred. Reduction is also possible with divalent vanadium (prepared by reduction with Zn / Hg / vanadium sulfate HCl) in a protic organic solvent such as methanol or ethanol, preferably methanol. In step 3 of scheme 4, the imine of formula 17 can be reduced to the corresponding imine of formula 18, by various procedures familiar to those skilled in the art. A preferred method incorporates the use of boron reducing reagents such as sodium borohydride, generally used in excess, 2-10 equivalents, in protic solvents such as methanol or ethylene glycol, at a temperature range of -5 to 40 ° C, preferably 0. -20 ° C. The compounds of the present invention can have asymmetric carbon atoms and therefore exist in different enantiomeric or diastereomeric forms. Such diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (eg, alcohol), separating the diastereomers and converting (eg, hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. The use of such isomers, including diastereomeric mixtures and pure enantiomers, is considered part of the invention. The compounds of the present invention which are basic in nature, are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts have to be pharmaceutically acceptable for administration to mammals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter into the free base compound by treatment with an alkaline reagent, and then converting the above free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treatment of the base compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol . After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired salt can also be precipitated in a solution of the free base in an organic solvent, by adding an appropriate mineral or organic acid to the solution. The compounds of the present invention which are acidic in nature, can form base salts with various cations. For compounds that are administered to mammals, fish or birds, such salts should be pharmaceutically acceptable. When pharmaceutically acceptable salts are necessary, it may be desirable to isolate the compound of the present invention initially in the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the above to a pharmaceutically acceptable salt in an analogous procedure to that described above with reference to the conversion of salts by the addition of pharmaceutically unacceptable acids. Examples of base salts include the alkali metal or alkaline earth metal salts and, particularly, the sodium, amine and potassium salts. These salts can be prepared by conventional techniques. The chemical bases that are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those that form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, magnesium, various amine cations etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations with cations such as sodium, potassium, calcium, magnesium, various amine cations, etc. and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkane solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, stoichiometric amounts of reagents are preferably employed to ensure that the reaction is completed and that maximum yields of the desired final product are obtained. The activity of the compounds of the present invention against bacterial and protozoan pathogens is demonstrated by the ability of the compounds to inhibit the development of defined strains of human pathogens (test I) or animals (tests II and III): Assay I Assay I, described below, employs conventional methodology and interpretation criteria and is designed to provide the direction of chemical modifications that can lead to compounds that circumvent defined mechanisms of macrolide resistance. In trial i, a series of bacterial strains are assembled, including a diversity of target pathogenic species, including representatives of macrolide resistance mechanisms that have been characterized. The use of this series allows to determine the chemical structure / activity relation with respect to the pharmacological potency, spectrum of activity and structural elements or modifications that may be necessary to circumvent the mechanisms of resistance. Bacterial pathogens included in the evaluation series are shown in the table below. In many cases both the parental strain susceptible to macrolides and the macrolide-resistant strain derived therefrom are available to provide a more accurate assessment of the ability of the compounds to circumvent the resistance mechanism. Strains containing the gene with the name ermA / ermB / ermC are resistant to antibiotics macrolides, lincosamides and streptogramin B, due to certain modifications (methylation) of the 23S rRNA molecules by an Erm methylase, which usually prevents the union of the three structural classes. Two types of macrolide expulsion have been described; msrA encodes a component of an expulsion system in staphylococci that prevents the entry of macrolides and streptogramins, while mefA / E encodes a transmembrane protein that seems to expel only macrolides. Inactivation of macrolide antibiotics can occur and can be mediated by 2'-hydroxyl phosphorylation. { mph) or by cleavage of macrocyclic lactone (esterase). Strains can be characterized using conventional polymerase chain reaction (PCR) technology and / or by sequencing the resistance determinant. The use of PCR technology in this application is described in J. Sutcliffe et al., "Detection of Erythromycin-Resistant Determinants by PCR", Antimicrobial Agents and Chemoterapy, 40 (11), 2562-2566 (1996). The assay is performed in microtiter trays and interpreted according to Performance Standards for Antimicrobial Disk Susceptibility Test - Sixth Edition; Approved Standard, published by The National Comm.ttee for Clinical Laboratory Standards (NCCLS) Guidelines; To compare the strains, the minimum inhibitory concentration (MIC) is used. The compounds are initially dissolved in dimethyl sulfoxide (DMSO) as stock solutions of 40 mg / mal.

Test II is used to test the activity against Pasteurella multocida and the III test is used to test the activity against Pasteurella haemolytica.

Ensavo 11 This test is based on the liquid dilution procedure in microtitre format. A single colony of P. multocida (strain 59A067) is inoculated into 5 ml of brain-cardiac infusion broth (BHI). The test compounds are prepared by solubilizing 1 mg of the compound in 125 μl of dimethyl sulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The concentrations of the test compound used range from 200 μg / ml to 0.098 μg / ml in serial double dilutions. The BHI inoculated with P. multocida is diluted with non-inoculated BHI broth to obtain a suspension of 104 cells per 200 μl. The BHI cell suspensions are mixed with the respective serial dilutions of the test compound and incubated at 37 ° C for 18 hours. The minimum inhibitory concentration (MIC) is equal to the concentration of the compound that exhibits a 100% inhibition of the development of multocide, as determined by comparison with a non-inoculated control.

Ensavo lll This assay is based on the agar dilution procedure using a Steers Replicator. Two to five colonies isolated from an agar plate in BHI broth are inoculated and incubated overnight at 37 ° C with shaking (200 rpm). The next morning, 300 μl of the fully grown P. haemolytica preculture are inoculated in 3 ml of fresh BHI broth and the mixture is incubated at 37 ° C with shaking (200 rpm). The appropriate amounts of the test compounds are dissolved in ethanol and a series of double dilutions are prepared in series. Two ml of the respective serial dilution is mixed with 18 ml of molten BHI agar and solidified. When the inoculated P. haemolytica culture reaches a standard McFarland density of 0.5, approximately 5 μl of the P. haemolytica culture is inoculated onto BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 37 ° C. The initial concentrations of the test compound vary between 100 and 200 μg / ml. The MIC is equal to the concentration of the test compound which shows a 100% inhibition of the development of P. haemolytica, as determined by comparison with a non-inoculated control. The in vivo activity of the compounds of formula (I) can be determined by conventional animal protection studies well known to those skilled in the art, usually performed in mice. Mice are distributed in cages (10 per cage) after arrival and allowed to acclimate for a minimum of 48 hours before use. The animals receive an inoculation of 0.5 ml of a bacterial suspension of 3 x 103 CFU / ml (strain of P. multocida 59A006) intraperitoneally. Each experiment has at least 3 non-medicated control groups including one infected with an exposure dose of 0.1X and two infected with an exposure dose caused by 1X; a group of exposure data triggered by 10X can also be used. Generally, all mice in a given study can be challenged in a 30-90 minute period, especially if a repeating syringe (such as a Corwall® syringe) is used to deliver the exposure dose caused. Thirty minutes after the provoked exposure has begun, the first treatment compound is administered. It may be necessary for a second person to begin dosing the compound if all animals have not received the exposure dose caused by the end of the 30 minute period. The routes of administration are subcutaneous or oral doses. Subcutaneous doses are administered to the skin on the back of the neck, while oral doses are administered by means of a feeding needle. In both cases, a volume of 0.2 ml per mouse is used. The compounds are administered 30 minutes, 4 hours and 24 hours after the challenge. A control compound of known efficacy administered by the same route is included in each assay. The animals are observed daily and the number of survivors in each group is recorded. The control of the model of P. multocida continues for 96 hours (four days) after the exposure caused. PD50 is a calculated dose at which the tested compound protects 50% of a group of mice from mortality due to bacterial infection that could be fatal in the absence of drug treatment. The compounds of formula 1, 1, 8 and 9 and the pharmaceutically acceptable salts thereof ("hereinafter" the active compounds "), can be administered orally, parenterally, topically or rectally, in the treatment or prevention of In general, these compounds are administered in the most desirable manner in doses ranging from approximately 0.2 mg per kg of body weight per day (mg / kg / day) to approximately 200 mg / kg / day. in a single dose or in divided doses (ie, from 1 to 4 doses per day) although variations will necessarily occur depending on the species, weight and condition of the subject to be treated and the particular route of administration chosen. more desirable is to employ a dosage level which is in the range of about 4 mg / kg / day to about 50 mg / kg / day.However, variations will occur depending on the species of mammal, fish or bird to be treated and e their individual response to said medication, as well as the type of pharmaceutical formulation chosen and the period of time and interval at which such administration is carried out. In some cases, dosage levels lower than the lower limit of the aforementioned range may be more than adequate, while in others, even higher doses may be employed without causing any untoward side effects, provided that such larger doses are first divided into several doses. small to be administered throughout the day. The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the routes indicated previously, and such administration can be carried out in a single dose or in multiple doses. More particularly, the active compounds can be administered in a wide variety of different dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, tablets, troches, hard candies, powders, sprays, creams, ointments , suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be conveniently sweetened and / or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used, together with various disintegrants such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, they are often very useful for forming lubricating tablets such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type can also be employed as fillers in gelatin capsules; Preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, emulsifying and / or suspending agents, together with diluents such as water. , ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions of an active compound in sesame or peanut oil or an aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably with a pH greater than 8) if necessary and the liquid diluent must first be made isotonic. The aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by conventional pharmaceutical techniques well known to those skilled in the art. In addition it is also possible to administer the active compounds of the present invention topically and this can be done by means of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with conventional pharmaceutical practice. For administration to animals other than humans, such as cattle or domestic animals, the active compounds can be administered in animal feed or orally as concoctions. The active compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidycins. The active compounds can also be associated with soluble polymers, such as target drug vehicles. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenyl, polyhydroxyethylaspartamide-phenol or poly (ethylene oxide) -polylysine substituted with palmitoyl residues. In addition, the active compounds can be associated with a class of biodegradable polymers useful for achieving controlled release of a drug, for example, poly (lactic acid), poly (glycolic acid), copolymers of poly (lactic acid) and poly (glycolic acid). ), poly (epsilon caprolactone), poly (hydroxybutyric acid), polyorthoesters, polyacetals, polydihydropyrans, polyanoacrylates and crosslinked or antipathetic block copolymers of hydrogels. The following examples further illustrate the process and intermediates of the present invention. It will be understood that the present invention is not limited to the specific details of the following examples. The compounds of Examples 1 to 9 have the general formula represented by the substituents R indicated in the following tables. The compounds were prepared as described in the preparations described below. In the tables, the performance and mass spectrum data ("Esp. Masas") are applied to the final product.

TABLE 1 PREPARATION 1 It was dissolved in 1.9-50 ml of anhydrous pyridine an amount of 0. 095-4.96 g of the corresponding macrolide of formula 1. Hydroxylamine hydrochloride (7.5 eq.) Was added and the solution was heated to 60 ° C and stirred for 24 hours. The reaction was treated by decanting in 50 ml of a 1: 1 mixture of methylene chloride and water. The pH of the reaction mixture was adjusted to 9-11 using 1N NaOH, the reaction mixture was extracted with 3 x 25 ml of methylene chloride and was extracted over Na2SO4. Filtration and concentration of the filtrate gave a solid and light yellow product. The product was taken to the next stage without further purification.

Preparation of Example 1-1 (Table 1) 400 mg of the corresponding macrolide of formula 1 were dissolved, where R1 is isopropyl and R2 is H, in 8 ml of anhydrous pyridine. Hydroxylamine hydrochloride (0.285 g, 7.5 eq.) Was added and the solution was heated to 60 ° C and stirred for 24 hours. The reaction was treated by decanting in 50 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na2SO4. Filtration and concentration of the filtrate gave a light yellow solid product. The product (0.403 g) was taken to the next stage without further purification.

Preparation of Example 1-2 (Table 1) 250 mg of the corresponding macrolide of formula 1, where R 1 is cyclopropyl and R 2 is H, were dissolved in 5 ml of anhydrous pyridine. Hydroxylamine hydrochloride (0.178 g, 7.5 eq.) Was added and the solution was heated to 60 ° C and stirred for 24 hours. The reaction was treated by decanting in 50 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na 2 SO 4. Filtration and concentration of the filtrate gave a light yellow solid product. The product (0.252 g) was taken to the next stage without further purification.

Preparation of Example 1-3 (Table 1) 250 mg of the corresponding macrolide of formula 1, where R1 is sec-butyl and R2 is H, were dissolved in 5 ml of anhydrous pyridine. Hydroxylamine hydrochloride (0.175 g, 7.5 eq.) Was added and the solution was heated to 60 ° C and stirred for 24 hours. The reaction was treated by decanting in 50 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na 2 SO 4. Filtration and concentration of the filtrate gave a light yellow solid product. The product (0.246 g) was brought to the next stage without further purification.

Preparation of Example 1-4 (Table 1) 250 mg of the corresponding macrolide of formula 1, where R 1 is cyclobutyl and R 2 is H, were dissolved in 5 ml of anhydrous pyridine. Hydroxylamine hydrochloride (0.175 g, 7.5 eq.) Was added and the solution was heated to 60 ° C and stirred for 24 hours. The reaction was treated by decanting in 50 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na2SO4.

Filtration and concentration of the filtrate gave a light yellow solid product. The product (0.249 g) was brought to the next stage without further purification.

Preparation of Example 1-5 (Table 1) 100 mg of the corresponding macrolide of formula 1 were dissolved, where R1 is cyclopentyl and R2 is H, in 5 ml of anhydrous pyridine. Hydroxylamine hydrochloride (0.070 g, 7.5 eq.) Was added and the solution was heated to 60 ° C and stirred for 24 hours. The reaction was treated by decanting in 50 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9-11 using 1 N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na2SO4. Filtration and concentration of the filtrate gave a light yellow solid product. The product (0.094 g) was taken to the next stage without further purification.

Preparation of Example 1-6 (Table 1) 250 mg of the corresponding macrolide of formula 1, where R 1 is methyltioethoyl and R 2 is H, were dissolved in 1.9 ml of anhydrous pyridine. Hydroxylamine hydrochloride (0.065 g, 7.5 eq.) Was added and the solution was heated to 60 ° C and stirred for 24 hours. The reaction was treated by decanting in 50 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na 2 S 4. Filtration and concentration of the filtrate gave a light yellow solid product. The product (0.091 g) was taken to the next stage without further purification.

Preparation of Example 1-7 (Table 1) 98 mg of the corresponding macrolide of formula were dissolved 1, where R1 is cyclopropyl and R2 is OH, in 2 ml of anhydrous pyridine. Hydroxylamine hydrochloride (0.068 g, 7.5 eq.) Was added and the solution was heated to 60 ° C and stirred for 24 hours. The reaction was treated by decanting in 50 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na 2 S 4. Filtration and concentration of the filtrate gave a light yellow solid product. The product (0.100 g) was taken to the next stage without further purification.

Preparation of Example 1-8 (Table 1) 4.96 mg of the corresponding macrolide of formula 1, where R1 is cyclobutyl and R2 is OH, were dissolved in 50.0 ml of anhydrous pyridine. Hydroxylamine hydrochloride (3.4 g, 7.5 eq.) Was added and the solution was heated to 60 ° C and stirred for 24 hours. The reaction was treated by decanting in 50 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na 2 S 4. Filtration and concentration of the filtrate gave a light yellow solid product. The product (4.24 g) was brought to the next stage without further purification.

TABLE 2 PREPARATION 2 A quantity of 60-500 mg of the corresponding oxime of formula 2 was dissolved in 1-7 ml of acetone. A 0.1 M aqueous solution of NaHCO 3 (2 equivalents) was added and the resulting mixture was cooled to 0-5 ° C. A 0.1M solution of para-toluenesulfonyl chloride in acetone, cooled to 0-5 ° C, was added and the mixture was stirred overnight. The reaction was treated by decanting in 25 ml of a 1: 1 mixture of methylene chloride and water. The pH of the reaction mixture was adjusted to 9-10 using 1N NaOH, the reaction mixture was extracted with 3 x 20 ml of methylene chloride and dried over Na2SO4. Filtration and concentration of the filtrate gave a solid product. The product was taken to the next stage without further purification.

Preparation of Example 2-1 (Table 2) 415 mg of the corresponding oxime of formula 2 were dissolved, where R1 is isopropyl and R2 is H, in 7 ml of acetone. An aqueous 0.1 M solution of NaHCO3 (0.093 g in 2.0 ml of water) was added and the resulting mixture was cooled to 0 ° C. A solution of para-toluenesulfonyl chloride (0.220 g) in acetone (2.0 ml), cooled to 0 ° C, was added and the mixture was stirred overnight. The reaction was treated by decanting in 25 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 20 ml of methylene chloride and dried over Na 2 S 4. Filtration and concentration of the filtrate gave a solid product. The product (0.329 g) was taken to the next stage without further purification.

Preparation of Example 2-2 (Table 2) 200 mg of the corresponding oxime of formula 2 were dissolved, where R1 is isopropyl and R2 is H, in 2 ml of acetone. A 0.1 M aqueous solution of NaHCO 3 (0.193 g in 1.0 ml of water) was added and the resulting mixture was cooled to 0 ° C. A solution of para-toluenesulfonyl chloride (0.106 g) in acetone (1.0 ml), cooled to 0 ° C, was added and the mixture was stirred overnight. The reaction was treated by decanting in 25 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 20 ml of methylene chloride and dried over Na 2 S 4. Filtration and concentration of the filtrate gave a solid product. The product (0.177 g) was taken to the next stage without further purification.

Preparation of Example 2-3 (Table 2) 420 mg of the corresponding oxime of formula 2 were dissolved, where R1 is sec-butyl and R2 is H, in 7 ml of acetone. A 0.1 M aqueous solution of NaHCO 3 (0.192 g in 2.0 ml of water) was added and the resulting mixture was cooled to 0 ° C. A solution of para-toluenesulfonyl chloride (0.220 g) in acetone (2.2 ml), cooled to 0 ° C, was added and the mixture was stirred overnight. The reaction was stirred by decanting in 25 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 20 ml of methylene chloride and dried over Na 2 SO 4. Filtration and concentration of the filtrate gave a solid product. The product (0.348 g) was taken to the next step without further purification.

Preparation of Example 2-4 (Table 2) 500 mg of the corresponding oxime of formula 2 were dissolved, where R1 is cyclobutyl and R2 is H, in 5 ml of acetone. A 0.1 M aqueous solution of NaHCO 3 (0.229 g in 2.0 ml of water) was added and the resulting mixture was cooled to 0 ° C. A solution of para-toluenesulfonyl chloride (0.260 g) in acetone (2.0 ml), cooled to 0 ° C, was added and the mixture was stirred overnight. The reaction was treated by decanting in 25 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 20 ml of methylene chloride and dried over Na 2 S 4. Filtration and concentration of the filtrate gave a solid product. The product (0.485 g) was taken to the next step without further purification.

Preparation of Example 2-5 (Table 2) 84 mg of the corresponding oxime of formula 2 were dissolved, where R1 is cyclopentyl and R2 is H, in 1 ml of acetone. A 0.1 M aqueous solution of NaHCO 3 (0.038 g in 0.5 ml of water) was added and the resulting mixture was cooled to 0 ° C. A solution of para-toluenesulfonyl chloride (0.043 g) in acetone (0.5 ml), cooled to 0 ° C, was added and the mixture was stirred overnight. The reaction was treated by decanting in 25 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 20 ml of methylene chloride and dried over Na 2 SO 4. Filtration and concentration of the filtrate gave a solid product. The product (0.042 g) was taken to the next stage without further purification.

Preparation of Example 2-6 (Table 2) 85 mg of the corresponding oxime of formula 2, where R 1 is methylthioethyl and R 2 is H, were dissolved in 1 ml of acetone. An aqueous 0.1M solution of NaHCO 3 (0.038 g in 0.5 ml of water) was added and the resulting mixture was cooled to 0 ° C. A solution of paratoluenesulfonyl chloride (0.043 g) in acetone (0.5 ml), cooled to 0 ° C, was added and the mixture was stirred overnight. The reaction was treated by decanting in 25 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 20 ml of methylene chloride and dried over Na 2 SO 4. Filtration and concentration of the filtrate gave a solid product. The product (0.024 g) was taken to the next stage without further purification.

Preparation of Example 2-7 (Table 2) 60 mg of the corresponding oxime of formula 2 were dissolved, where R1 is cyclopropyl and R2 is OH, in 1 ml of acetone. A 0.1 M aqueous solution of NaHCO 3 (0.027 g in 0.5 ml of water) was added and the resulting mixture was cooled to 0 ° C. A solution of para-toluenesulfonyl chloride (0.031 g) in acetone (0.5 ml), cooled to 0 ° C, was added and the mixture was stirred overnight. The reaction was treated by decanting in 25 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 20 ml of methylene chloride and dried over Na 2 SO 4.

Filtration and concentration of the filtrate gave a solid product. The product (0.058 g) was taken to the next stage without further purification.

Preparation of Example 2-8 (Table 2) 500 mg of the corresponding oxime of formula 2 were dissolved, where R1 is cyclobutyl and R2 is OH, in 5 ml of acetone. An aqueous 0.1 M solution of NaHCO 3 (0.224 g in 2.5 ml of water) was added and the resulting mixture was cooled to 0 ° C. A solution of para-toluenesulfonyl chloride (0.255 g) in acetone (2.5 ml), cooled to 0 ° C, was added and the mixture was stirred overnight. The reaction was treated by decanting in 25 ml of a 1: 1 mixture of methylene chloride and water. The pH was adjusted to 9 using 1 N NaOH, extracted with 3 x 20 ml of methylene chloride and dried over Na 2 SO 4. Filtration and concentration of the filtrate gave a solid product. The product (0.485 g) was taken to the next step without further purification.

PREPARATION 3 An amount of 42-165 mg of the corresponding imidate of formula 3 was dissolved in glacial acetic acid. Platinum oxide catalyst (50 mole%) was added, nitrogen was blown into the reaction, placed under a pressure of 3.44 x 10 5 Pa of hydrogen and stirred at room temperature for 24 hours. Additional platinum oxide catalyst (50 mole%) was added, nitrogen was blown into the reaction, placed under a pressure of 3.44 x 10 5 Pa of hydrogen and stirred at room temperature for another 24-48 hours. The reaction was treated by filtering through Celite ™. 25 ml of water were added and the pH of the reaction mixture was adjusted to 9-10 using 1N NaOH, the reaction mixture was extracted with 3 x 25 ml of methylene chloride and dried over Na2SO4. Filtration and concentration of the filtrate afforded a solid product mixture containing the azalide of formula 4 and the lactam of formula 5. Isolation was performed by preparative HPLC.

PREPARATION 4 An amount of 1 1-250 mg of the corresponding imidate of formula 3 was dissolved in THF and ethylene glycol and then cooled to 0-5 ° C. NaBH 4 (5-10 equivalents) was added and the reaction was stirred for 4 hours at 0-5 ° C and then warmed to room temperature. The reaction was treated by decanting in 10 ml of a 1: 1 mixture of methylene chloride and water. The aqueous layer was back-extracted with 3 x 5 ml of methylene chloride. The organic layers were combined and dried over Na2SO4. Filtration and concentration provided a solid product.

Preparation of Example 3-1 (Table 3) 150 mg of the corresponding imidate of formula 3 were dissolved, where R1 is isopropyl and R2 is H, 3.75 ml of tetrahydrofuran and 7.5 ml of ethylene glycol and then cooled to 0-5 ° C. . NaBH 4 (0.039 g) was added and the reaction was stirred for 6 hours at 0-5 ° C and then warmed to room temperature. The reaction was treated by decanting in 10 ml of a 1: 1 mixture of methylene chloride and water. The aqueous layer was back-extracted with 3 x 5 ml of methylene chloride. The organic layers were combined and dried over Na2SO4. Filtration and concentration gave a solid product (0.149 g).

Preparation of Example 3-2 (Table 3) 165 mg of the corresponding imidate of formula 3 were dissolved, where R 1 is cyclopropyl and R 2 is H in glacial acetic acid, (20 ml). Platinum oxide catalyst (0.026 g, 50 mole%) was added, nitrogen was blown into the reaction, placed under a pressure of 3.44 x 10 5 Pa of hydrogen and stirred at room temperature for 24 hours. Additional platinum oxide catalyst (50 mole%) was added, nitrogen was blown into the reaction, placed under a pressure of 3.44 x 10 5 Pa of hydrogen and stirred at room temperature for a further 24 hours. The reaction was treated by filtering through Celite ™. 25 ml of water was added and the pH of the reaction mixture was adjusted to 9 using 1N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na2SO4. Filtration and concentration of the filtrate afforded a solid product mixture containing the azalide of formula 4 and the lactam of formula 5. Isolation was performed by preparative HPLC (0.019 g).

Preparation of Example 3-3 (Table 3) 11 mg of the corresponding imidate of formula 3 were dissolved, where R1 is sec-butyl and R2 is H, in 0.275 ml of tetrahydrofuran and 0.55 ml of ethylene glycol and then cooled to 0-5. ° C. NaBH (0.003 g) was added and the reaction was stirred for 6 hours at 0-5 ° C and then warmed to room temperature. The reaction was treated by decanting in 10 ml of a 1: 1 mixture of methylene chloride and water. The aqueous layer was back-extracted with 3 x 5 ml of methylene chloride. The organic layers were combined and dried over Na2SO4. Filtration and concentration gave a solid product (0.005 g).

Preparation of Example 3-4 (Table 3) 250 mg of the corresponding imidate of Formula 3 were dissolved, where R1 is cyclobutyl and R2 is H, in 3.83 ml of tetrahydrofuran and 5.0 ml of ethylene glycol and then cooled to 0-5 ° C. NaBH 4 (0.191 g) was added and the reaction was stirred for 6 hours at 0-5 ° C and then warmed to room temperature. The reaction was treated by decanting in 10 ml of a 1: 1 mixture of methylene chloride and water. The aqueous layer was back-extracted with 3 x 5 ml of methylene chloride. The organic layers were combined and dried over Na2SO4. Filtration and concentration gave a solid product (0.201 g).

Preparation of Example 3-5 (Table 3) 42 mg of the corresponding imidate of formula 3 were dissolved, where R1 is cyclopentyl and R2 is H, in glacial acetic acid (10 ml). Platinum oxide catalyst (0.006 g, 50 mole%) was added, nitrogen was blown into the reaction, placed under a pressure of 3.44 x 10 5 Pa of hydrogen and stirred at room temperature for 24 hours. Additional platinum oxide catalyst (50 mole%) was added, nitrogen was blown into the reaction, placed under a pressure of 3.44 x 10 5 Pa of hydrogen and stirred at room temperature for a further 24 hours. The reaction was treated by filtering through Celite ™. 25 ml of water was added and the pH of the reaction mixture was adjusted to 9 using 1N NaOH, extracted with 3 x 25 ml of methylene chloride and dried over Na2SO4. Filtration and concentration of the filtrate afforded a solid product mixture containing the azalide of formula 4 and the lactam of formula 5. The isolation was performed by preparative HPLC (0.037 g).

Preparation of Example 3-6 (Table 3) 60 mg of the corresponding imidate of formula 3, where R 1 is cyclopropyl and R 2 is OH, were dissolved in 0.6 ml of tetrahydrofuran and 1.8 ml of ethylene glycol and then cooled to 0-5 ° C. . NaBH 4 (0.046 g) was added and the reaction was stirred for 6 hours at 0-5 ° C and then warmed to room temperature. The reaction was treated by decanting in 10 ml of a 1: 1 mixture of methylene chloride and water. The aqueous layer was back-extracted with 3 x 5 ml of methylene chloride. The organic layers were combined and dried over Na2SO4. Filtration and concentration gave a solid product (0.055 g).

Preparation of Example 3-7 (Table 3) 250 mg of the corresponding imidate of Formula 3 were dissolved, where R1 is cyclobutyl and R2 is OH, in 3J5 mL of tetrahydrofuran and 5.0 mL of ethylene glycol and then cooled to 0-5 ° C. . NaBH 4 (0.187 g) was added and the reaction was stirred for 6 hours at 0-5 ° C and then warmed to room temperature. The reaction was treated by decanting in 10 ml of a 1: 1 mixture of methyl chloride and water. The aqueous layer was back-extracted with 3 x 5 ml of methylene chloride. The organic layers were combined and dried over Na2SO4. Filtration and concentration gave a solid product (0.226 g). The NMR data of the compounds included in formula 5 are shown below in tables 3A and 3B.

BOX 3A TABLE 3B TABLE 4 PREPARATION 5 The corresponding azalide of formula 5 was dissolved in chloroform. 37% formaldehyde (3.0 equivalents) and formic acid (3.0 equivalents) were added and the solution was stirred at 45-50 ° C for 12-24 hours. The reaction mixture was then concentrated in vacuo. The residue was dissolved in 1-2 ml of methylene chloride. 2-5 ml of saturated aqueous NaHCO3 solution were then added. The layers were separated and the aqueous layer was back extracted with an equal volume of methyl chloride, the organic layers were combined and dried over Na2SO4. It was filtered, concentrated and a solid isolated.

Preparation of Example 4-1 (Table 4) 25 mg of the corresponding azalide of formula 5 were dissolved, where R1 is isopropyl and R2 is H, in 1.0 ml of chloroform. 37% formaldehyde (7.5 microliters, 3.0 equivalents) and formic acid (10.5 microliters, 3.0 equivalents) were added and the solution was stirred at 45-50 ° C for 24 hours. The reaction mixture was then concentrated in vacuo. The residue was then dissolved in 2 ml of methylene chloride. Then 5.0 ml of saturated aqueous solution of NaHCO3 was added. The layers were separated and the aqueous layer was extracted again with an equal volume of methylene chloride. The organic layers were combined and dried over Na2SO4. It was filtered, concentrated and a solid isolated (0.023 g).

Preparation of Example 4-2 (Table 4) 20 mg of the corresponding azalide of Formula 5 were dissolved, where R1 is isopropyl and R2 is OH, in 2.0 ml of chloroform. 37% formaldehyde (6 microliters, 3.0 equivalents) and formic acid (8.5 microliters, 3.0 equivalents) were added and the solution was stirred at 45-50 ° C for 12 hours. The reaction mixture was then concentrated in vacuo. The residue was then dissolved in 2 ml of methylene chloride. Then 5.0 ml of saturated aqueous solution of NaHCO 3 was added. The layers were separated and the aqueous layer was extracted again with an equal volume of methylene chloride. The organic layers were combined and dried over Na2SO4. It was filtered, concentrated and a solid isolated (0.019 g).

TABLE 5 PREPARATION 6 The oxime correspondence of formula 2 is dissolved in ethanol. Lithium hydroxide monohydrate (2 equivalents) is added and the reaction mixture is stirred overnight at room temperature. The reaction is concentrated in vacuo and partitioned between brine and ethyl acetate, the pH of the reaction mixture is adjusted to 9-10, the reaction mixture is extracted with ethyl acetate and dried over Na2SO4. A 4: 1 ratio of Z: E isomers is produced. Isolation of the isomers is carried out by chromatography on silica gel or crystallization in nitromethane.

TABLE 6 PREPARATION 7 The corresponding oxime of formula 2a is dissolved in acetone. A 0.1 M aqueous solution of NaHCO3 (2 equivalents) is added and the resulting mixture is cooled to 0-5 ° C. A 0.1 M solution of para-toluenesulfoyl chloride in acetone is added and the mixture is stirred overnight. The reaction is treated by decanting in 25 ml of a 1: 1 mixture of methyl chloride and water. The pH of the reaction mixture is adjusted to 9-10 using 1 N NaOH, the reaction mixture is extracted with 3 x 10 ml of methyl chloride and dried over Na2SO4. Filtration and concentration provide a solid product. The product is taken to the next stage without further purification.

TABLE 7 PREPARATION 8 The corresponding imidate of formula 3a is dissolved in glacial acetic acid. Platinum oxide catalyst (50 mole%) is added, nitrogen is blown into the reaction mixture, placed under 3.44 x 10 5 Pa of hydrogen and stirred at room temperature for 24 hours. Additional platinum oxide catalyst (50 mole%) is added, nitrogen is insulted in the reaction mixture, placed under a pressure of 3.44 x 105 Pa of hydrogen and stirred at room temperature for another 24-48 hours. The reaction is treated by filtering through Celite ™. A volume of 25 ml of water is added and the pH of the reaction mixture is adjusted to 9-10 using 1 N NaOH, the reaction mixture is extracted with 3 x 25 ml of methylene chloride and Na2SO is dried. Filtration and concentration provide a solid product. Isolation is carried out by HPLC.

PREPARATION 9 The corresponding imidate of formula 3a is dissolved in 0.5 ml of MeOH and cooled to 0-5 ° C. NaBH 4 (10 equiv.) Is added and the reaction is stirred for 4 hours at 0-5 ° C, warmed to room temperature and stirred overnight. The reaction is treated by decanting in 10 ml of a 1: 1 mixture of methylene chloride and water, adjusting the pH of the reaction mixture to 8-9 using 1 N NaOH, extracting with 3 x 5 ml of methylene chloride and dried over Na2SO4. Filtration and concentration provide a solid product. The purification is carried out by HPLC.

TABLE 8 PREPARATION 10 The corresponding azalide of formulas 5a is dissolved in chloroform. 37% formaldehyde (1.0 equiv.) And formic acid (1.0 equiv.) Are added and the solution is stirred at 45-50 ° C for 48-72 hours. The reaction mixture is then decanted into a 1: 1 mixture of chloroform and water, the pH of the reaction mixture is adjusted to 9-10 using 1N NaOH, the reaction mixture is extracted with chloroform and dried over Na2SO. Filtration and concentration provide a solid product. The product is isolated by chromatography on silica gel or HPLC.

PREPARATION 11 Dissolve in a solution of MeOH (5-10 ml) and acetyl chloride (2.6 equivalents) an amount of 100-200 mg of the corresponding azalide. The resulting mixture is stirred overnight at room temperature, concentrated in vacuo and then suspended in a small amount of MeOH (1 ml). The mixture is then heated, combined with hot cyclohexane (10 ml) and cooled to room temperature. The product is isolated by filtration.

Claims (7)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula or a pharmaceutically acceptable salt thereof, wherein: Y is H, C1-C10 alkyl, C2-C2 alkenyl, C2-C2 alkynyl, - (CH2) m (aryl Ce-Cι), - (CH 2 ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4 and wherein the alkyl, alkenyl, aryl, heteroaryl and alkynyl groups are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R21, -OC (0) R21, -NR21C (0) R22, -C (0) NR21R22, -NR21R22, hydroxy, C? -C6 alkyl, C? -C6 alkoxy , Ce-Cio aryl and hereroaryl of 5 to 10 links; R1 is an alkyl, alkenyl, alkynyl, alkoxyalkyl or branched C3-C8 alkyl alkylthioalkyl group, which may be any of which optionally substituted by one or more hydroxyl groups, a C5-C8 cycloalkylalkyl group in which the alkyl group is an alkyl group C2-C5 alpha-branched; a C3-C8 cycloalkyl or Cs-Cs cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more Cr C4 alkyl groups or halogen atoms; or R 1 is phenyl which may be optionally substituted with at least one substituent selected from C 1 -C 4 alkyl groups C 1 -C 4 alkoxy and (C 1 -C 4 alkyl) thio, halogen atoms, hydroxyl groups, trifluoromethyl and cyano; or R1 can be a group with a formula (a) as shown below: wherein X is O, S or -CH2-, a, b, c, and d, each independently being an integer ranging from 0 to 2 and a + b + c + d < 5; or R1 is CH2R24, where R24 is H, C2-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and may be any of said alkyl, alkoxy, alkenyl or alkynyl groups substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or C3-C8 cycloalkenyl, any of which may be optionally substituted by methyl or one or more C1-C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and may be optionally substituted by one or more C 1 -C 4 alkyl groups or halogen atoms; or a group of formula SR23 wherein R23 is C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C? -C4 alkyl, C1-C4 alkoxy or halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms; R2 is H or OH; R3 is H, OH or OCH3; R 4 is H, -C (0) R 9, -C (0) OR 9, -C (0) NR 9 R 10 or a hydroxy protecting group; R 5 is -SR 8, - (CH 2) n C (0) R 8, where n is 0 or 1, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (C 6 aryl) C10) or - (CH2) m (5-10 membered heteroaryl), where m is an integer ranging from 0 to 4 and where the above R5 groups are optionally substituted by 1 to 3 R16 groups; each R6 and R7 is, independently, H, hydroxy, C6C6 alkoxy, C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2) m (C6-C6 aryl) or - (CH2) m (heteroaryl of 5-10 links), where m is an integer that varies from 0 to 4; each R 8 is independently H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, or - (CH 2) aCR 11 R 12 (CH 2) r-NR 13 R 14, where q and r are each independently, an integer ranging from 0 a 3, except that q and y are not both 0, - (CH2) m- (aryl Ce-Cio) or - (CH2) m (heteroaryl of 5-10 links), where m is an integer ranging from 0 to 4, and where the above R8 groups, except H, are optionally substituted by 1 to 3 R16 groups; or when R8 is -CH2NR8R15, R15 and R8 can be taken together to form a saturated mono- or polycyclic ring of 4 to 10 links or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and -N (R8) -, in addition to the nitrogen to which R15 and R8 are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds and said saturated and heteroaryl rings are optionally substituted by 1 to 3 groups R16; each of R9 and R10 is, independently, H or C? -C6 alkyl; each of R 11, R 12, R 13 and R 14 is independently selected from H, C 1 -C 10 alkyl, - (CH 2) m (C 6 -C 0 aryl) and - (CH 2) m (5-10 link heteroaryl) , where m is an integer ranging from 0 to 4 and where the groups R11, R12, R13 and R14 above, except H, are optional substituted by 1 to 3 groups R16; or R11 and R13 are taken together to form - (CH2) P-, where p is an integer ranging from 0 to 3, such that a saturated 4-7-membered ring is formed which optionally includes 1 or 2 double or triple carbon bonds -carbon; or R13 and Ru are taken together to form a saturated monocyclic or polycyclic ring of 4-10 links or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and -N (R8) -, in addition to the nitrogen to which R13 and R14 are attached, said saturated ring optionally includes 1 or 2 double or triple carbon-carbon bonds and said saturated ring and heteroaryl are optionally substituted by 1 to 3 R16 groups; R 5 is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, or C 2 -C 8 alkynyl, wherein the above R 15 groups are optionally substituted by 1 to 3 substituents independently selected from halogen and -OR 9; each R16 is independently selected from halogen, cyano, nitro trifluoromethyl, azido, -C (0) R17, -C (0) OR17, -C (0) OR17, -OC (0) OR17, -NR6C (0) R7, -C (0) NR6R7, -N-R6R7, hydroxy, C? -C? Alkyl, CrC6 alkoxy, - (CH2) m (C6-C10 aryl) and - (CH2) m (5-10 membered heteroaryl) , wherein m is an integer ranging from 0 to 4 and wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) R17, - C (0) OR17, -C (0) OR17, -OC (0) OR17, -NR6C (0) R7, -C (0) NR6R7; -NR6R7, hydroxy, d-C6 alkyl and C6-C6 alkoxy; and each R 17 is independently selected from H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m- (C 6 -C 0 aryl) and - (CH 2) m (5-10 membered heteroaryl), where m is an integer ranging from 0 to 4, provided that R8 is not H when R19 is -CH2-S (0) nR8; R18 is OH; R19 is C-pCto alkyl, C2-C? Alkenyl, C2-C alqu alkynyl, cyano, -CH2S (0) nR8, where n is an integer ranging from 0 to 2, -CH2OR8, -CH2N (OR9) R8, -CH2NR8R15, - (CH2) m (C6-C10 aryl), or - (CH2) m (5-10-membered heteroaryl), where m is an integer ranging from 0 to 4, and the R19 groups being above optionally substituted by 1 to 3 R16 groups; or R18 and R19 are taken together to form an oxazolyl ring as shown below and; each of R21 and R22 is independently H, hydroxy, C? -C6 alkoxy, C? -C6 alkyl, C2-C6 alkenyl, (CH2) m (C6-C? o aryl), (CH2) m (heteroaryl), to 10 links), where m is an integer ranging from 0 to 4, or C2-C alkynyl? 0.

2. A compound of formula or a pharmaceutically acceptable salt thereof, wherein: Y is H, alkyl C1-C10, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) m (C6-C? 0 aryl), - (CH2) m (5-10-membered heteroaryl), where m is an integer ranging from 0 a 4 and wherein the alkyl, alkenyl, aryl, heteroaryl and alkynyl groups are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) R21, -OC (0) R21, - NR21C (0) R22, -C (0) NR21R22, -NR21R22, hydroxy, C6 alkyl. C 1 -C 6 alkoxy, C 6 -C 0 aryl and heteroaryl of 5 to 10 links; R1 is a branched C3-C8 alpha alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, which may be any of which optionally substituted by one more hydroxyl; a Cs-C8 cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or Cs-Cs cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C1-C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms; or R 1 is phenyl which may be optionally substituted with at least one substituent selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy and (C 1 -C 4 alkyl) thio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R1 can be a group with a formula (a) as shown below: wherein X is O, S or -CH2-, a, b, c and d are each, independently an integer ranging from 0 to 2 and a + b + c + d = 5; or R is CH2R24, where R24 is H, C2-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing from 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and may be any of said alkyl, alkoxy, alkenyl or alkynyl substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or Cs-Cs cycloalkenyl, any of which may be optionally substituted by methyl or one or more C1-C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms; or a group of formula SR23 wherein R23 is C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C1-C4 alkyl. C1-C4 alkoxy or halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated, or wholly or partly unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms; R2 is H or OH; R3 is H, OH or OCH3; R 4 is H, -C (0) R 9, -C (0) NR 9 R 10 or a hydroxy protecting group; each of R9 and R10 is, independently, H or CrC6 alkyl; R18 is OH; R19 is H; and each of R21 and R22 is independently H, hydroxy, C? -C6 alkoxy, C? -C6 alkyl, C2-C6 alkenyl, (CH2) m (C6-C? 0 aryl), (CH2) m (heteroaryl 5 to 10 links), where m is an integer ranging from 0 to 4, or C2-C alkynyl 0. 3- Compound of formula I according to claim 1, wherein R20 is and R1 is isopropyl, R2 is H and R19 is OH; R1 is isopropyl, R2 is OH and R19 is OH; R1 is cyclopropyl, R2 is H and R19 is OH; R1 is cyclopropyl, R2 is OH and R19 is OH; R1 is sec-butyl, R2 is H and R19 is OH; R1 is sec-butyl, R2 is OH and R19 is OH; R1 is cyclobutyl, R2 is H and R19 is OH; R1 is cyclobutyl, R2 is OH and R19 is OH; R1 is cyclopentyl, R2 is H and R19 is OH; R1 is cyclopentyl, R2 is OH and R19 is OH; R1 is methylthioethyl, R2 is H and R19 is OH; R1 is methylthioethyl, R2 is OH and R19 is OH; R1 is 3-furyl, R2 is H and R19 is OH; or R is 3-furyl, R2 is OH and R19 is OH. 4. Compound of formula II according to claim 2, wherein R20 is and R1 is isopropyl, R2 is H and R19 is OH; R1 is isopropyl, R2 is OH and R19 is OH; R is cyclopropyl, R 2 is H and R 19 is OH; R1 is cyclopropyl, R2 is OH and R19 is OH; R1 is sec-butyl, R2 is OH and R19 is OH; R1 is sec-butyl, R2 is OH and R19 is OH; R1 is cyclobutyl, R2 is H and R19 is OH; R1 is cyclobutyl, R2 is OH and R19 is OH; R1 is cyclopentyl, R2 is H and R19 is OH; R1 is cyclopentyl, R2 is OH and R19 is OH; R1 is methylthioethyl, R2 is H and R19 is OH; R1 is methylthioethyl, R2 is OH and R19 is OH; R1 is 3-furyl, R2 is H and R19 is OH; or R1 is 3-furyl, R2 is OH and R 9 is OH. 5. A compound of formula or a pharmaceutically acceptable salt thereof, wherein: R1 is a branched C3-C8 alpha alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, which may be any of which optionally substituted by one or more hydroxyl groups; a Cs-C8 cycloalkyalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C? -C alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more C? -C alkyl groups or halogen atoms; or R 1 is phenyl which may be optionally substituted with at least one substituent selected from C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy and C 1 -C 4 alkylthio, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R1 can be a group with a formula (a) as shown below: wherein X is O, S or -CH2-, a, b, c and d are each, independently, an integer ranging from 0 to 2 and a + b + c + d = 5; or R1 is CH2R24, where R24 is H, C2-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and may be any of said alkyl, alkoxy, alkenyl or alkynyl groups substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or Cs-Cs cycloalkenyl, any of which may be optionally substituted by methyl or one or more C? -C alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C?-C4 alkyl groups or halogen atoms; or a group of formula SR23, wherein R23 is CrC8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C?-C4 alkyl, C1 alkoxy -C or halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated, or wholly or partially unsaturated and which may be optionally substituted by one or more C? -C alkyl groups or halogen atom; and R2 is H or OH. 6. A compound of formula or a pharmaceutically acceptable salt thereof, wherein: R1 is a branched C3-C8 alpha alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, which may be any of which optionally substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-C5 alkyl group; a C3-C8 cycloalkyl or Cs-Cs cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more C 4 alkyl groups or halogen atoms; or R1 is phenyl which may be optionally substituted with at least one substituent selected from C?-C alkyl, C 1 -C 4 alkoxy and (C 1 -C 4 alkyl), halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R1 can be a group with a formula (a) as shown below: wherein X is O, S or -CH2-, a, b, c and d are each, independently, an integer ranging from 0 to 2 and a + b + c d = 5; or R1 is CH2R24, where R24 is H, C2-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and may be any of said alkyl, alkoxy, alkenyl or alkynyl groups substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or C5-C8 cycloalkenyl, any of which may be optionally substituted by methyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C?-C4 alkyl groups or halogen atoms; or a group of formula SR23 wherein R23 is C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C1-C4 alkyl, alkoxy C1-C4 or halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated, or wholly or partially unsaturated and which may be optionally substituted by one or more C1-C4 alkyl groups or halogen atoms; and R2 is H or OH. 7. A pharmaceutical composition for the treatment of a bacterial infection or an infection caused by protozoa in a mammal, fish or bird, comprising a therapeutically effective amount of a compound according to claims 1, 2, 3, 4, 5, or 6 and a pharmaceutically acceptable vehicle. 8. The use of a compound according to claims 1, 2, 3, 4, 5, or 6 for the manufacture of a medicament for treating a bacterial infection or an infection caused by protozoa in a mammal, fish or bird. 9. A process for preparing a compound of formula wherein R1 and R2 are as defined in claim 1, which comprises treating a compound of the formula wherein R1 and R2 are as defined in claim 1, with a reducing agent. 10. Process according to claim 9, wherein the reducing agent is NaBH or platinum oxide. 11. A process for preparing a compound of formula wherein R1 and R2 are as defined in claim 1, which comprises treating a compound of the formula wherein R1 and R2 are as defined in claim 1, with a methylating agent. 12. Process according to claim 1, wherein the methylating agent is formaldehyde. 1

3. A process for preparing a compound of formula wherein R1 and R2 are as defined in claim 1, which comprises treating a compound of the formula wherein R1 and R2 are as defined in claim 1, with a reducing agent. 1

4. Process according to claim 13, wherein the reducing agent is NaBH4 or platinum oxide. 1

5. A process for preparing a compound of formula wherein R1 and R2 are as defined in claim 1, which comprises treating a compound of the formula wherein R1 and R2 are as defined in claim 1, with a methylating agent. 1

6. Process according to claim 15, wherein the methylating agent is formaldehyde. 17.- A compound of formula or a pharmaceutically acceptable salt thereof, wherein: Y is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (C 6 -C 0 aryl), - (CH 2) ) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4 and wherein the alkyl, alkenyl, aryl, heteroaryl and alkynyl groups are optionally substituted by 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) R21, -OC (0) R2 \ -NR21C (0) R22, -C (0) NR21R22, -NR21R22, hydroxy, C6 alkyl, C6-C6 alkoxy, aryl C6-C? 0 and heteroaryl of 5 to 10 links; R1 is a branched C3-C8 alpha alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group, which may be any of which optionally substituted by one or more hydroxyl groups; a C5-C8 cycloalkylalkyl group in which the alkyl group is an alpha-branched C2-Cs alkyl group; a C3-C8 cycloalkyl or C5-C8 cycloalkenyl group, any of which may be optionally substituted by methyl or one or more hydroxyl or one or more C? -C4 alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or, wholly or partially unsaturated and which may be optionally substituted by one or more C1-C alkyl groups or halogen atoms; or R 1 is phenyl which may be optionally substituted with at least one substituent selected from C 1 -C 4 alkyl, C 1 -C 6 alkoxy and C 1 -C 4 alkyl, halogen atoms, hydroxyl, trifluoromethyl and cyano groups; or R1 can be a group with a formula (a) as shown below: wherein X is O, S or -CH2-, a, b, c and d are each independently an integer ranging from 0 to 2 and + b + c + d < 5; or R1 is CH2R24, where R24 is H, C2-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkoxyalkyl or alkylthioalkyl, containing from 1 to 6 carbon atoms in each of the alkyl or alkoxy groups, and may be any of said alkyl, alkoxy, alkenyl or alkynyl groups substituted by one or more hydroxyl groups or by one or more halogen atoms; or a C3-C8 cycloalkyl or C5-C8 cycloalkenyl, any of which may be optionally substituted by methyl or one or more C? -C alkyl groups or halogen atoms; or a heterocyclic ring containing oxygen or sulfur of 3 to 6 links which may be saturated or totally or partially unsaturated and which may be optionally substituted by one or more C?-C4 alkyl groups, or halogen atoms; or a group of formula SR23 wherein R23 is C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, phenyl or substituted phenyl, where the substituent is C? -C4 alkyl, C-C-alkoxy or halogen, or a heterocyclic ring containing oxygen or sulfur of 3 to 6 bonds which may be saturated, or wholly or partly unsaturated and which may be optionally substituted by one or more C? -C4 alkyl groups or halogen; R2 is H or OH; R3 is H, OH or OCH3; R 4 is H, -C (O) R 9, -C (O) OR 9, -C (O) NR 9 R 10 or a hydroxy protecting group; R5 is -SR8, - (CH2) nC (0) R8, where n is 0 or 1, C? -C? 0 alkyl, > C2-C? 0 alkenyl, C2-C10 alkynyl, - (CH2) m (C6-C? 0 aryl) or - (CH2) m (5-10-membered heteroaryl), where m is an integer ranging from 0 to 4 and where the above R5 groups are optionally substituted by 1 to 3 R16 groups; each R6 and R7 is, independently, H, hydroxy, Ci-Cß alkoxy, C?-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CH2) m (C6-C? aryl) or - (CH2) ) m (5-10 membered heteroaryl), where m is an integer ranging from 0 to 4; each R 8 is independently H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 0 alkynyl, - (CH 2) qCR 11 R 12 (CH 2) r NR 13 R 14, where q and r are each independently, an integer ranging from 0 to 3, unless q and y are not both 0, - (CH2) m- (C6-C? o, or) aryl, or - (CH2) m (5-10-membered heteroaryl), where m is an integer ranging from 0 to 4, and wherein the above R8 groups, except H, are optionally substituted by 1 to 3 R16 groups; or when R8 is -CH2NR8R15, R15 and R8 can be taken together to form a saturated mono- or polycyclic ring of 4 to 10 links or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 selected heteroatoms of O, S and -N (R8) -, in addition to the nitrogen to which R15 and R8 are attached, said saturated ring optionally includes 1 or 2 double or triple carbon-carbon bonds and said saturated and heteroaryl rings are optionally substituted by 1 to 3 groups R16; each of R9 and R10 is, independently, H or C? -C6 alkyl; each of R11, R12, R13 and R14 is independently selected from H, C1-C10 alkyl, - (CH2) m (aryl Ce-Cio) and - (CH2) m (heteroaryl from 5-10 links), where m is an integer that varies from 0 to 4 and where the groups R11, R12, R13 and R14 above, except H, are optionally substituted by 1 to 3 groups R16; or R11 and R13 are taken together to form - (CH2) P-, where p is an integer ranging from 0 to 3, such that a saturated 4-7-membered ring is formed which optionally includes 1 or 2 double or triple carbon bonds -carbon; or R13 and R14 are taken together to form a saturated monocyclic or polycyclic ring of 4-10 links or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and -N (R8) -, in addition to the nitrogen to which R13 and R14 are attached, said saturated ring optionally includes 1 or 2 double or triple carbon-carbon bonds and said saturated and heteroaryl rings are optionally substituted by 1 to 3 R16 groups; R 15 is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, or C 2 -C 0 alkynyl, wherein the above R 15 groups are optionally substituted by 1 to 3 substituents independently selected from halogen and -OR 9; each R16 is independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) R17, -C (0) OR17, -C (0) OR17, -OC (0) OR17, -NR6C (0 ) R 7, -C (0) NR 6 R 7, -N-R 6 R 7, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, - (CH 2) m (C 1 -C 10 aryl) and - (CH 2) m (heteroaryl 5) -10 links), wherein m is an integer ranging from 0 to 4 and wherein said aryl and heteroaryl substituents are optionally substituted by 1 or 2 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0 ) R17, -C (0) OR17, -C (0) OR17, -OC (0) OR17, -NR6C (0) R7, -C (0) NR6R7, -NR6R7, hydroxy, C? -C6 alkyl and alkoxy C? -C6; and each R 17 is independently selected from H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m- (C 6 -C 0 aryl) and ~ (CH 2) m (heteroaryl of 5-10 links), where m is an integer ranging from 0 to 4, provided that R8 is not H when R19 is -CH2-S (0) nR8; R18 is OH; R 9 is C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, cyano, -CH 2 S (0) n R 8, where n is an integer ranging from 0 to 2, -CH 2 OR 8, -CH 2 N (OR 9) R8, -CH2NR8R15, - (CH2) m (aryl Ce-Cio), or - (CH2) m (heteroaryl of 5-10 links), where m is an integer ranging from 0 to 4, and the groups R19 above optionally substituted by 1 to 3 R16 groups; or R18 and R19 are taken together to form an oxazolyl ring as shown below Y; each of R21 and R22 is independently H, hydroxy, C6-C6 alkoxy, Ci-Ce alkyl, C2-C6 alkenyl, (CH2) m (C6-C10 aryl, (CH2) m (5- to 10-membered heteroaryl) , where m is an integer ranging from 0 to 4, or C2-C10 alkynyl.