MXPA00011389A - New macrolide - Google Patents

Abstract

The invention relates to compounds of Formula 1 and to pharmaceutically acceptable salts, solvates, and prodrugs thereof, wherein X, Y, Z, R<1>, R<2>, R<3>, R<4>, and R<5>are defined herein. The invention further relates to methods of making compounds of Formula 1 and to pharmaceutical compositions comprising compounds of Formula 1. The invention is also related to methods of treating diseases and disorders such as, but not limited to, bacterial and protozoal infections which comprise the administration of a compound of Formula 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Description

NEW MACROLIDES FIELD OF THE INVENTION The invention relates to new macrolide derivatives, to pharmaceutical compositions comprising them, and to methods of using them in the treatment or prevention of, for example, bacterial or protozoal infections in mammals, fish or birds.

BACKGROUND OF THE INVENTION Macrolide antibiotics, which can be used in the treatment or prevention of bacterial or protozoal infections in mammals, fish or birds, include various derivatives of erythromycin A, such as azithromycin, which is commercially available and is mentioned in the U.S. Patents. Nos. 4,474,768 and 4,517,359, both of which are incorporated herein by reference. Examples of additional macrolides are described in: the provisional patent application of E.U.A. No. 60/049348, filed June 11, 1997 (by Brian S. Bronk, Michael A. Letavic, Takushi Kaneko, Bingwei V. Yang, E.A. Glazer, and Hengmiao Cheng); the provisional patent application of E.U.A. No. 60/049348 filed June 11, 1997 (by Brian S. Bronk, Michael A. Letavic, Takushi Kaneko, Bingwei V. Yang, E.A. Glazer, and Hengmiao Cheng); international patent applications WO 98/01571 (Peter Francis Leadlay, James Staunton, Jesus Cortes and Michael Stephen Pacey); WO 98/01546 (Peter Francis Leadlay, James Staunton, and Jesus Cortes); the provisional patent application of E.U.A. No. 60/070343 filed January 2, 1998 (by John P. Dirlam); the provisional patent application of E.U.A. No. 60/097075, filed August 19, 1998 (Hengmiao Cheng, Michael A. Letavic, Carl B. Ziegler, Peter Bertinato, Jason K. Dutra, Brian S. Bronk); and international patent application WO 98/09978, all of which are incorporated herein by reference.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to new compounds of formula 1: and its pharmaceutically acceptable salts, solvates and prodrugs, wherein: X is -CH2NR7- or -NR7CHR6-, in which the first line of each of the preceding groups X is attached to Y and the last line of each of the preceding groups X is bonded to carbon C-8; Y is -CH (CH3) -; or X, Y and R can be taken together to form the rest of formula a Z is selected from the group consisting of -C (O) -, -CH (-OR8) -, and the rest of formula b R1 is H or a hydroxy protecting group; R2 is -OR13, or R2 and R3 are taken together to form the remainder of formula c or if X is -NR7CHR6-, R2 and R6 can be taken together to form the remainder of formula d R3 is -OC (O) R14, or R3, X and Y are taken together to form the residue of formula a, or R3 and R2 are taken together to form the residue of formula c; R is -OR15; R5 is a C2-C8 alkyl group, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkoxyalkyl or C2-C8 alkylthioalkyl branched alpha, optionally substituted with at least one hydroxyl group, a C2-C5 alkyl group branched at alpha, linked to a C5-C8 cycloalkyl group; a C3-C8 cycloalkyl or cycloalkenyl group optionally substituted with at least one moiety selected from the group consisting of methyl, hydroxy, halo and C? -C alkyl groups; or a saturated, or fully or partially unsaturated, heterocycle of 3-6 members, comprising at least one oxygen or sulfur atom and optionally substituted with one or more C C alkyl groups or halogen atoms; R6 is H, or if X is -NR7CHR6-, R6 and R2 can be taken together to form the remainder of formula d; R 7 is selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (C 1 -C 6 aryl) and - (CH 2) m (heteroaryl 5-10 members), in which the alkyl, alkenyl, aryl, heteroaryl and alkynyl moieties of the preceding R7 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido , -C (O) R11, -OC (O) R11, -NR11C (O) R12, -C (O) NR11R12, -NR11R12, hydroxy, C-C-alkyl, C-C6-alkoxy, C-C-io aryl and heteroaryl of 5-10 members; R 8 is selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, -C (O) R 17, -C (O) NR 17 R 18, - (CH 2) m (C 6 aryl) -C10) and - (CH2) m (5-10 membered heteroaryl), in which the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the preceding R8 groups are optionally substituted with 1 to 3 substituents independently selected from the group which consists of halo, cyano, nitro, trifluoromethyl, azido, -C (O) R11, -OC (O) R11, -R11C (O) R12, -C (O) NR 1R12, -NR11R12, hydroxy, alkyl C? -C6, C6-C6 alkoxy, C6-C6aryl aryl and 5-10 membered heteroaryl; R9 is hydroxy; R10 is selected from the group consisting of H, C -? - C? Alkyl or > C2-C? 0 alkenyl, C2-C10 alkynyl, cyano, -CH2S (O) nR11, -CH2OR11, -CH2NR11R12, - (CH2) m (C6-C8 aryl) and - (CH2) m (5-10 heteroaryl) members), wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the preceding R10 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C- (O) R 11, -OC (O) R 11, -NR 11 C (O) R 12, -C (O) NR 11 R 12, -NR 11 R 12, hydroxy, C C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl and heteroaryl 5- 10 members; each R 11 and R 12 is independently selected from the group consisting of H, CrC 6 alkyl, C 2 -C 6 alkenyl, (CH 2) m (C 6 -C 6 aryl), (CH 2) m (5-10 membered heteroaryl) and alkynyl C2-C10, in which the alkyl, alkenyl, aryl, heteroaryl and alkynyl moieties of the preceding groups R11 and R12 are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, alkyl C Cß and C C β alkoxy; R 13 is selected from the group consisting of H, C -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, -R 16 (C 6 -C 10 aryl), and -R 16 (5-10 membered heteroaryl) , wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the preceding R13 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C; ) R11, -OC (O) R11, -NR11C (O) R12, -C (O) NR1iR12, -NR11R12, hydroxy, C6 alkyl, alkoxy d-Ce, aryl C6-C? 0 and heteroaryl 5-10 members; R 14 is selected from the group consisting of 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 5-10 members), in which the alkyl, alkenyl, aryl, heteroaryl and alkynyl moieties of the preceding R14 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido , -C (O) R11, -OC (O) R11, -NR11C (O) R12, -C (O) NR11R12, -NR11R12, hydroxy, C-C-alkyl, C-C6-alkoxy, Ce-C-aryl and heteroaryl -10 members. R15 is independently selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, C2-C2 alkynyl, or - (CH2) m (C6-C? 0 aryl) and - (CH2) m (heteroaryl) 5-10 members), wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the preceding R15 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C (O) R 1 \ -OC (0) R 11, -NR 11 C (O) R 12, -C (O) NR 11 R 12, -NR 11 R 12, hydroxy, C 1 -C 6 alkyl, Ci-C 1 alkoxy, C 6 -C aryl ? o and 5-10 membered heteroaryl; R16 is selected from the group consisting of Ci-Cß alkyl, C3-C6 alkenyl, and C3-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the preceding R16 groups are optionally substituted with 1 to 3 substituents independently selected between the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C (O) R11, -OC (0) R11, -NR11C (O) R12, -C (O) NR11R12, -NR11R12, hydroxy, alkyl d-Ce, C6-C6 alkoxy, C6-C aryl and 5-10 membered heteroaryl, and in which at least one carbon atom of each of the foregoing R16 groups can optionally be replaced by 1 to 3 atoms or residues independently selected from the group consisting of O, N (R15) and S; each of R 17 and R 18 is independently selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 10 alkynyl, - (CH 2) m (C 6 -C 0 aryl) and - (CH2) m (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the foregoing groups R17 and R18 are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C (O) R11, -OC (O) R11, -NR11C (O) R12, -C (O) NR11R12, -NR11R12, hydroxy, Ci-Cß alkyl, Ci alkoxy -Cß, Ce-Cι aryl and 5-10 membered heteroaryl; each n independently represents an integer from 0 to 2; and each m independently represents an integer from 0 to In a preferred compound of formula 1, X is -CH2NR7- or -NR7CHR6-, Z is a residue of formula b, R2 is OH, R3 is -OC (O) R14, R4 is OH and R6 is H. In another compound of formula 1, X is -NR7CHR6-; Z is a residue of formula b, R2 and R6 are taken together to form a residue of formula d, R3 is -OC (O) R14, R4 is OH and R7 is CH3. In another preferred compound of formula 1, X, Y and R3 are taken together to form a moiety of formula a, Z is a moiety of formula b, R2 is OH and R4 is OH. In another preferred compound of formula 1, X is -CH2NR7 or -NR7CHR6-, Z is a residue of formula b, R2 and R3 are taken together to form a moiety of formula c, and R4 is OH. In another preferred compound of formula 1, X, Y and R3 are taken together to form a moiety of formula a, Z is -CH (OR8) -, R2 is -OR13 and R4 is OR15. In another preferred compound of formula 1, X, Y and R3 are taken together to form a moiety of formula a, Z is -C (O) -, R2 is -OR3 and R4 is OR15. In a more preferred compound of formula 1, R1 is H; R5 is ethyl; R15 is H or methyl and R13 is a residue of the formulas e-g. ff in which R19 is C6-C? 0 aryl or 5-10 membered heteroaryl, wherein the aryl and heteroaryl moieties of the preceding R9 groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C (O) R11, -OC (O) R12 -NR11C (O) R12, -C (O) NR11R12, -NR11R12, hydroxy, C-C-alkyl, C-alkoxy C6, aryl C6-C? 0 and heteroaryl of 5-10 members. In an even more preferred compound of formula 1, R19 is selected from the group consisting of phenyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, -pyridyl, 3-pyridyl and 4-pyridyl. In another preferred compound of formula 1, R5 is selected from the group consisting of ethyl, isopropyl, cyclopropyl, sec-butyl, cyclobutyl, cyclopentyl, methylthioethyl and furyl.

The invention further encompasses a method for preparing a compound of formula 2 wherein R2, R5, R9, R10, and R15 are defined in this specification, which comprises contacting a compound of formula f with a Grignard reagent for a period of time and at a temperature sufficient to form a compound of formula 2. The invention further encompasses a method for preparing a compound of formula 4 wherein R5, R9, R10, and R15 are defined in this specification, which comprises contacting a compound of formula h with an amine oxidizing reagent for a period of time and at a temperature sufficient to form a compound of formula 4. In a preferred embodiment of the invention, the amine oxidizing reagent is selected from the group consisting of N-bromo-succinimide, N-chlorosuccinimide, iodine and bromine. The invention further encompasses a method for preparing a compound of formula 5 wherein R2, R5, R9 and R10 is defined herein, which comprises contacting a compound of formula I with a Grignard reagent or base for a period of time and at a temperature sufficient to form a compound of formula 5. In a preferred method, the Grignard reagent is benzylmagnesium chloride. In another preferred method the base is (isopropyl-cyclohexyl-amino) -magnesium chloride. The invention further encompasses a method for forming a compound of formula 7 wherein R2 and R5 are defined herein, which comprises contacting a compound of formula wherein R9 and R10 are defined herein, under acidic conditions for a period of time and at a temperature sufficient to form a compound of formula 7. The invention further encompasses pharmaceutical compositions comprising a compound of formula 1 or a salt thereof , pharmaceutically acceptable solvates or prodrugs and a pharmaceutically acceptable carrier. The invention further encompasses a method for treating a bacterial or protozoal infection in a mammal, fish or bird, which comprises administering to a mammal, fish or bird in need of such treatment a therapeutically effective amount of a compound of formula 1 or one of its pharmaceutically acceptable salts, solvates or prodrugs.

Definitions As used in the present context and unless otherwise indicated, the term "infection (s)" includes bacterial infection (s) and protozoan infection (s) that occur in mammals, fish or birds, as well as disorders related to bacterial infections and protozoal infections that can be treated or prevented by administering antibiotics such as the compounds of the invention. Such bacterial infections and protozoa infections 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 Peptostrepcoccus spp .; pharyngitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Streptococcal 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; infections of skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever uncomplicated related to infection by Staphylococcus aureus, coagulase positive staphylococci (p. eg. S. epidermis and S. hemolyticus), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal CF groups (tiny colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp. or Bartonella henselae; watery infections of the urinary tract without complications, related to an infection by Staphylococcus saprophyllus or Enterococcus spp .; urethritis and cervicitis; and sexually transmitted diseases, related to infection by Chlamydia trachomatis, Haemophylus ducreyi, Treponema pallidum, Ureaplasma urealyticum or Neiserria gonorrheae; diseases caused by toxins, related to infection by S. aureus (food poisoning and toxic shock syndrome), or streptococci of groups A, B and C; ulcers related to a Helicobacter pylori infection; systemic febrile syndromes, related to an infection by Borrelia recurrentis; Lyme disease related to an infection by Borrelia burgdorieri; conjunctivitis, keratitis and dacryocyst related to infection by Chlamydia trachomatis, Neisseria gonorrhea, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae or Listeria spp .; complex disease with disseminated Mycobacterium avium (MAC), related to an infection by Mycobacterium avium or Mycobacterium intracellulare; gastroenteritis related to an infection by Campylobacter jejunr ', intestinal protozoa related to an infection by Cryptosporidium ssp .; odontogenic infection related to a viridans streptococcal infection; persistent cough related to infection by Bordetella pertussis; gaseous grangrena related to infection by Clostridium perfringens or Bacteroides spp .; and atherosclerosis related to an infection by Helicobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoal infections and disorders related to such infections, which can be treated or prevented in animals, include the following: bovine respiratory disease, related to an infection by P. haem., P. multocida, Mycoplasma bovis or Bordetella spp .; enteric disease of cows, related to an infection by E. coli or protozoa (eg coccidia and cryptosporidia); milk cow mastitis, related to a Staph infection. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium or Enterococcus spp .; the swine respiratory disease, related to an 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 cows legs, related to an infection by Fusobacterium spp .; cow metritis, related to an E. coli infection; hairy warts of cows, related to an infection by Fusobacterium necrophorum or Bacteroides nodosus; flu with purulent conjunctivitis of cows, related to an infection by Moraxella bovis; premature abortion of cows, related to a protozoa infection (eg, neosporium); urinary tract infection in dogs and cats, related to an E. coli infection; skin and soft tissue infections in dogs and cats, related to an infection by Staph, epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental or oral infections in dogs and cats, related to an infection of Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas or Prevotella. Other bacterial infections and protozoal infections and other disorders related to such infections, which can be treated or prevented according to the method of the present invention, are mentioned in the work of J.P. Sanford et al., "The Sanford Guide To Antimicrobial Therapy", 26th Edition (Antimicrobial Therapy, Inc., 1996). As used in the present context, and unless otherwise indicated, the term "treatment" includes treatment or prevention.

As used in the present context and unless otherwise indicated, the term "halo" means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo. As used in the present context and unless otherwise indicated, the term "alkyl" includes saturated monovalent hydrocarbyl radicals having linear, cyclic or branched moieties, or a combination of the foregoing moieties. An alkyl group may include one or two double or triple bonds. It is understood that the cyclic alkyl groups comprise at least three carbon atoms. As used in the present context and unless otherwise indicated, the term "alkanoyl" includes -C (O) -alkyl groups in which "alkyl" is defined herein. As used in the present context and unless otherwise indicated, the term "aralkyl" includes an aryl substituted with an alkyl group or an alkyl substituted with an aryl group. As used in the present context and unless otherwise indicated, the term "aryl" includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl. As used in the present context and unless otherwise indicated, "Ac" denotes an acetyl group. As used in the present context and unless otherwise indicated, "Me" denotes a methyl group.

As used in the present context and unless otherwise indicated, "Et" denotes an ethyl group. As used in the present context and unless otherwise indicated, the term "heteroaryl" means an aryl group in which at least one carbon atom has been replaced by an atom selected from the group consisting of O, S and N. As used in the present context and unless otherwise indicated, the terms "heterocyclic group" and "heterocycle" include heterocyclic aromatic and non-aromatic groups, which contain one or more heteroatoms selected in each case from O , S and N. The non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but the aromatic heterocyclic groups (ie, the heteroaryl groups) must have at least 5 atoms in their ring system. The heterocyclic groups include ring systems fused with benzo and ring systems substituted with one or more oxo moieties. An example of a 4-membered heterocyclic group is azetidinyl (azetidine derivative), an example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanil, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2,3 , 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, -azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanil, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxaiinyl, naphthyridinyl and furopyridinyl. The preceding groups, as derived from the compounds listed above, can be linked by C or N-linked when such a binding mode is possible. For example, a pyrrole derivative group can be pyrrol-1-yl (N-linked) or pyrrole-3-yl (linked by C). As used in the present context and unless otherwise indicated, the phrase "pharmaceutically acceptable salts" includes acidic or basic group salts 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. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of said basic compounds are those which form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions such as, but not limited to, hydrochloride salts, hydrobromides, hydroiodides, nitrates, sulfates, bisulphates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, pantothenates, bitartrates, ascorbates, succinates, maleates, gentisinates, fumarates, gluconates, glucuronates , sacchates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates benzene sulphonates, p-toluene sulphonates and pamoatos [ie 1,1'-methylene-bis- (2-hydroxy-3-naphthoates)] . The compounds of the invention that include a basic moiety, such as an amino group, can form pharmaceutically acceptable salts with various amino acids, in addition to the aforementioned acids. 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 or alkaline earth metal salts and the calcium, magnesium, sodium and potassium salts in particular. In the chemical structures described herein, a wavy line indicates that the stereochemistry at the chiral center, to which the wavy line is connected, is in an R or S configuration when the wavy line is connected to a carbon atom. The compounds of the present invention 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 to all methods of treatment which may employ or contain them. The compounds of formula 1 can also exist in the form of tautomers. This invention relates to the use of all said tautomers and their mixtures. This invention also encompasses isotopically-labeled compounds of formula 1, which are identical to those of formula 1 except for the fact that one or more atoms are replaced by an atom having an atomic mass or atomic number different from the atomic mass respectively. of the atomic number that is usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F and 36CI , respectively. The isotopically-labeled compounds of formula 1, and their pharmaceutically acceptable salts, solvates and prodrugs, are encompassed by this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful. in tissue distribution analysis of drugs and / or substrates. Tritiated (ie, with 3H) and carbon-4 (ie, with 14C) isotopes are particularly preferred for their ease of preparation and detectability. In addition, replacement with heavier isotopes, such as deuterium (i.e., with 2H) can provide certain therapeutic advantages resulting from increased metabolic stability, for example an increased in vivo half-life or reduced dosage requirements and, therefore they may be preferred in some circumstances. The isotopically-labeled compounds of the invention and their prodrugs can generally be prepared by carrying out the methods described herein, by replacing an easily available isotopically-labeled reagent for an isotopically unlabeled reagent. This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula 1, and methods for treating bacterial or protozoal infections, comprising the administration of prodrugs of compounds of formula 1. The compounds of the invention having amino, amido, hydroxy or Free carboxylic acids can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues, is covalently linked through an amide or ester linkage with a free amino, hydroxy or carboxylic group, of compounds of formula 1. The amino acid residues include, but are not limited to, the 20 amino acids present in nature, which are commonly designated by three-letter symbols, and also include -hydroxyproline, hydroxylysine, demosin, isodemosin, 3-methyl-histidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserin, ornithine and methionine-sulfone. Additional types of prodrugs are also encompassed by the invention. For example, free carboxyl groups can be derivatized in the form of amides or alkyl esters. The amide and ester moieties may incorporate groups including, but not limited to, functionalities of ether, amine, and carboxylic acid. Free hydroxy groups may be derivatized using groups including, but not limited to, hemisuccinates, phosphate esters, dimethylamino-acetates and phosphoryloxy-methyloxy-carbonyls, as noted in the citation of D. Fleisher, R. Bong, BH Stewart, Advanced Drug Delivery Reviews 19: 115 (1996). Prodrugs with hydroxy and amino group carbamates are also encompassed by the invention, as are prodrugs with carbonates and sulfate esters of hydroxy groups. The derivatization of hydroxy groups in the form of (acyloxy) methyl-y (acyloxy) ethyl esters, in which the acyl group can be an alkyl ester, optionally substituted with groups including but not limited to ether, amine functionalities and carboxylic acid, or in which the acyl group is an ester of an amino acid such as those described above, are also encompassed by the invention. Prodrugs of this type are described in the R.P. Robinson et al., J. Medicinal Chemistry 39:10 (1996).

DETAILED DESCRIPTION OF THE INVENTION This invention relates to new macrolide compounds, to methods for preparing them, and to pharmaceutical compositions comprising them. The invention further relates to methods for treating or preventing bacterial and protozoal infections in mammals (eg, humans), fish and birds, as well as methods for treating or preventing other diseases or conditions such as, but not limited to, cancer, atherosclerosis and disorders of the gastric modality. Specific compounds of the invention have the formula 2, and are listed in table 1: TABLE 1 The information on mass spectra (MS) and yields, which are given in Table 1, are related to the preparation of the compounds 2 (a) -2 (n), as described below in the examples. The compounds of formula 2 can be prepared according to the method shown in scheme 1: SCHEME 1 According to scheme 1, the compounds of formula 2 can be prepared from compounds of formula e, the synthesis of which is described by the patents of E.U.A. Nos. 4,474,768 and 4,517,359, both of which are incorporated herein by reference. According to this method, a carbonate compound of formula f is prepared from the compound e using the synthesis conditions that are known to those skilled in the art. Preferred conditions comprise the use of ethylene carbonate and a base such as potassium carbonate in a solvent such as ethyl acetate. Then, carbonate f can be reacted with a Grignard reagent to provide compound 2. Other compounds of the invention are those of formula 3, of which specific examples are listed in Table 2: TABLE 2 As above, the information on MS and yields given in table 2 are given in relation to the preparation of compounds 3 (a) -3 (m), as described below in the examples. The compounds of formula 3 can be prepared according to the method shown in scheme 2: SCHEME 2 Amine According to scheme 2, the compounds of formula 3 can be prepared easily from compounds of formula g, which can be prepared according to scheme 1. In particular, compounds of formula 3 can be prepared by dissolving the compounds of formula g in a liquid amine and subsequently stirring the resulting mixture for a sufficient period of time and at a sufficient temperature (eg, approximately for 2 days at room temperature). Alternatively, the compounds of formula g and a liquid or solid amine can be dissolved in a solvent, which can then be stirred for a sufficient period of time and at a temperature sufficient to provide compounds of formula 3. Still other compounds of the invention are of formula 4, of which specific examples are listed in table 3: TABLE 3 In which the information on MS and yields given in table 3 are related to the preparation of the compounds 4 (a) -4 (b), as described below in the examples. The compounds of formula 4 can be prepared according to the method shown in scheme 3: SCHEME 3 Amine oxidizing agent According to scheme 3, the compounds of formula 4 can be prepared easily from compounds of formula h, which in turn can be prepared according to the method of scheme 1. In particular, the compounds of formula 4 are they can be prepared by reacting compounds of formula h with an amine oxidizing reagent in an appropriate solvent such as, but not limited to, ethyl acetate and tetrahydrofuran (THF). Suitable amine oxidizing agents include, but are not limited to, N-bromo-succinimide (NBS), N-chlorosuccinimide (NCS), iodine and bromine. Other examples of compounds of the invention and of preferred methods for their synthesis are provided in the examples presented below. The compounds of the present invention may have asymmetric carbon atoms, and the diastereoisomeric mixtures thereof, can be separated into their individual diastereomers on the basis of their physical and chemical 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 an alcohol), separation of the diastereomers and conversion (eg by hydrolysis) of the individual diastereoisomers in the corresponding pure enantiomers. All such isomers, including mixtures of diastereomers and pure enantiomers, are considered as a part of the invention. The compounds of the invention (ie, compounds of formula 1) which are basic in nature, are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the invention from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter back into the compound in free base form by treatment with an alkaline reagent and subsequently converting the latter free base into a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating a compound of basic character with a substantially equivalent amount of the chosen inorganic or organic acid in an aqueous solvent medium or in an appropriate organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate inorganic or organic acid to the solution. The compounds of the 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 or alkaline earth metal salts and, particularly, the sodium 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 which form non-toxic base salts with the acidic compounds of the invention. Non-toxic base salts include those which are derived from pharmacologically acceptable cations such as, but not limited to, sodium, potassium, calcium and magnesium. These salts can be prepared by treatment of the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then by evaporation of the resulting solution to dryness, preferably under reduced pressure. Alternatively, these can be prepared by mixing together solutions in lower alkanols of the acidic compounds and the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness, in the same manner as above. In either case, stoichiometric amounts of reagents are preferably employed in order to ensure the completion of the reaction and maximum yield of the desired final product. 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 growth of defined strains of human pathogens (analysis I) or animals (analyzes II and III).

Analysis I Analysis I, described below, employs a conventional methodology and interpretation criteria and is designed to provide guidelines for chemical modifications that can lead to compounds that avoid defined mechanisms of resistance to macrolides. In analysis I, a panel of bacterial strains including a diversity of target pathogenic species, including those representative of mechanisms of resistance to macrolides that have been characterized, is assembled. The use of this panel makes it possible to determine the relationship of the chemical structure and the activity with respect to the power, the spectrum of activity and structural elements or modifications that may be necessary to avoid the mechanisms of resistance. The bacterial pathogens that the screening panel comprises are shown below in Table 4. In many cases, both the macrolide-susceptible parent strain and the macrolide-resistant strain derived therefrom are available to provide a more accurate investigation of the capacity of the macrolide. the compounds to avoid the resistance mechanism. Strains containing the gene with the designation ermA / ermB / ermC are resistant to antibiotics macrolides, lincosamides and streptogramin B due to modifications (by methylation) of 23S rRNA molecules by an Erm-methylase that generally prevents the fixation of the three structural classes. Two types of macrolide efflux have been described; msrA encodes a component of an efflux system in staphylococci, which prevents the entry of macrolides and streptogramins, while mefA / E encodes a transmembrane protein that manifests effluir only macrolides. Deactivation of macrolide antibiotics can occur and this can be mediated either by phosphorylation of the 2'-hydroxyl group (mph) or by dissociation of the macrocyclic lactone (esterase). The strains can be characterized using a conventional polymerase chain reaction (PCR) technology and / or by sequencing the resistance determinant. The use of a PCR technology in this application is described in the work of J. Sutcliffe et al., "Detection Of Erythromycin-Resistant Determinants by PCR", Antimicrobial Agents and Chemotherapy, 40 (11): 2562-2666 (1996). The antibacterial analysis is performed in microtitre trays and is interpreted according to the guidelines of the work Performance Standards for Antimicrobial Disk Susceptibilitv Tests-Sixth Edition; Approved Standard, published by the National Committee for Clinical Laboratory Standards (NCCLS); The minimum inhibitory concentration (MIC) is used to compare the strains. Acr AB or similar to acr AB indicates that there is an intrinsic multiple drug efflux pump in the strain. The compounds are initially dissolved in dimethyl sulfoxide (DMSO) as original solutions of 40 mg / ml.

TABLE 4 Analysis II, as described below, is used to assay for activity against Pasteurella multocida and analysis III is used to test for activity against Pasteurella haemolytica.

Analysis II This analysis is based on the dilution method with liquids in the microliter format. A single colony of P. multocida (strain 59A067) is inoculated into 5 ml of brain and heart infusion broth (BHI, from Brain Heart Infusion). The test compounds are prepared by solubilizing 1 mg of the compound in 125 ml of dimethyl sulfoxide (DMSO). Dilutions of the test compound are prepared using an inoculated BHI broth. The concentrations used of the test compound range from 200 mg / ml to 0.098 mg / ml by serial dilutions of double ratio. The BHI inoculated with P. multocida is diluted with uninoculated BHI broth to prepare a suspension of 104 cells per 200 ml. The cell suspensions in BHI are mixed with 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 exhibiting a 100% inhibition of growth of P. multocida as determined by comparison with an uninoculated control.

Analysis III The analysis is based on the dilution method of agar using a Replicator of Steers. Two to five colonies isolated from an agar plate are inoculated in a BHI broth and incubated overnight at 37 ° C with shaking (200 rpm). The next morning, 300 ml of fully grown P. haemolytica preculture are inoculated in 3 ml of fresh BHI broth and incubated at 37 ° C with shaking (200 rpm). The appropriate amounts of the test compounds are dissolved in ethanol and a series of double-ratio serial dilutions are prepared. Two ml of the respective serial dilution are mixed with 18 ml of molten BHI agar and solidified. When the inoculated P haemolytica culture reaches a standard density according to McFarland of 0.5, approximately 5 ml of P. haemolytica culture are inoculated on 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 range from about 100 to about 200 mg / ml. The MIC is equal to the concentration of the test compound exhibiting a 100% inhibition of growth of P. haemolytica as determined by comparison with an uninoculated control. The in vivo activity of the compounds of the invention can be determined by conventional animal protection studies that are also known to those skilled in the art, usually carried out in mice. Mice are assigned to cages (10 per cage) after arrival, and allowed to: acclimatize for a minimum of 48 hours before being used. The animals are inoculated with 0.5 ml of a bacterial suspension of 3 x 103 CFU / ml (P. multocida strain 59A006) intraperitoneally. Each experiment has at least 3 non-medicated control groups including one infected with a 0.1X stimulation dose and two infected with a 1X stimulation dose; a group of 10X stimulation data can also be used. Generally, all mice in a given study can be stimulated for about 30 to about 90 minutes, especially if a repeating syringe (such as a Comawallá syringe) is used to administer the stimulus. Thirty minutes after the stimulation has begun, the first compound treatment is administered. It may be necessary for a second person to begin dosing the compound if all the animals have not been stimulated at the end of 30 minutes. The routes of administration are subcutaneous or oral doses. Subcutaneous doses are administered to the loose 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 stimulus. 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. Surveillance of the P. multocida model continues for 96 hours (four days) after stimulation. DP5o is a calculated dose with which the compound tested protects 50% of a group of mice with respect to a mortality due to bacterial infection that would be lethal in the absence of drug treatment. The compounds of the invention and their pharmaceutically acceptable salts, solvates and prodrugs (herein also referred to as "active compounds of this invention") can be administered alone or in combination with pharmaceutically acceptable carriers, in single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the active compounds of this invention can then be administered easily in a variety of dosage forms, such as, but not limited to, tablets, powders, rhombic pills, syrups and injectable solutions. These pharmaceutical compositions may contain, if desired, additional ingredients such as, but not limited to, flavors, flavors, binders and excipients. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be used together with various disintegrating agents such as starch, methylcellulose, alginic acid and a hundred complex silicates, together with binding agents such as poly (vinyl pyrrolidone), sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and ta 'o are often useful for tablet compression purposes. Solid compositions of a similar type can also be used as fillings in capsules filled with hard and soft gelatin. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient in these formulations may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol and combinations thereof. For parenteral administration, solutions containing an active compound of this invention, or a pharmaceutically acceptable salt thereof, in sesame or peanut oil, aqueous propylene glycol or in a sterile aqueous solution can be employed. Said aqueous solutions should be appropriately buffered if necessary and the liquid diluent should first be made isotonic with sufficient amount of saline or glucose. These particular aqueous solutions are especially suitable for administration intravenously, intramuscularly, subcutaneously and intraperitoneally. The sterile aqueous media used are readily available from all of them by conventional techniques that are known to those skilled in the art. To perform the methods of this invention, an effective dose of an active compound of this invention is administered to a susceptible or infected animal (including mammals, fish and birds) by parenteral (iv, im or sc), oral or rectal routes, or locally as a topical application to the skin and / or mucous membranes. The route of administration will depend on the mammal, fish or bird that is being treated. The effective dose will vary with the severity of the disease, and with the age, weight and condition of the animal. However, the daily dose will usually fluctuate between about 0.25 and about 150 mg / kg of body weight of the patient being treated, preferably from about 0.25 to about 25 mg / kg. The examples given below illustrate specific embodiments of the invention, but the invention is not limited in scope to the examples specifically exemplified.

EXAMPLES 1-12 Synthesis of compounds 2 (a) -2 (l) Compounds 2 (a) -2 (l), whose structures are presented in Table 1, were prepared as shown in scheme 1 from the azalide derivative e, the synthesis of which has been described by the patents of E.U.A. Nos. 4,474,768 and 4,517,359. The derivative e (10 g) was dissolved in EtOAc (150 ml), followed by the addition of ethylene carbonate (10 eq.) And K2CO3 (2 eq.). The resulting solution was stirred at 75 ° C for one to five days, and the reaction was monitored by thin TLC (Thin Layer Chromatography) chromatography. After the reaction was complete, the reaction mixture was cooled to room temperature, and diluted with EtOAc (250 ml) and with water (100 ml). The organic strain was washed with water (4 x 100 ml), with brine (2 x 100 ml) and dried (Na2SO). Then the solvent was removed in vacuo to give the crude product, which was purified either by flash chromatography using 3% MeOH and 0.5% ammonia in CH2Cl2 or by recrystallization from CH3CN to give compound f (shown in the scheme 1), typically with a yield greater than about 80%. The azalide carbonate f (0.5 mmol - 5 mmol) was dissolved in CH2Cl2 (10 ml -100 ml) and cooled to -78 ° C. The Grignard reagent (eg, vinylmagnesium bromide) (6-10 equivalents) was then added slowly at this temperature and the reaction was monitored by TLC. If there was no reaction at this temperature and the reaction was monitored by TLC. If there was no reaction at this temperature, the reaction mixture was then heated to a higher temperature. After the reaction was complete, usually over a period of time between 15 minutes and 4 hours, it was quenched with a saturated solution of NH CI (25 ml -250 ml). The aqueous layer was extracted with CH2Cl2 (100 ml-500 ml) and the organic layer was then washed with a saturated solution of NaHCO3 (25 ml-100 ml) and with brine (25 ml-100 ml). The organic layer was dried with Na 2 SO 4 and the solvent was removed in vacuo to give the crude product of formula 2, which was purified by flash chromatography using 1-5% MeOH and 0.5% ammonia in CH 2 Cl 2.

EXAMPLE 13 Synthesis of compound 2 (m) The azalide carbonate f, shown in scheme 1 and prepared according to examples 1-12, in which R7 is methyl (3.00 g, 3.87 mmol) was dissolved in a mixture of ethylene glycol dimethyl ether (75 ml) ) and NNN'N'-tetramethyl-ethylene-diamine (30 ml). The reaction solution was cooled to -78 ° C, and then 1 M vinylmagnesium bromide in THF (31 ml, 31 mmol) was slowly added at this temperature. After the stirring had been continued for 2 hours at -78 ° C, the reaction was quenched with a saturated solution of NH CI (100 ml). The aqueous layer was extracted with EtOAc (400 ml) and the organic layer was washed with a saturated solution of NaHCO3 (50 ml) and with brine (50 ml). Then the organic layer was dried with Na2SO and the solvent was removed in vacuo to give the crude product, which was purified by flash chromatography using 5% MeOH and 0.5% ammonia in CH2Cl2 (1.43 g, 46%).

EXAMPLE 14 Synthesis of compound 2 (n) The azalide carbonate f, shown in scheme 1 and prepared according to examples 1-12, in which R7 is methyl (3.00 g, 3.87 mmol) was dissolved in a mixture of ethylene glycol dimethyl ether (75 ml) ) and N, N, N'N'-tetramethyl-ethylene-diamine (30 ml). The reaction solution was cooled to -40 ° C, and then 1 M methylmagnesium bromide in ether solution (12.9 mL, 38.7 mmol) was added slowly at this temperature. After the stirring had been continued for 2 hours at -40 ° C, the reaction was quenched with a saturated solution of NH CI (100 ml). The aqueous layer was extracted with EtOAc (400 ml) and the organic layer was washed with a saturated solution of NaHCO3 (50 ml) and with brine (50 ml). The organic layer was then dried with Na2SO and the solvent was removed in vacuo to give the crude product, which was purified by flash chromatography using 5% MeOH and 0.5% ammonia in CH2Cl2 (1.08 g, 40%).

EXAMPLE 15-26 Synthesis of compounds 3 (a) -3 (l) The compounds 3 (a) -3 (l), whose structures are presented in Table 2, were prepared as shown in scheme 2 from the azalide derivative g, which can be prepared according to scheme 1 and Example 13. The azaiide derivative g (50-200 mg) was dissolved in 0.2-1.0 ml of the appropriate amine (e.g., t-butyl-amine) and the reaction mixture was stirred at room temperature for 2 hours. days. The reaction mixture was then diluted with CH2Cl2 (200 ml) and washed with water (6 x 25 ml) and brine (25 ml). Then the organic layer was dried with Na 2 SO 4 and the solvent was removed in vacuo to give the crude product, which was purified by flash chromatography using 3-5% 2 M ammonia in a MeOH solution in CH 2 Cl 2.

EXAMPLE 27 Synthesis of compound 3 (m) The azalide derivative g shown in scheme 2, wherein R7 is methyl (188 mg, 0.234 mmol) and tryptamine (129 mg, 0.802 mmol) were dissolved in THF (2 ml), and the reaction mixture was stirred at the room temperature for 25 hours. Then the reaction mixture was diluted with CH2Cl2 (200 ml) and washed with a 0.1 M sodium phosphate buffer pH 7 (3 x 25 ml). Then the organic layer was washed with brine (25 ml), and dried with Na2SO4. The solvent was evaporated in vacuo to give the crude product, which was purified by flash chromatography using 5% 2 M ammonia in a MeOH solution in CH 2 Cl 2 to give the title compound (35.6 mg, 16%).

EXAMPLE 28 Synthesis of compound 4 (a) The derivative of azalide h, shown in scheme 3 and prepared according to scheme 1 and examples 1-12 above, in which R15 is methyl (0.528 g, 0.667 mmol) was dissolved in THF (50 ml) and the solution The resultant was cooled to 0 ° C. Under stirring conditions, NBS (0.119 g, 0.670 mmol) was added and stirring was continued at 0 ° C for 0.5 hours. EtOAc (250 ml) was added and the organic layer was washed with a 0.1 N NaOH solution (50 ml) and with brine (50 ml). The organic layer was then dried with Na2SO4 and the solvent was removed in vacuo to give the crude product, which was purified by flash chromatography using 3% 2M ammonia in MeOH solution in CH2Cl2 to give the title compound (275 mg, 52%).

EXAMPLE 29 Synthesis of compound 4 (b) The azalide derivative h, shown in scheme 3, in which R15 is vinyl (85.1 mg, 0.106 mmol) was dissolved in THF (10 ml) and the resulting solution was cooled to 0 ° C. Under stirring conditions, NBS (19.7 mg, 0.111 mmol) was added, and stirring was continued at 0 ° C for 2 hours. EtOAc (100 ml) was added and the organic layer was washed with a 0.3 N NaOH solution (10 ml) and with brine (10 ml). Then the organic layer was dried with Na2SO4 and the solvent was removed in vacuo to give the crude product. The product was purified by flash chromatography using first 7% 2 M ammonia in a MeOH solution in CH 2 Cl 2 and then 7% 2 M ammonia in a MeOH solution in EtOAc (28.4 mg, 33%).

EXAMPLE 30 Synthesis of compound 5 (a Compound 5 (a), wherein R2 is OH, R5 is ethyl, R9 is H, and R) is OH, was prepared according to scheme 4: SCHEME 4 BnMgCI CH2Cl2 According to scheme 4, compounds of formula 5 can be prepared by reacting a compound of formula i with a Grignard reagent such as benzyl magnesium chloride or with a base such as (isopropyl-cyclohexyl-amino) chloride. magnesium in a solvent such as dichloromethane at an appropriate temperature. In particular, the azalide carbonate i wherein R 2 is OH, R 5 is ethyl, R 9 is H and R 0 is OH, the synthesis of which is described by the provisional patent application in E.U.A. 60/097075, which is incorporated herein by reference, (2.28 g, 3 mmol) was dissolved in CH 2 Cl 2, under stirring conditions, benzyl magnesium chloride (15.0 mL, 30 mmol) was added over 2 minutes. After the resulting reaction mixture had been stirred at room temperature for 1 hour, it was quenched with a saturated solution of NH CI (50 ml). The product was extracted with CH2Cl2 (300 ml). Then the organic layer was washed with brine (50 ml), dried with Na 2 SO 4, and the solvent was removed in vacuo to give the crude product which was purified by flash chromatography using 1.25% MeOH, 0.5% ammonia in CH 2 Cl 2 to give the title compound (851 mg, 40%, MS: 717.2).

EXAMPLE 31 Synthesis of compound 6 (a) Compound 6 (a) was prepared according to scheme 5: SCHEME 5 BnMgCI CH CI Í6a) According to scheme 5, the compounds of formula 6 (a) can be prepared by reacting compounds of formula i with a Grignard reagent such as vinyl magnesium bromide in a solvent such as dichloromethane at a temperature appropriate Appropriate reaction times are typically from about 0.5 hours to about 24 hours. In particular, the azalide carbonate i (3.00 g, 3.95 mmol) was dissolved in CH2Cl2 (100 ml) and cooled to -78 ° C. Under stirring conditions, vinyl magnesium bromide was added and stirring was continued at -78 ° C for 1.5 hours. The reaction was then quenched with a saturated solution of NH 4 Cl (50 ml) and the reaction mixture was warmed to room temperature. The aqueous layer was extracted with CH2Cl2 (200 ml) and the combined organic layers were washed with a saturated solution of NaHCO3 (50 ml) and brine (50 ml). The organic layer was dried with Na 2 SO 4, and the solvent was removed in vacuo to give the crude product which was purified by flash chromatography using •% MeOH, 0.5% ammonia in CH 2 Cl 2 to give the compound of Example 5 as the product main (27%) and the compound of Example 31 as the secondary product (40.0 mg, 1.4%, MS: 717.2).

EXAMPLE 32 Synthesis of compound 7 (aT) As shown below in scheme 6, acidic conditions can be used to remove the cladinose residue of the compounds of formula 5, thereby forming compounds of formula 7: SCHEME 6 acid In this example, compound 7 (a), which is of formula 7, wherein R 2 is OH and R 5 is ethyl, was prepared by adding acetyl chloride (5.95 μl) to methanol (2 ml) in a round-bottomed flask of 25 ml capacity. The resulting solution was stirred at room temperature for 5 minutes. The azalide derivative 5 (a) (20.0 mg) was added to the solution, and the reaction mixture was stirred at room temperature for 48 hours. The MeOH was then removed in vacuo, the residue was dissolved in methylene chloride (20 ml) and in a saturated solution of sodium hydrogen carbonate (10 ml). After separation, the organic layer was washed with brine (10 ml) and dried with MgSO 4. The solvent was then removed in vacuo to give the crude product, which was purified by flash chromatography using 5% MeOH and 1% ammonia in methylene chloride to give the title compound (14 mg, 89%, MS: 559.2).

EXAMPLE 33 Synthesis of compound 8 'a) As shown below in scheme 7, compounds such as 5 (a) can be converted to compounds such as 8 (a) using methods such as those described in WO 98/09978, which is incorporated herein by reference. reference.

SCHEME 7 5th] SCHEME 7 (continued) 0) AcCl, MeOH 15 twenty SCHEME 7 (continued) 0) (1) Benzoic anhydride E jN, CH2CI (2) EDC, DMSO, CH2CI2 m (1) 3-bromoquinoline Pd (OAc) 2, P (-o-tolyl) 3 CH 3 CN (2) MeOH 15 8 (a) Scheme 7 shows a specific embodiment of a general method encompassed by the invention for preparing compounds such as that of formula 8 (a). As will be recognized by those skilled in the art, the specific order of operations, and the specific reactants and reaction conditions shown in Scheme 7 can be varied. For example, hydroxyl groups of sugars can be protected, and forming the 6-O-alkenyl derivative, before dissociating the cladinose residue. However, in the preferred embodiment of the general method of synthesis of the invention shown in scheme 7. The 2'- and 4"-hydroxy groups of a compound such as that of the formula 5 (a) are first protected by reaction with an appropriate hydroxy protecting reagent such as TMS-CI, acetic anhydride or benzoic anhydride, in an aprotic solvent such as dichloromethane to provide the compound I. The 6-hydroxy group of compound i is then alkylated by reaction with an agent alkylator in the presence of a base, followed by removal of the 2'- and 4"-hydroxy protecting groups to give compound K. Alkylating agents include, but are not limited to, alkyl chlorides, bromides or iodides or alkyl sulfonates. Alkylating agents include, but are not limited to, allyl bromide, propargyl bromide, benzyl bromide, and allyl O-tosylate Examples of solvents include, but are not limited to, aprotic solvents such as DMSO, DMF, THF, and diethyl ether. ether and mixtures thereof Examples of a base that can be used to provide a compound of formula k include, but are not limited to, potassium hydroxide, potassium isopropoxide and potassium tert-butoxide. and 4"-hydroxy is carried out by classical methods known to those skilled in the art. Compound k is converted to compound I by removal of the cladinose residue. The appropriate reaction conditions include those described above in Example 31. The 2 'hydroxyl group of compound I is then protected by reaction with benzoic anhydride as in step 1. Depending on the compound, this reaction time may vary between about 1 hour and about 2 days. The 3-hydroxyl group of compound I is then oxidized to provide the ketone of compound m using a modified Swern oxidation procedure. Suitable oxidizing agents include, but are not limited to, carbodiimide-dimethyl sulfoxide and N- (chlorosuccinimide) -dimethyl sulphide. In the final operation of the general method exemplified by scheme 7, compound m is converted to the 6-O- (substituted alkenyl) derivative (eg, of formula 8 (a)) by reaction with an aryl halide , a substituted aryl halide, a heteroaryl halide or a substituted heteroaryl halide, under the conditions of Heck, with Pd (ll) or Pd (O), phosphine, and an amine or organic base. See, p. ex. Organic Reactions, 27: 345-390 (1982). The 2'-hydroxyl protecting group is then removed by conventional methods to give the compound of formula 8 (a). In a specific application of the synthesis of scheme 7, the azalide derivative 5 (a) (1 mmol) is dissolved in methylene chloride, followed by the addition of triethylamine (2.2 mmol). The resulting reaction mixture is cooled in an ice-water bath, TMS-CI (2.2 eq.) Is added slowly, and the reaction mixture is stirred at room temperature overnight. After the reaction is complete, the reaction mixture is concentrated in vacuo and the residue is dissolved in methylene chloride. The organic layer is washed with water, with brine and dried with MgSO 4. The solvent is evaporated in vacuo to give the azalide derivative i. To a solution at 0 ° C of compound i (1 mmol) in 5 ml of DMSO and 5 ml of THF is added freshly distilled allyl bromide (1.1 mmoles). After about 5 minutes, a solution of potassium tert-butoxide (1 M, 1.1 ml) in 5 ml of DMSO and 5 ml of THF is added dropwise over 4 hours. The reaction mixture is taken up in ethyl acetate (200 ml) and washed with water and brine. The organic solvent is removed in vacuo to give the allyl derivative. This allyl derivative (1 mmol) is dissolved in 10 ml of CH3CN and 5 ml of H2O, followed by the addition of AcOH (5 eq.), And the resulting solution is stirred at room temperature for 4 to 24 hours. After the reaction is complete, the reaction mixture is diluted with toluene (100 ml) and concentrated in vacuo, and the crude product is purified by flash chromatography using 3% MeOH and 0.5% ammonia in CH 2 Cl 2 for give the derivative of azalide k. AcCl (3 mmol) is added to MeOH (30 mL) and the resulting solution is stirred at room temperature for 15 minutes. After which the reaction solution had cooled to 0 ° C, compound k (1 mmol) is added and the reaction mixture is stirred at room temperature for 48 hours. The solvent is removed in vacuo and the residue is dissolved in CH2Cl2. After washing with a saturated solution of NaHCO3 and with brine and drying with Na2SO4, the organic solvent is removed in vacuo to the crude product, which is purified by flash chromatography using 3% MeOH and 0.5% ammonia in CH 2 Cl 2 to provide the azalide derivative I. To a solution of compound I (1 mmol ) in CH 2 Cl 2 (10 mL) is added benzoic anhydride (1 mmol) and Et 3 N (1 mmol), and the resulting reaction mixture is stirred at room temperature for 1 to 2 days. The reaction mixture is diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and with brine, and dried with Na2SO4, and the organic solvent is removed under vacuum to give the benzoylated derivative. This is then dissolved in 20 ml of CH2Cl2, followed by the addition of DMSO (10 mmol). The reaction mixture is then cooled to 0 ° C and EDC (4 mmol) is added. The reaction solution is stirred at room temperature overnight. After the reaction is complete, the reaction mixture is diluted with 100 ml of CH 2 Cl 2, washed with a saturated solution of NaHCO 3 and with brine, and dried with Na 2 SO 4. The organic solvent is removed in vacuo to give the crude product, which is purified by chromatography on silica gel using 30% acetone in hexanes to provide the azalide derivative m. A mixture of compound m (0.25 mmol), palladium (II) acetate (0.2 eq.), Tri-o-tolyl-phosphine (0.4 eq.), 3-bromo-quinoline (2 eq.) And triethylamine ( 2 eq.) In 2 ml of acetonitrile is cooled to -78 ° C, degassed, and hermetically sealed. The reaction mixture is then heated at 50 ° C for 2 hours and stirred at 80 ° C for 16 hours. The reaction mixture is taken up in CH 2 Cl 2, washed with a saturated solution of NaHCO 3 and with brine, and dried with Na 2 SO 4, the organic solvent is removed in vacuo to give the crude product, which is purified by chromatography with silica gel using 2% MeOH in CH2Cl2. This purified product is then dissolved in MeOH and the resulting solution is stirred at reflux for 6 to 24 hours. The solvent is then removed in vacuo and the crude product is purified by flash chromatography using 2% MeOH and 0.5% ammonia in CH 2 Cl 2 to give compound 8 (a).

Claims (18)

1. the ones the R3
2. Z is selected from the group consisting of -C (O) -, -CH (-OR8) -, and the rest of formula b
3. R1 is H or a hydroxy protecting group; R2 is -OR13, or R2 and R3 are taken together to form the remainder of formula c or if X is -NR7CHR6-, R2 and R6 can be taken together to form the remainder of formula d
4. R3 is -OC (0) R14, or R3, X and Y are taken together to form the rest of formula a, or R3 and R2 are taken together to form the remainder of formula c; R4 is -OR15; R5 is a C2-C8 alkyl group, C2-Cs alkenyl, C2-C8 alkynyl, C2-C8 alkoxyalkyl or C2-C8 alkylthioalkyl branched alpha, optionally substituted with at least one hydroxyl group, a C2-C5 alkyl group branched at alpha, linked to a Cs-Cs cycloalkyl group; a C3-C8 cycloalkyl or cycloalkenyl group optionally substituted with at least one moiety selected from the group consisting of methyl, hydroxy, halo and C4 alkyl groups; or a saturated, or fully or partially unsaturated, heterocycle of 3-6 members, comprising at least one oxygen or sulfur atom and optionally substituted with one or more C1-C4 alkyl groups or halogen atoms; R6 is H, or if X is -NR7CHR6-, R6 and R2 can be taken together to form the remainder of formula d; R7 is selected from the group consisting of H, C1-C10 alkyl, C2-C10 alkenyl, C2-C0 alkynyl, - (CH2) m (aryl Ce-Cio) and 5-10 members), wherein the residues of alkyl, alkenyl, aryl, heteroaryl and alkynyl of the preceding R7 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C (O) R11, -OC (O) R 11, -NR 11 C (O) R 12, -C (O) NR 11 R 12, -NR 11 R 12, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 6 -C 10 aryl and 5-10 membered heteroaryl; R 8 is selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl > C 2 -C 0 alkynyl, -C (O) R 17, -C (O) NR 7 R 18, - (CH 2) m (C 1 -C aryl) and - (CH 2) m (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the preceding R8 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C (O) R11, -OC (O) R11, -R11C (O) R12, -C (O) NR11R12, -NR11R12, hydroxy, C? -C6 alkyl, C? -C6 alkoxy, C6-C? 0 aryl and 5-10 heteroaryl members; R9 is hydroxy; R10 is selected from the group consisting of H, C1-C10 alkyl, C2-C? Alkenyl, C2-C alqu alkynyl, cyano, -CH2S (O) nR11, -CH2OR11, -CH2NR11R12, - (CH2) m (C6-C8 aryl) and - (CH2) m (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the preceding R10 groups are optionally substituted with 1 to 3 substituents independently from each other the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C (O) R11, -OC (O) R11, NR11C (O) R12, -C (O) NR11R12, -NR11R12, hydroxy, C alkyl? -C6, C6-C6 alkoxy, C6-C6 aryl and 5-10 membered heteroaryl; each R 11 and R 12 is independently selected from the group consisting of H, C C β alkyl, C 2 -C 6 alkenyl, (CH 2) m (C 6 -C 0 aryl), (CH 2) m (5-10 membered heteroaryl) and C2-C? alkynyl, wherein the alkyl, alkenyl, aryl, heteroaryl and alkynyl moieties of the foregoing groups R11 and R12 are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, CrCß alkyl and C6-C6 alkoxy; R13 s selected from the group consisting of H, C1-C10 alkyl, C2-C0 alkenyl, C2-C10 alkynyl, -R16 (Ce-Cio aryl), and -R16 (5-10 membered heteroaryl), in that the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the preceding R13 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C (O) R1 ? -OC (O) R11, -NR11C (O) R12, -C (O) NR1 R12, -NR11R12, hydroxy, C? -C6 alkyl, Ci-C? Alkoxy, C? -Ci aryl and heteroaryl? 10 members; R 14 is selected from the group consisting of C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 10 alkynyl, - (CH 2) m (C 6 -C 0 aryl) and - (CH 2) m (5- heteroaryl) 10 members), in which the alkyl, alkenyl, aryl, heteroaryl and alkynyl moieties of the preceding R14 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro trifluoromethyl, azido, -C (O) R11, -OC (O) R11, -NR11C (O) R12, -C (O) NR11R12, NR11R12, hydroxy, CrC6 alkyl, CrCβ alkoxy, Ce-Cι aryl and 5-10 membered heteroaryl; each R 15 is independently selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (C 6 -C 0 aryl) and - (CH 2) m ( 5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the preceding R15 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl , azido, -C (O) R11, -OC (O) R11, -NR11C (O) R12, -C (O) NR1 R12, -NR11R12, hydroxy, CrC6 alkyl, CrC6 alkoxy, C6-C6 aryl, and 5-10 membered heteroaryl; R16 is selected from the group consisting of CrCß alkyl, C3-C6 alkenyl, and C3-C6 alkynyl, wherein the alkyl, aikenyl, and alkynyl moieties of the preceding R16 groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, azido, -C (0) R11, -OC (O) R1 \ -NR11C (O) R12, -C (O) NR11R12, -NR11R12, hydroxy, CrC6 alkyl, alkoxy CrC6, Ce-Cryl aryl and 5-10 membered heteroaryl, and in which at least one carbon atom of each of the foregoing R16 groups may optionally be replaced by 1 to 3 atoms or residues independently selected from the group consisting of O, N (R15) and S; each of R 17 and R 18 is independently selected from the group consisting of H, CrCl 3 alkyl, C 2 -C 0 alkenyl, C 2 -C 0 alkynyl, - (CH 2) m (C 6 -C 0 aryl) and - ( CH2) m (5-10 membered heteroaryl), wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl moieties of the foregoing groups R17 and R18 are optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo , cyano, nitro, trifluoromethyl, azido, -C (O) R11, -OC (O) R11, -NR11C (0) R12, -C (0) NR11R12, -NR1 R12, hydroxy, C1-C6 alkyl, alkoxy CrC6 , Ce-Cι aryl and 5-10 membered heteroaryl; each n independently represents an integer from 0 to 2; and each m independently represents an integer from 0 to 4. 2. The compound of claim 1, wherein X is -CH2NR7- or -NR7CHR6-, Z is a residue of formula b, R2 is OH, R3 is -OC (O) R14, R4 is OH and R6 is H. 3. The compound of claim 1, wherein X is -NR7CHR6-, Z is a residue of formula b, R2 and R6 are taken together to form a residue of formula d, R3 is -OC (O) R14, R4 is OH and R7 is CH3. 4. The compound of claim 1, wherein X, Y and R3 are taken together to form a moiety of formula a, Z is a moiety of formula b, R2 is OH and R4 is OH.
5. 5. The compound of claim 1, wherein X is -CH2NR7 or -NR7CHR6-, Z is a residue of formula b, R2 and R3 are taken together to form a moiety of formula c, and R4 is OH.
6. 6. The compound of claim 1, wherein X, Y and R3 are taken together to form a moiety of formula a, Z is -CH (OR8) -, R2 is -OR13 and R4 is OR15.
7. 7. The compound of claim 1, wherein X, Y and R3 are taken together to form a moiety of formula a, Z is -C (O) -, R2 is -OR3 and R4 is OR15.
8. 8. The compound of claim 7, wherein R1 is H; R5 is ethyl; R15 is H or methyl and R13 is a residue of the formulas e-q ff in which R19 is Ce-Cry aryl or 5-10 membered heteroaryl, wherein the aryl and heteroaryl moieties of the preceding R19 groups are optionally substituted with 1 to 3 substituents selected from the group consisting of halo, cyano , nitro, trifluoromethyl, azido -C (O) R11, -OC (O) R12, NR 1C (O) R12, -C (O) NR1 R12, -NR11R12, hydroxy, CrC6 alkyl) CrC6 alkoxy, aryl Ce-Cio and 5-10 membered heteroaryl.
9. 9. The compound of claim 8, wherein R19 is selected from the group consisting of phenyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8- quinolyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.
10. 10. The compound of claim 1, wherein R5 is selected from the group consisting of ethyl, isopropyl, cyclopropyl, sec-butyl, cyclobutyl, cyclopentyl, methylthioethyl, and furyl.
11. 11. A method for preparing a compound of formula 2 wherein R2, R5, R9, R10 and R15 are defined herein, which comprises contacting a compound of formula f f with a Grignard reagent for a period of time and at a temperature sufficient to form a compound of formula 2.
12. 12. - A method for preparing a compound of formula 4, wherein R5, R9, R10 and R15 are defined in this specification, which comprises contacting a compound of formula h with an amine oxidizing reagent for a period of time and at a temperature sufficient to form a compound of formula 4.
13. 13. The method of claim 12, wherein the amine oxidizing reagent is selected from the group consisting of -bromo-succinimide, N-chloro-succinimide, iodine and bromine.
14. 14. A method of preparing a compound of formula 5 wherein R2, R5, R9 and R10 are defined in this specification, which comprises contacting a compound of formula I with a Grignard reagent or a base for a period of time and at a temperature sufficient to form a compound of formula 5.
15. 15. The method of claim 14, wherein the Grignard reagent is benzyl magnesium chloride or the base is (isopropyl-cyclohexyl-amino) -magnesium chloride.
16. 16. A method of forming a compound of formula 7 wherein R2 and R5 are defined in this specification, which comprises contacting a compound of formula wherein R9 and R10 are defined in this specification, under acidic conditions for a period of time and at a temperature sufficient to form a compound of formula 7.
17. 17. A pharmaceutical composition comprising a compound of formula 1 or one of its pharmaceutically acceptable salts, solvates or prodrugs and a pharmaceutically acceptable carrier.
18. 18. The use of a compound of formula 1 or one of its pharmaceutically acceptable salts, solvates or prodrugs for the manufacture of a medicament for treating a bacterial or protozoal infection in a mammal, fish or bird.