MXPA99011496A - C-4''-substituted macrolide derivatives - Google Patents

Abstract

This invention relates to compounds of formula (1) and to pharmaceutically acceptable salts thereof. The compounds of formula (1) are potent antibacterial agents that may be used to treat various bacterial infections and disorders related to such infections. The invention also relates to pharmaceutical compositions containing the compounds of formula (1) and to methods of treating bacterial infections by administering the compounds of formula (1). The invention also relates to methods of preparing the compounds of formula (1) and to intermediates useful in such preparation.

Description

DERIVATIVES OF MACROLIDOS C-4"SUBSTITUTE BACKGROUND OF THE INVENTION This invention relates to new derivatives of macrolides C-4"substituted which are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and poultry This invention also relates to pharmaceutical compositions containing the new compounds and methods for the treatment of infections bacterial and protozoal in mammals, fish and birds, by administering new compounds to mammals, fish and birds that need such treatment .. Macrolide antibiotics are known to be useful in the treatment of a broad spectrum of bacterial and protozoal infections in mammals , fish and birds Such antibiotics include various derivatives of erythromycin A such as azithromycin, which is commercially available and is cited in US Patents 4,474,768 and 4,517,359, which are hereby incorporated by reference in their entirety. Like the azithromycin and other macrolide antibiotics, the new mac compounds Rolides of the present invention possess potent activity against various bacterial and protozoal infections, as described below.

SUMMARY OF THE INVENTION The present invention relates to compounds of formula and pharmaceutically acceptable salts thereof, wherein: X is -CH (NR9R10) -, -C (O) -, C (= NOR9) -, -CH2NR9, or -N (alkyl d-Cß) CH2- wherein the first line of each of the above groups X is attached to the carbon C-10 of the compound of formula 1 and the last line of each group is attached to the carbon C-8 of the compound of formula 1; R1 is H, hydroxy or methoxy; R2 is hydroxy; R 3 is C 1 -C 0 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, cyano, -CH 2 S (O) n R, wherein n is an integer ranging from 0 to 2, CH 2 OR 8, -CH 2 N (OR 9) R 8, -CH2NR8R15, - (CH2) m (C6-C10 aryl), or - (CH2) m (heteroaryl of 5-10 elements) wherein m is an integer ranging from 0 to 4 and in which the above groups R3 are optionally substituted with 1 to 3 R16 groups; or R2 and R3 join to form an oxazolyl ring as shown below 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 (O) R8, wherein n is 0 or 1, C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 alkynyl, - (CH2) m (aryl C6-C? 0) or - (CH2) m (heteroaryl of 5-10 elements), wherein m is an integer ranging from 0 to 4, and in which the above R5 groups are optionally substituted with 1 to 3 groups R16; each R6 and R7 is independently H, hydroxy, C? -C6 alkoxy, C? -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CH2) m (C6-C? 0 aryl) or - (CH2) m (heteroaryl of 5-10 elements), wherein m is an integer ranging from 0 to 4; each R8 is independently H, alkyl CIC-IO, C2-C-io alkenyl, C2-C10 alkynyl, - (CH2) qCR11R12 (CH2) rNR13R14, wherein q and r are each independently an integer ranging from 0 to 3, except that q and r are not any of them OR, - (CH2) m (C-C-io aryl) or - (CH2) m (5-10 elements heteroaryl), where m is an integer that ranges from 0 to 4 and in which the above R8 groups, except H, are optionally substituted with 1 to 3 R16 groups; or when R8 is -CH2NR8R15, R15 and R8 can be taken together to form a saturated monocyclic ring of 4-10 elements or a saturated polycyclic ring or a 5-10 membered heteroaryl ring, where 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 including 1 or 2 double or triple carbon-carbon bonds and said saturated rings and heteroaryls being optionally substituted with to 3 groups R16; each R9 and R10 is independently H or C-? -C6 alkyl; each R11, R12, R13 and R14 is independently selected from H, C 1 -C 10 alkyl, - (CH 2) m (C 6 -C 0 aryl) and - (CH 2) m (5-10 elements heteroaryl), wherein m is an integer ranging from 0 to 4 and wherein the groups R11, R12, R13 and R14 above, except H, are all optionally substituted with 1 to 3 R16 groups; or R11 and R13 join to form - (CH2) P-, where p is an integer ranging from 0 to 3, said saturated ring of 4-7 elements being formed in such a way that optionally includes 1 or 2 doubles or triple carbon-carbon bonds; or R13 and R14 are joined to form a saturated monocyclic or polycyclic ring of 4-10 elements or a 5-10 membered heteroaryl ring, wherein said saturated rings and heteroaryls 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 including 1 or 2 double or triple carbon-carbon bonds and said saturated rings and heteroaryls being optionally substituted with 1 to 3 R16 groups; R 15 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 2 -C 8 alkynyl, wherein the above R 15 groups are optionally substituted with 1 to 3 substituents independently selected from halogen and -OR 9; each R16 is independently selected from halogen, cyano, nitro, trifluoromethyl, azyl, -C (0) R17, -C (0) R17, -OC (O) OR17, -NR6C (O) R7, -C (O) NR6R7 , -NR6R7, hydroxy, CrC6 alkyl, C? -C6 alkoxy, - (CH2) m (Cd-Cio aryl) and - (CH2) m (heteroaryl of 5-10 elements), wherein m is an integer which ranges from 0 to 4 and wherein said aryl and heteroaryl substituents are optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) R17, -C (0) R17, -OC ( 0) OR17, -NR6C (O) R7, -C (0) NR6R7, -NR6R7, hydroxy, C-C-alkyl, CI-CT alkoxy. each R 17 is independently selected from H, d-C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (C 6 -C 0 aryl) or - (CH 2) m (heteroaryl 5) -10 elements), where m is an integer that ranges from 0 to 4; with the proviso that R8 is not H when R3 is -CH2S (O) nR8. Preferred compounds of formula 1 include those in which R1 is hydroxy, R2 is hydroxy, R3 is -CH2NR8R15 or -CH2SR8 and R4 is H. Other preferred compounds of formula 1 include those in which R1 is hydroxy, R2 is hydroxy, R3 is -CH2NR8R15, R4 is H, R15 and R8 are each selected from H, C1-C6alkyl, C2-C6alkenyl and C2-C20 alkynyl, wherein said groups R15 and R8, except H , are optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen and C 1 -C 6 alkoxy. Specific preferred compounds having the above general structure include those in which R15 is or H or is selected from the following groups, among which R8 is also independently selected: methyl, ethyl, allyl, n-butyl, isobutyl, 2- methoxyethyl, cyclopentyl, 3-methoxypropyl, 3-ethoxypropyl, n-propyl, isopropyl, 2-hydroxyethyl, cyclopropyl, 2,2,2-trifluoroethyl, 2-propynyl, sec-butyl, fer-butyl and n-hexyl. Other preferred compounds of formula 1 include those in which R 1 is hydroxy, R 2 is hydroxy, R 3 is -CH 2 NR 8 R 15, R 4 is H, and R 8 is - (CH 2) m (C 1 -C 1 aryl), wherein m is an integer ranging from 0 to 4. Preferred specific compounds having the above general structure include those in which R8 is phenyl or benzyl. Other preferred compounds of formula 1 include those in which R1 is hydroxy, R2 is hydroxy, R3 is -CH2NR8R15, R4 is H, and R15 and R8 are taken together to form a saturated ring. Preferred specific compounds having the above general structure include those in which R15 and R8 are joined to form a piperidino, trimethylenimino or morpholino ring. Other preferred compounds of formula 1 include those in which R1 is hydroxy, R2 is hydroxy, R3 is -CH2NR15R8, R4 is H, and R15 and R8 are taken together to form a heteroaryl ring optionally substituted with 1 or 2 CI- alkyl groups. CT- Preferred specific compounds having the above general structure include those in which R15 and R8 are taken together to form a pyrrolidino ring, triazolyl or imidazolyl, wherein said heteroaryl groups are optionally substituted with 1 or 2 methyl groups. Other preferred compounds of formula 1 include those in which R 1 is hydroxy, R 2 is hydroxy, R 3 is -CH 2 SR 8, R 4 is H, and R 8 is selected from C 1 -C 10 alkyl, C 2 -C 0 alkenyl, and C 2 -C 8 alkynyl or, wherein said R8 groups are optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen and Ci-Cβ alkoxy. Preferred specific compounds having the above general structure include those in which R8 is methyl, ethyl or 2-hydroxyethyl. Other preferred compounds of formula 1 include those in which R 1 is hydroxy, R 2 is hydroxy, R 4 is H and R 3 is selected from C 1 -C 10 alkyl, C 2 -C 0 alkenyl and C 2 -C 8 alkynyl, wherein R3 groups are optionally substituted with 1 or 2 substituents independently selected from hydroxy, -C (O) R17, -NR6R7, halogen, cyano, azido, 5-10 membered heteroaryl and Ci-Cβ alkoxy. Preferred specific compounds having the above general structure include those in which R3 is methyl, allyl, vinyl, ethynyl, 1-methyl-propenyl, 3-methoxy-1-propynyl, 3-dimethylamino-1-propynyl, 2-pyridylenyl , 1-propynyl, 3-hydroxy-1-propynyl, 3-hydroxy-1-propenyl, 3-methoxy-1-propenyl, 3-methoxypropyl, 1-propynyl, n-butyl, ethyl, propyl, 2-hydroxyethyl, formylmethyl , 6-cyano-1-pentynyl, 3-dimethylamino-1-propenyl or 3-dimethylaminopropyl. Other preferred compounds of formula 1 include those in which R1 is hydroxy, R2 is hydroxy, R4 is H and R3 is - (CH2) m (heteroaryl of 5-10 elements), wherein m is an integer ranging from 0 to 4. Preferred specific compounds having the above general structure include those in which R3 is 2-thienyl, 2-pyridyl, 1-methyl-2-imidazolyl, 2-furyl or 1-methyl-2-pyrrolyl. Other preferred compounds of formula 1 include those in which R 1 is hydroxy, R 2 is hydroxy, R 4 is H and R 3 is - (CH 2) m (C 6 -C 0 aryl), wherein m is an integer ranging from 0 to 4. Preferred specific compounds having the above general structure include those in which R3 is phenyl. Specific compounds of formula 1 include those in which R2 and R3 are taken together to form an oxazolyl ring as shown below wherein R5 is as defined above. Specific compounds of formula 1 include those in which R3 is selected from the following: wherein X3 is O, S or -N (R15) - and the -OR9 group can be attached to any available carbon of the phenyl group. The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoan infection in a mammal, fish or bird, which includes a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle. The invention also relates to a method for the treatment of a bacterial infection or a protozoal infection in a mammal, fish or bird, comprising the administration to said mammal, fish or bird of a therapeutically effective amount of a compound of formula 1 or of a pharmaceutically acceptable salt thereof. The term "treatment", as used herein, unless otherwise indicated, includes treating or preventing a bacterial infection or a protozoal infection, as provided in the method of the present invention.

As used herein, unless otherwise indicated, the term "bacterial infection (s)" or "protozoan infection" includes bacterial infections and protozoal infections that occur in mammals, fish and birds, as well as disorders related to bacterial infections and protozoal infections that can be treated or prevented by the administration of antibiotics, such as the compounds of the present invention. Said bacterial infections and protozoal infections and disorders related to said 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, Leogionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae or chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (eg, S. eipidermis, S. hemoyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, groups of CF streptococci (streptococci from minute colonies), Streptococcus viridans, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; urinary tract infections without 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 Neiserria gonorrheae; diseases caused by toxins related to S. aureus infection (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 infection by Borrelia burgdorferí; conjunctivitis, keratitis and dacrocystitis related to infection by Chlamydia trachomatis, Neiserria gonorrheae, S. aureus, S. pneumonia, S. pyogenes, H. Influenzae or Listeria spp .; Mycobacterium avium disseminado (MAC) complex related to infection by Mycobacterium avium intracellulare; gastroenteritis related to Campylobacter jejuni infection; intestinal protozoa related to infection by Cryptosporidium spp; odontogenic infection related to infection by Streptococcus viridans; 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 protozoal infections 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 (eg, coccidia, cryptosporidia, etc.); milk cow mastitis related to infection by S. aureus, S. uberis, S. agalactiae, S. dysgalactiae, Klebsiella spp .; Corynebacterium 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; the rot of the hoof in cows related to the 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 pink eye of the cows related to the infection by Moraxella bovis; premature bovine abortion related to protozoal infection (eg, neosporium); urinary tract infection in dogs and cats related to E. coli infection; Skin and soft tissue infections in dogs and cats related to infection by S. epidermis, S. intermedius, S. coagulase negative or P. multocida and dental or oral infections in dogs and cats related to the infection by Alcaligenes spp. ., Bacterioides spp., Clostridium spp., Enterobacter spp., Eubecterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and protozoal infections 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 method for the preparation of the above compound of formula 1, or a pharmaceutically acceptable salt thereof, wherein R3 is -CH2 (O) nR8, -CH2OR8 or -CH2NR8R15, wherein R15 and R8 are as defined above with the proviso that R8 is not H when R3 is -CH2S (0) nR8, which comprises the treatment of a compound of formula wherein X, R1 and R4 are as defined above, with a compound of the formula HSR8, HOR8 or HNR15R8, wherein n, R15 and R8 are as defined above, optionally followed by oxidation of the SR8 substituent to form -S (O) R8 or -S (0) 2R8.

In another aspect of the above process of preparing the compound of formula 1, or a pharmaceutically acceptable salt thereof, the above compound of formula 3 is prepared by treating a compound of formula. wherein X, R1 and R4 are as defined above, with (CH3) 3S (0) nX2 + 'wherein n is 0 or 1 and X2 is halogen, -BF4 or-PF6, preferably iodine or -BF4, in the presence from a base, such as potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium hydride, 1, 1, 3,3-tetramethyl-guanidine, 1,8-diazabicyclo [5.4.0] undec -7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, potassium hexamethyldisilazide (KHMDS), potassium ethoxide or sodium methoxide, preferably KHMDS or a sodium-containing base, such as sodium hydride . The present invention also relates to the above compounds of formulas 2 and 3, which, as indicated above, are useful for the preparation of the foregoing of formula 1 and the pharmaceutically acceptable salts thereof. The 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 cited in T.W. Greene, P.G.M. Wuts, "Protective Groups in Organic Synthesis" (J. Wiley &Sons, 1991). The term "halogen", as used herein, unless otherwise indicated, means fluorine, chlorine, bromine, or iodine. 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 cyclic moieties are discussed, at least three carbonates 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 groups - (O) -alkyl wherein "alkyl" is as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl.

The term "5-10 element heteroaryl", as used herein, unless otherwise indicated, includes aromatic heterocyclyl groups containing one or more heteroatoms, each selected from O, and N, in which each heterocyclyl group has 5-5 10 atoms in its ring system. Examples of heteroaryl groups of 5-10 suitable elements are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, (1, 2,3,) and (1, 2,4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxasolyl, pyrrolyl. and thiazolyl. The phrase "pharmaceutically acceptable salt (s)", such as is used herein, unless otherwise indicated, includes the 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 broad < * • *** "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, that is, the salts containing the faramacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate salts, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [eg, 1,1-methyl-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. Those compounds of the present invention which are acidic in nature, are capable of forming basic 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, the pharmaceutically acceptable salts thereof, wherein the hydrogens, carbons or other atoms are substituted by isotopes. These may be useful in research or as diagnostic tools, in pharmacokinetic studies of metabolism and in affinity assays.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention can be prepared according to the following schemes 1-3 and with the corresponding description. In the following schemes, unless otherwise indicated, the substituents X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, and R17 are as defined above. SCHEME 1 SCHEME 2 SCHEME 3 SCHEME 3 (continued) SCHEME 3 (continued) This invention uses several template macrolides as starting materials. It includes azithromycin, erythromycin, clarithromycin, erythromycylamine, as well as their analogues. Azithromycin can be prepared according to the methods described in US Patents 4,474,768 and 4,517,359, cited above. Erythromycin can be prepared, or isolated, according to the methods described in US Pat. Nos. 2,653,899 and 2,823,203. Clarithromycin can be prepared according to the methods described in US Pat. No. 4,331,803. The above starting materials require appropriate protection of the functional group before carrying out various modifications, deprotecting them once the desired modifications have been made. The protecting groups most commonly used for the amino moieties in the macrolide compounds of this invention are the benzyloxycarbonyl (Cbz) and t-butyloxycarbonyl (Boc) groups. The hydroxyl groups are generally protected as Cbz acetates or carbonates. The relative reactivity of various hydroxyl groups in the macrolide molecules of the general type claimed in this invention has been established. Said differences in reactivity allow the selective modification of the different parts of the compounds of this invention. In the above schemes, the hydroxy group C-2 '(R4 is H) is selectively protected by treating the macrolide compound with one equivalent of acetic anhydride in dichloromethane in the absence of an external base to give the corresponding compound wherein R4 is acetyl. The acetyl protecting group can be removed by treating the compound of formula 3 with methanol at 23-65 ° C for 10-48 hours. The hydroxy C-2 'can also be protected with other protecting groups familiar to those skilled in the art, such as the Cbz group. When X is -CH2NH-, the amino group C9 may also require protection before other synthetic modifications are made. Suitable protecting groups for the amino moiety are the Cbz and Boc groups. To protect the amino group C-9, the macrolide can be treated with t-butyl dicarbonate in anhydrous tetarahydrofuran (THF) or N-hydroxysuccinimide benzyloxycarbonyl ester or benzyl chloroformate to protect the amino group as its t-butyl or carbamate. benzyl Both the C-9 amino and the C-2 'hydroxy can be selectively protected with the Cbz group in one step, treating the compound of formula 2 with benzyl chloroformate in THF and water. The Boc group can be separated by acid treatment and the Cbz group can be separated by conventional catalytic hydrogenation. In the following description, it is assumed that, when X is -CH2NH-, the C-9 amino moiety, as well as the C-2 'hydroxy group, are protected and deprotected as deemed appropriate by those skilled in the art. In scheme 1, the compound of formula 2 can be prepared according to methods familiar to those skilled in the art, including one or more methods described in the Journal of Antibotics, 1988, pages 1029-1047. In step 1 of scheme 1, the compound of formula 2 is treated with R3MgX1 or R3-Li and Mg (X1) 2, wherein X1 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), hexanes, or a mixture of two or more of the above solvents, preferably an ethereal solvent, at a temperature ranging from about -78 ° C to about environment (20-25 ° C) to give the compound of formula 1, wherein R2 is hydroxy and R1, R3 and R4 are as defined above. Scheme 2 illustrates the preparation of the compounds of formula i by the use of epoxide intermediates. In step 1 of scheme 2, the compound of formula 3 can be prepared by two methods. In one of the methods (method A), the compound of formula 2 is treated with (CH3) 3S (0) X2, wherein X2 is halogen, -BF4 or -PF6, preferably iodine, in the presence of a base such as potassium tert-butoxide, sodium ethoxide, sodium tert-butoxide, sodium hydride, 1,1-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 such as sodium hydride, in a solvent such as THF, an ethereal solvent, dimethylformamide (DMF) or sulfoxide of methyl (DMSO) or a mixture of two or more of the above solvents, at a temperature in the range of from about 0 ° C to about 60 ° C, giving the compound of formula 3 in which the following configuration of the epoxide moiety predominates.

In a second method (method B), the compound of formula 2 is treated with (CH3) 3SX2, wherein X2 is halogen, -BF4 or -PF6, preferably -BF4, in the presence of a base such as potassium tert-butoxide , sodium 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 hexamethyldisilazide (KHMDS) or sodium methoxide, preferably KHMDS in a solvent such as THF, an ethereal solvent, DMF or DMSO, or a mixture of two or more of the above solvents, at a temperature in the range of about 0 ° C to about 60 ° C, giving the compound of formula 3 in which the following configuration of the epoxide moiety predominates In step 2 of scheme 2, the compound of formula 3 can be converted to a compound of formula 1, wherein R 2 is hydroxy and R 3 is a group that is linked to the C 4 -carbon ", by a methylene group, as when R3 is -CH2NR15R8 or -CH2S (O) nR8, wherein R15 and R8 are as defined above To prepare a compound of formula 1, wherein R3 is CH2NR15R8, the compound of formula 3 can be treated with a compound of formula HNR15R8, wherein R15 and R8 are as defined above, in the absence or in the presence of a polar 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 about 60 ° C, optionally in the presence of a halide reagent such as potassium iodide, lithium perchlorate, magnesium preclorate, lithium tetrafluoroborate, pyridinium hydrochloride or a tetralkylammonium halide reagent , such as tetrabutylammonium iodide. To prepare a compound of formula 1 wherein R3 is CH2S (O) nR8, wherein n and R8 are as defined above, the compound of formula 3 can be treated with a compound of formula HSR8 in the presence of K2CO3, Kl or methoxide sodium, in an aromatic solvent such as methanol, benzene or toluene at a temperature ranging from room temperature to approximately 120 ° C. If appropriate, the sulfur radical can be oxidized to -SO- or -SO2- according to methods familiar to those skilled in the art. To prepare a compound of formula 1 wherein R3 is -CH2SR8 and R8 is - (CH2) qCR11R12 (CH2) rNR13R14, wherein the substituents of said R8 group are as defined above, the compound of formula 3 can be treated with a compound of formula HS- (CH2) qCR11R12 (CH2) rNPhth, wherein NPhth represents phthalimido and potassium iodide giving the compound of formula 1, wherein R3 is -CH2S (CH2) qCR11R12 (CH2) rNH2, after separating the phthalimido radical, which can be modified later if necessary. By an analogous method, a compound of formula 1, wherein R3 is -CH2NR15R8 and R8 is - (CH2) qCR11R12 (CH2) rNR13R14 can be prepared by treating the compound of formula 3 with a compound of formula HNR9- (CH2) qCR11R12 (CH2) rNR13R14 or a compound of formula H2N- (CH2) qCR11R12 (CH2) rNH2 followed by a reductive alkylation of the nitrogen atoms. Using the same or an analogous method, a compound of formula 1 in which R3 is -CH2OR8 and R8 is as defined above, can be prepared by treating a compound of formula 3 with a compound of formula HOR8. Scheme 3 illustrates the preparation of the compounds of formula 1 wherein R2 and R3 are taken together to form an oxazolyl radical. In step 1 of scheme 3, the compound of formula 3 is treated with sodium azide in the presence of NH 4 Cl in methanol or water, or a mixture of two solvents, at a temperature ranging from about 0 ° C to about 100 ° C, preferably at about 80 ° C to give the compound of formula 4. In step 2 of scheme 3, the compound of formula 4 can be converted to the corresponding amine of formula 5 by conventional catalytic hydrogenation. Preferably, said hydrogenation is done using Pd (10% on carbon) powder under H2 atmosphere (1 atm = 101.32 kPa). The resulting amine of formula 5 can be converted to various compounds of formula 1, wherein R3 is -CH2NR15R8 using conventional synthetic methods, such as reductive amination. In step 3 of scheme 3, the compound of formula 5 can be converted to the compound of formula 1, wherein R2 and R3 are taken together as shown, by treating the compound of formula 5 with a compound of formula R5 -CN, R5-C = N (OCH3), R5-C = N (OC2H5), R5-C (0) CI, or R5-C02H, wherein R5 is as defined above, except that it is not NH2, in presence or absence of an acid, such as HCl or a Lewis acid, such as ZnCI2 or BF4Et30 or a base, such as NaOH or TEA, in a solvent such as THF, a hydrocarbon (such as CH2Cl2 or chlorobenzene), at a temperature that fluctuates from about room temperature to reflux. To prepare the corresponding compound wherein R5 is amino, the compound of formula 5 is treated with BrCN and sodium acetate in methanol at a temperature ranging from about room temperature to reflux. Otherwise, for the compound of formula 5 it is possible to proceed as indicated in steps 4 and 5 of scheme 3. In step 4 of scheme 3 the compound of formula 5 is treated with thiocarbonylimidazole in methylene chloride at a temperature which ranges from about 0 ° C to room temperature to give the compound of formula 25. In step 5 of scheme 3, the compound of formula 25 is treated with R 5 -X 1, wherein X 1 is a halide, such as bromine or iodine and a base, such as sodium methoxide in a solvent such as methanol or acetone at a temperature ranging from about 0 ° C to room temperature. The compounds of the present invention can have asymmetric carbon atoms and, therefore, exist in different enantiomeric and diastereomeric forms. The 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 diastereoisomers and converting (eg, hydrolyzing) the individual diastereomers wn the corresponding pure enantiomers. Such separations can be performed using standard chiral HPLC. The use of all these isomers, including the diastereomeric mixtures and the pure enantiomers are considered part of the invention. The compounds of the present invention which are basic in nature are capable of forming a wide range of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration in mammals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter into the free base compound. by treatment with an alkaline reagent and subsequently converting this free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in an appropriate organic solvent, such as methanol or ethanol . The solvent is carefully evaporated and the desired solid salt is easily obtained. The desired acid 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. Those compounds of the present invention that are acidic in nature, are capable of forming basic salts with various cations. For compounds that are to be administered to mammals, fish or birds, said salts must be pharmaceutically acceptable. When a pharmaceutically acceptable salt is required, it may be desired to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter to a pharmaceutically acceptable salt according to the analogous procedure described relating to the conversion of pharmaceutically unacceptable acid addition salts in pharmaceutically acceptable salts. Examples of basic salts are the alkali metal or alkaline earth metal salts and, especially the sodium salts, of amines and potassium.

All these salts can be prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable basic salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Said non-toxic basic salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, various amine cations etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the pharmacologically acceptable bases with cations such as sodium, potassium, calcium, magnesium and various amine cations, etc. and then evaporating the resulting solution to dryness, preferably under reduced pressure. On the other hand, it can also be prepared by mixing alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of reagents are preferably used in order to ensure that the reaction and the maximum yields of the desired final product are complete. The antibacterial and antiprotozoal activity of the compounds of the present invention is demonstrated by the ability of the compounds to inhibit the growth of defined strains of human pathogens (test I) or animals (tests II and III).

ASSAY I Test I, described below, uses a conventional methodology and interpretation criteria and has been designed to provide guidance for chemical modifications that can result in compounds that circumvent defined mechanisms of macrolide resistance. In trial I, a panel of bacterial strains is assembled to include a variety of target pathogenic species, including representatives of the mechanisms of resistance to macrolides that have been characterized. The use of this panel allows to determine the chemical structure / activity relation with respect to the power, spectrum of activity and structural elements or modifications that may be necessary to obviate the mechanisms of resistance. The bacterial pathogens that make up the selection range are presented in the following table. In many cases, both the parental strain susceptible to the macrolides and the macrolide resistant strain derived therefrom are available, to obtain a more accurate assessment of the ability of the compounds to circumvent the mechanism of resistance. Strains containing the genes with the designation ermA / ermB / ermC are resistant to antibiotics macrolides, lincosamides and streptogramin B due to modifications (methylation) of the 23S rRNA molecules by an Erm methylase, so that it usually prevents union of the three structural classes. Two types of macrolide flux have been described; msrA codes for a component of a flow system in staphylococci that prevents the entry of macrolides and streptogramins while mefA / E codes for a transmembrane protein that appears to allow only the macrolides to pass. Inactivation of macrolide antibiotics can occur, which may be mediated by 2'-hydroxyl phosphorylation (mph) or by separation of macrocyclic lactone (esterase). The strains can be characterized using the polymerase chain reaction (PCR) technology and / or by sequencing the determinants of resistance. 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 Chemotherapy, 40 (11), 2562-2566 (1996). The assay is carried out in microtiter trays and interpreted according to the guidelines of the Performance Standards for antimicrobial disc susceptibility tests. Sixth Edition; approved standard, published by the National Committee for Clinical Laboratory Standards (NCCLS); The minimum inhibitory concentration (MIC) is used to compare strains. The compounds are initially dissolved in dimethylsulfoxide (DMSO) as stock solutions of 40 mg / ml.

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

ASSAY II This test is based on the method of liquid dilution in microtiter format. A single colony of P. multocida (strain 59A067) is inoculated in 5 ml of a breeding broth of a heart and brain infusion (BHI). The test compounds are prepared by solubilizing 1 mg of the compound in 125 μl of dimethyl sulfoxide (DMSO). The solutions of the test compound are prepared using a non-inoculated BHI broth. The concentrations of the test compound used range from 200 μg / ml to 0.098 μg / ml in double serial dilutions. The BHI inoculated with P multocida is diluted with a non-inoculated BHI broth to obtain a cell suspension of 10 4 cells per 200 μl. The cell suspensions of the BHI 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 showing a 100% inhibition of P multocida growth as determined by comparison with a non-inoculated control.

ESSAY lll This assay is based on the agar dilution method Using a Steers replicator. 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 μl of a pre-culture of P. haemolytica of total growth in 3 ml of fresh BHI broth is inoculated 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 serial dilutions are prepared. Two ml of the respective serial dilution is mixed with 18 ml of agar with molten BHI and solidified. When the inoculated P haemolytica culture reaches a standard McFarland density of 0.5, approximately 5 μl of the culture of P. haemolytica is inoculated on BHI agar plates containing various concentrations of the test compound using a replicator steers and incubated for 18 hours at 37 ° C. The initial concentrations of the test compound range between 100 and 200 μg / ml. The MIC is equal to the concentration of the test compound that exhibits a 100% inhibition of P. haemolytica growth 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, being carried out generally in mice. The mice are housed in cages (10 per cage) at the time of arrival and are allowed to acclimate for a minimum of 48 hours before use. The animals are inoculated intraperitoneally with 0.5 ml of a bacterial suspension with 3x103 CFU / ml (P. multocida strain 59A006), Each experiment has at least 3 non-medicated control groups including one infected with a dose of 0.1X stimulation and two infected with a dose of 1X stimulation; a group of 10X stimulation data can also be used. Generally, all mice in a given study can be stimulated for 30-90 minutes, especially if a repeating syringe (such as a Cornwall® syringe) is used to administer the dose. Thirty minutes after the stimulation has begun, the treatment with the first compound is administered. It may be necessary for a second person to initiate administration of the compound if all animals have not yet 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 via a feeding needle. In both cases, a volume of 0.2 ml per mouse is used. The compounds are administered for 30 minutes, 4 hours and 24 hours after the stimulation. 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 of each group is recorded. The control of the P. multocida model continues for 96 hours (four days) post-stimulation. The PD5o dose is a calculated dose for which the tested compound protects 50% of a group of mice from mortality due to infection due to bacterial infection that would be lethal in the absence of pharmacological treatment. The compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter "the active compounds") can be administered orally, parenterally, topically or rectally in the treatment or prevention of bacterial or protozoal infections. In general, these compounds are most desirably administered in dosages ranging from about 0.2 mg per kg of body weight per day (mg / kg / day) to about 200 mg / kg / day in single or divided doses (e.g. 1 to 4 doses per day), although the necessary variations will occur depending on the species, weight and condition of the subject to be treated and the route of administration chosen. However, a dosage level that is in the range of about 4 mg / kg / day to about 50 mg / kg / day is more desirably employed. However, the variations occur depending on the species of mammal, fish or bird treated and their individual response to said drug, as well as the type of pharmaceutical formulation chosen and the period and time interval in which the administration is carried out. . In some cases, dosage levels below the lower limit of the aforementioned range may be the most appropriate, while in other cases higher doses may be used without causing any side effects, assuming that said higher doses are divided first into several small doses for administration throughout the day. The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents through the previously indicated routes, said administration being carried out in single or multiple doses. More specifically, the active compounds can be administered in a wide range of different dosage forms, i.e., they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, lozenges, tablets, hard candies, powders, sprays, creams , ointments, suppositories, jellies, gels, paste, lotions, ointment, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include solid fillers or diluents, sterile aqueous media and various non-toxic organic solvents, etc. Also, oral pharmaceutical compositions can carry sweeteners and / or flavorings. 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 may be used, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrants such as starch (and especially corn starch, potato or tapioca), acid alginic and certain complex silicates, together with binders for granulation such as polyvinylpyrrolidone, sucrose, gelatin and acacia gum. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for the manufacture of tablets. Solid compositions of a similar type can also be used 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 the aqueous suspensions and / or elixirs are for oral administration, the active compound can be combined with various sweetening or flavoring agents, coloring agents or dyes, and if desired, also 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 can be used either in sesame or in peanut oil or in aqueous propylene glycol. The aqueous solutions should be suitably buffered (preferably at a pH above 8) if necessary, first obtaining an isotonic liquid diluent. These aqueous solutions are suitable for intravenous injections. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injections. The preparation of all these solutions under sterile conditions is easily done by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the active compounds of the present invention topically and this can be done by creams, gelatins, gels, pastes, patches, ointment and the like, in accordance with standard pharmaceutical practice. For administration to animals other than humans, such as cattle or domestic animals, the active compounds can be administered in the animal's food or orally as an embedded composition. The active compounds can also be administered in the form of liposomal delivery systems, such as small size unilamellar vesicles, large size unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine. The active compounds can also be bound to soluble polymers as vehicles of the desired drug. Such polymers can be polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenyl, polyhydroxyethylaspartamide-phenol or polyethylene oxide-polylysine substituted with palmitoyl residues. Also, the active compounds can be attached to a class of biodegradable polymers useful for achieving a controlled release of the drug, for example, polylactic acid, pololytic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. The following examples further illustrate the method and intermediates of the present invention. It is understood that the scope of the present invention is not limited to the specific details of the examples given below.

TABLE 1 The compounds of examples 1-18 have the following general formula 6, the substituents R being indicated in the following table. The compounds were prepared as described in the following preparations 1-6. In the table, the performance data and the mass spectra ("Mass Spec.") Refer to the final product PREPARATION 1 250-500 mg of the compound of formula 3 were dissolved, where X is -N (CH3) CH2-, R1 is hydroxy and R4 is H, prepared according to method A cited above, in 1-2 ml of a corresponding amine to the R groups indicated in table 1 above. A catalytic amount (20 mg) of pyridinium hydrochloride was added and the solution was heated at 50-75 ° C for about two to five days. The reaction was completed by quenching with 50 mL of saturated NaHC 3. The organic layer was extracted with 3 x 50 ml of CH 2 Cl 2 and dried over Na 2 SO 4. Filtration, concentration of the filtrate and drying gave a crude oil or solid. Subsequent purification on a column of silica gel (1.4-4% MeOH / CHCl3, 0.2% NH4OH) gave the final alcoholic amino product.

PREPARATION 2 250-500 mg of the compound of formula 3 were dissolved, where X is -N (CH3) CH2-, R1 is hydroxy and R4 is H, prepared according to method A cited above, in 1-2 ml of a corresponding amine to the R groups indicated in Table 1 above in a sealed tube. A catalytic amount (20 mg) of pyridinium hydrochloride was added and the solution was heated at 40-75 ° C for about four to eight days. The reaction was worked up by quenching with 50 ml of saturated Na 2 HCO 3. The organic layer was extracted with 3 x 50 ml of CH2Cl2 and dried over Na2SO4. Filtration, concentration of the filtrate and drying gave a crude oil or solid. Subsequent purification on a column of silica gel (1.5-4% MeOH / CHCl3, 0.2% NH4OH) gave the final alcoholic amino product.

PREPARATION 3 300 mg of the compound of formula 3 were dissolved, wherein X is -N (CH3) CH2-, R1 is hydroxy and R4 is H, prepared according to method A cited above, in 2-4 ml of MeOH / H20. To this was added an imidazole reagent corresponding to the R groups indicated in Table 1 above (25 equivalents) and a catalytic amount (20 mg) of pyridinium hydrochloride. The reaction mixture was refluxed at 45-50 ° C for three to four days. The reaction was quenched with saturated NaHCO 3, extracted with 3 x 300 mL of CH 2 Cl 2 and dried over Na 2 SO 4, filtered and concentrated to give a solid. The solid was redissolved in 500 ml of EtOAc and 3 x 150 ml of 2N NaOH was washed to remove excess imidazole. Subsequent purification on a column of silica gel (2-4% MeOH / CHCl3, 0.2% NH4OH) gave the final product.

PREPARATION 4 200-500 mg of the compound of formula 3 were dissolved, wherein X is -N (CH3) CH-, R1 is hydroxy and R4 is H, prepared according to method A cited above, in 1-2 ml of 2-propanol or methanol. To this was added excess reagent and a catalytic amount (20 mg) of pyridinium hydrochloride. The solution was heated at 40-75 ° C for about two to seven days. The reaction was concentrated to give a crude product. Subsequent purification on a column of silica gel (2-4% MeOH / CHCl3, 0.2% NH4OH) gave the final alcoholic amino product.

PREPARATION 5 180 mg of the compound of formula 3 were dissolved, wherein X is -N (CH 3) CH 2 -, R 1 is hydroxy and R 4 is H, prepared according to method A cited above, in 2 ml of benzene. To this was added K2C03 in excess and 0.5 ml of thiol. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with 100 mL of saturated NaHC 3, extracted with 3 x 25 mL of CH 2 Cl 2, dried over Na 2 SO, filtered and concentrated to give a solid. Subsequent purification on a column of silica gel (2% MeOH / CHCl3, 0.2% NH4OH) gave the final product.

PREPARATION 6 115 mg of the compound of formula 3 were dissolved, where X is -N (CH3) CH2-, R1 is hydroxy and R4 is H, prepared according to method A cited above, in 3 ml of methanol. To this was added thiol in excess. The mixture was heated at 50 ° C for 4 hours. The reaction was quenched with 100 mL of saturated NaHCO 3, extracted with 3 x 25 mL of CH 2 Cl 2, dried over Na 2 SO 4, filtered and concentrated to give a solid. Subsequent purification on a column of silica gel (2-4% MeOH / CHCl3, 0.2% NH4OH) gave the final product. The following examples 19-35 describe the preparation of compounds having the following general structure of formula 7 in which R is as defined in the examples.

EXAMPLE 19 To a solution of methylmagnesium bromide in Et20 (3.0 M, 1.7 ml) at 0 ° C was added a solution of methylpropargyl ether (0.421 g, 6 mmol) in THF (ml). After stirring at 0 ° C, a solution of 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (0.224 g, 0.3 mmol) in DME was added. ml) at room temperature. After stirring for 1 hour, the reaction mixture was diluted with water (50 ml) and AcOEt (50 ml). After separation, the aqueous layer was washed with AcOEt (3 x 30 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (40 ml) and brine (40 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH-CH2Cl2-NH4OH (6: 93.5: 0.5 to 8: 91.5: 0.5) gave 0.095 g (yield 39%) of the compound of formula 7, wherein R is 3-methoxy-1- propynyl: MS: 817 (API).

EXAMPLE 20 To a solution of methylmagnesium bromide in Et20 (3.0 M, 1.7 ml) at 0 ° C was added a solution of 1-dimethylamino-2-propyne (0.499 g, 6 mmol) in THF (5 ml). After stirring at 0 ° C for 6 hours, a solution of 4"-deoxy-4" -oxo-9-deoxo-9a-aza-methyl-9a-homoerythromycin A (0.224 g, 0.3 mmol) in DME was added ( 10 ml) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (50 ml) and AcOEt (40 ml). After separation, the aqueous layer was washed with AcOEt (3 x 30 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (40 ml) and brine (50 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH-CH2Cl2-NH4OH (6: 93.5: 0.5 to 10: 89.5: 0.5) gave 0.093 g (yield 37%) of the compound of formula 7, wherein R is 3-dimethylamino-1 - propynyl: MS: 831 (API).

EXAMPLE 21 To a suspension of trimethylsulfonium tetrafluoroborate (1.03 g, 6.3 mmol) in THF (40 ml) at -10 ° C was added KHMDS (1.20 g, 6.0 mmol).

After stirring below 0 ° C for 0.5 hours, the reaction vessel was cooled to -78 ° C and a solution of the compound of formula IV was added, wherein X is -N (CH 3) CH 2 -. and R13 is benzyloxycarboxy (2.60 g, 3 mmol) in DME (10 ml). After 0.5 hours, the reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (40 ml) and AcOEt (50 ml). After separation, the aqueous layer was washed with AcOEt (3 x 30 ml). The combined organic extracts were washed with brine (40 ml), dried over Na2SO4 and concentrated in vacuo. Chromatography on silica gel with MeOH-CH2Cl2-NH4OH (2: 97.6: 0.4 to 4: 95.5: 0.4) gave 0.834 g (yield 37%) of the compound of formula 3, wherein X-N (CH3) CH2- and R13 is benzyloxycarboxy: MS: 881 (API). The configuration of the epoxide residue was as obtained by method B in relation to scheme 2, which is presented below.

EXAMPLE 22 To a solution of the compound of Example 21 (0.101 g, 0.115) in DME was added dropwise LiAIH4 (1.0 M, 2.1 mL). After 10 minutes, the reaction mixture was treated successively with water (0.044 ml), a solution of 15% NaOH (0.044 ml) and water (0.132 ml) and then stirred at room temperature for 0.5 hour. The mixture was diluted with AcOEt (20 ml) and water (20 ml). After separation, the aqueous layer was extracted with AcOEt (3 x 30 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (50 ml) and brine (60 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH-CH2Cl2-NH4OH (3: 96.5: 0.5 to 3.5: 95: 0.5) gave 0.042 g (49% yield) of an intermediate: MS: 749 (API). A palladium catalyst (0.075 mg, 10% Pd / C) was added to a solution of the intermediate compound described above (0.51 g, 0.202 mmol) and formaldehyde (0.17 mL, 2.02 mmol) in methanol (20 mL). The reaction vessel was discharged and filled with hydrogen (50 psi = 344.75 Pa) and stirred at room temperature for 24 hours. The reaction mixture was filtered through Celite ™ and concentrated in vacuo. Chromatography on silica gel with hexanes-acetone-n-propanol-NH4OH (100: 10: 3: 0.5 to 50: 10: 3: 0.5) gave 0.098 g (64% yield) of 4"S-methyl-9- deoxo-9a-aza-9a-methyl-9a-homoerythromycin A: MS: 763 (API).

EXAMPLE 23 To a solution of 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (1.0 g, 1.34 mmol) in DME (50 ml) at 0 ° C was added bromide of ethinylmagnesium in THF (0.5 M, 40.2 ml). After stirring at 0 ° C for 0.5 hour, the reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (100 ml) and AcOEt (100 ml). After separation, the aqueous layer was washed with AcOEt (3 x 30 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (100 ml) and brine (100 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH-CH2Cl2-NH4OH (4: 95.5: 0.5) gave 0.089 g (yield 9%) of the compound of formula 7, wherein R is ethynyl: MS: 774 (API).

EXAMPLE 24 To a solution of N-methylpyrrole (0.217 g, 2.68 mmol) in THF (5 ml) at -78 ° C was added BuLi (2.5 M, 1.08 ml). The solution was heated at room temperature for 2 hours and then added via cannula to a flask containing MgCl 2 (0.38 g 4.02 mmol) and THF (5 ml) at room temperature. After 1 hour at room temperature, a solution of 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (0.200 g, 0.268 mmol) in THF (2%) was introduced. ml) and stirring was continued at room temperature for 45 minutes. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (50 ml) and AcOEt (50 ml). After separation, the aqueous layer was washed with AcOEt (3 x 50 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (50 ml) and brine (50 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH-CH2Cl2-NH4OH (1: 98: 1 to 8:91: 1) gave 0.032 g (yield 14%) of the compound of formula 7, wherein Ri is 1-methyl-2- pirroli-lo: MS: 829 (API).

EXAMPLE 25 To a solution of N-methylimidazole (0.440 g, 5.36 mmol) in THF (5 ml) at -78 ° C was added BuLi (2.5 M, 2.15 ml). The solution was warmed to room temperature for 1 hour and then added via cannula to a flask containing MgCl 2 (0.6374 g, 6.69 mmol) and THF (5 ml) at room temperature. After 2 hours at room temperature, a solution of 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (0.200 g, 0.268 mmol) in DME (2) was introduced. ml) and stirring was continued at room temperature for 45 minutes. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (50 ml) and AcOEt (50 ml). After separating, the aqueous layer was washed with AcOEt (3 x 50 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (50 ml) and brine (50 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH-CH2Cl2-NH4OH (1: 98: 1 to 8:91: 1) gave 0.042 g (yield 19%) of the compound of formula 7, in which Ri is 1-methyl-2- imidizalolyl: MS: 830 (API).

EXAMPLE 26 To a solution of an unpurified sample of the compound prepared in Example 20 (0.360 g) in isopropanol (40 ml) was added platinum oxide (0.076 g, 0.335 mmol). The reaction vessel was discharged and filled with hydrogen (50 psi = 344.75 Pa) and stirred at room temperature for 24 hours. Filtration of an aliquot of the reaction mixture through Celite ™ and concentration in vacuo gave the compound of formula 7, wherein R is 3-dimethylamino-1-propenyl: MS: 833 (API).

EXAMPLE 27 Platinum oxide (0.076 g, 0.335 mmol) was added to the remaining solution of Example 26, the reaction vessel was discharged, filled with hydrogen (50 psi = 344.75 Pa) and stirred at room temperature for 96 hours. The reaction mixture was filtered through Celite ™ and concentrated in vacuo. Chromatography on silica gel with MeOH-CH 2 Cl 2 -NH 4 HH (1: 98: 1 to 8:91: 1) gave 0.027 g (5% yield) of the compound of formula 7, wherein R is 3-dimethylaminopropyl: MS: 835 (API).

EXAMPLE 28 To a solution of an unpurified sample of the compound prepared in example 19 (0.400 g) in isopropanol (40 ml) was added platinum oxide (0.076 g, 0.335 mmol). The reaction vessel was discharged and filled with hydrogen (50 psi = 344.75 Pa) and stirred at room temperature for 24 hours. Filtration of an aliquot of the reaction mixture through Celite ™ and concentration in vacuo gave the compound of formula 7, wherein R is 3-methoxy-1-propenyl: MS: 819 (API).

EXAMPLE 29 Platinum oxide (0.076 g, 0.335 mmol) was added to the remaining solution of Example 26, the reaction vessel was discharged, filled with hydrogen (50 psi = 344.75 Pa) and stirred at room temperature for 96 hours. The reaction mixture was filtered through Celite ™ and concentrated in vacuo. Chromatography on silica gel with MeOH-CH2Cl2-NH4OH (1: 98: 1 to 8:91: 1) gave 0.019 g (21% yield) of the compound of formula 7, wherein R is 3-methoxypropyl lo: MS: 822 (API).

EXAMPLE 30 To a flask containing MgB2 OEt2 (2.28 g, 8.84 mmol) in DME (5 ml) at 0 ° C was added propynyl lithium (1865 g, 8.03 mmol). After 6 hours at 0 ° C, a solution of 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (0.300 g, 0.402 mmol) in DME was introduced ( 2 ml) and stirring was continued at 0 ° C for 1 hour, then at room temperature for 0.5 hour. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (75 ml) and AcOEt (75 ml). After separation, the aqueous layer was washed with AcOEt (3 x 75 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (75 ml) and brine (75 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH-CH2Cl2-NH4OH (1: 98: 1 to 8:91: 1) gave 0.099 g (31% yield) of the compound of formula 7, wherein R is 1-propynyl as a mixture of isomers: MS: 788 (API).

EXAMPLE 31 To a solution of 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (0.59 g, 0.79 mmol) in THF (20 ml) was added a solution of MeMgBr in Et20 (1.7 ml, 5.1 mmol, Et20 3.0 M solution) at 0 ° C. The suspension was stirred at 0 ° C for one hour and gradually warmed to room temperature. After 3 hours the reaction mixture was quenched with a saturated solution of NH 4 Cl (10 ml). The organic solvent was removed under vacuum in a rotary evaporator. The remaining aqueous solution was adjusted to pH 9.5 with a saturated solution of NaHC 3 followed by the addition of ethyl acetate (30 ml). The aqueous layer, after separation, was extracted with ethyl acetate (2 x 30 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude product. Chromatographic purification (silica gel with MeOH / CHCl3 / NH4OH (4:95, 9: 0.1) as eluents) gave the 4"-R-methyl-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin. A (which is the compound of formula 7, wherein R is methyl and having the specified R configuration) as a white solid, 240 mg (0.315 mmol, 40% yield): FABMS: m / e 763 (MH +) .

EXAMPLE 32 Following the procedure of Example 31, the 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin was reacted A (299 mg, 0.403 mmol) and phenylmagnesium bromide (0.87 ml, 2.61 mmol, 3.0 M THF solution), to give the compound of formula 7, wherein R is phenyl, 74 mg (0.09 mmol, yield 22 %); FAMBS: m / e 825 (MH +).

EXAMPLE 33 Following the procedure of Example 31, the 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (482 mg, 0.646 mmol) and vinyl magnesium bromide were reacted (4.2 ml, 4.2 mmol, 1.0 M THF solution), to give the compound of formula 7, wherein R is vinyl, 133 mg (0.172 mmol, yield 26.6%); FAMBS: m / e 774 (MH +).

EXAMPLE 34 Following the procedure of Example 31, the 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (494 mg, 0.662 mmol) and benzylmagnesium chloride (4.4) were reacted ml, 4.4 mmol, 1.0 M THF solution), to give the compound of formula 7, wherein R is benzyl, 30 mg (0.172 mmol, yield 5.4%); FAMBS: m / e 839 (MH +).

EXAMPLE 35 To a solution of 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (602 mg, 0.806 mmol) in chloroform (8 ml) was added TMSCN (220 ml, 1.64 mmol) followed by Znl2 (13 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 30 minutes. A solution of 10% K2C03 in water (10 ml) was added. The organic layer was washed with brine, dried (MgSO 4) and concentrated in vacuo to give the crude product. Chromatography on silica gel with CHCl3-MeOH-NH4 (97: 3: 0.1) as eluents gave the compound of formula 7, wherein R is cyano, as a white solid, 94.4 mg (0.122 mol, 15% yield ): FAMBS: m / e 774 (MH +). The following scheme illustrates the preparation of the compounds mentioned below in Table 2. In the following scheme, Cbz represents benzyloxycarbonyl.

The compound of formula 8, cited in the scheme above, (20.0 g, 22.7 mmol) was dissolved in chloroform (150 ml), followed by the addition of formaldehyde (5.1 ml solution 37% 68.1 mmole) and formic acid (2.8 ml, 74.9 mmoles). The resulting solution was heated at 60 ° C overnight to give the compound of formula 9. The reaction mixture was poured into water (150 ml) and methylene chloride (50 ml). The organic layer was washed with water (150 ml) once more and the aqueous layers were combined, the pH of the solution was adjusted to 9 by the addition of a 5N NaOH solution. The product was then extracted with methylene chloride (3 x 100 ml). The combined organic layers were washed with brine, dried over sodium sulfate and the organic solvent was removed in vacuo to give the compound of formula 9 (19.6 g, 96%). MS (TS) m \ z 895. 1-2 g of the compound of formula 9 were dissolved in methanol (10 ml), followed by the addition of Kl (10 eq.) And an amine corresponding to the R groups cited in the table. 2 back (10 eq.). After the reaction time indicated below, the reaction mixture was diluted with water (10 ml) and extracted with CH 2 Cl 2 (3 x 15 ml). The combined organic layers were washed with brine, dried over Na 2 SO, filtered and purified by flash chromatography to give the compounds of formula 10 with the R groups indicated in Table 2 below.

TABLE 2 TABLE 2 (CONTINUED) The following scheme illustrates the preparation of the compounds mentioned in the following examples 48-49.

EXAMPLE 48 To a solution of sodium hydride (41.5 mg, 1.73 mmol) in DMF (5 mL) was added trimethyisulfoxonium iodide (399 mg, 1.77 mmol). After 15 minutes, the suspension of the reaction mixture became clear. A solution of 4"-deoxy-4" -oxo-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (940 mg, 1.26 mmol) in DMSO (3 mL) was slowly added. The resulting yellow solution was stirred for 15 minutes at room temperature and 45 minutes at 55 ° C and then at room temperature overnight. The reaction mixture was taken up in water (20 ml) and ethyl acetate (20 ml). The organic layer was washed with brine, dried (MgSO) and concentrated to give the crude product, which was chromatographed on silica gel (CHCl3-MeOH-NH4OH) (97/3 / 0.1) to give the above compound of formula 12 as a white solid, 362 mg (0.476 moles, 38% yield): FAMBS: m / e 761 (MH +).

EXAMPLE 49 To a solution of the compound prepared in example 48 (95 mg, 0.12 mmol) in 9 ml of MeOH-H20 (8/1) was added sodium azide (30 mg, 0.60 mmol) followed by NH4CI (19 mg, 0.36 mmol) . The reaction mixture was heated at 80 ° C for 24 hours. The methanol was removed under vacuum in a rotary evaporator. The product mixture was taken up in ethyl acetate (15 ml) and H20 (15 ml). The aqueous layer, after separation, was extracted with ethyl acetate (15 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the compound of formula 13 as a white solid, 90 mg (0.11 mmol, yield 93%): (FABMS: m / e 804 (MH) + ).

The following scheme illustrates the preparation of the compounds mentioned in the following examples 50-54.

EXAMPLE 50 To a solution of the compound prepared in Example 49 (709 mg, 0.882 mmol) was added Pd (10% on carbon) powder (94 mg, 0.088 mmol). The suspension was stirred in H2 (1 atm) for 18 hours. The reaction mixture was filtered through Celite ™. Evaporation of the filtrate gave the title compound of formula 14 as a white solid, 670 mg (0.88 mol, 100% yield): FABMS: m / e 778 (MH +).

EXAMPLE 51 To a solution of the compound prepared in Example 50 (163 mg, 0.209 mmol) in CH 2 Cl 2 (10 mL) at 0 ° C was added thiocarbonyldiimidazole (43 mg, 0.242 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was removed. The product mixture was taken up in ethyl acetate and water. The organic layer was washed with a 5% K2CÜ3 solution and then brine, dried over magnesium sulfate and concentrated to give the compound of formula 15 as a white solid, 170 mg (0.207 mmol, 99% yield). The compound of formula 15 (168 mg, 0.205 mmol) was dissolved in acetone (6 ml) or followed by the addition of 3,4-dichlorophenacyl bromide (63 mg, 0.234 mmol) and sodium bicarbonate (38 mg, 0.417 mmol) . The reaction mixture was stirred at room temperature for 20 hours. The organic solvent was removed. The product mixture was taken up in ethyl acetate and washed with 5% K2CO3, brine, dried over magnesium sulfate and concentrated to give the crude product. Chromatography on silica gel (CHCl3-MeOH-NH4OH = 98/2 / 0.1) gave the compound of formula 16, wherein R is the white solid represented below, 90 mg (0.09 mmol, 44% yield): FABMS : m / e 1006 (MH +).

EXAMPLE 52 To a solution of the compound of formula d (225 mg, 0.274 mmol) in anhydrous methanol (10 ml) was added sodium methoxide (50 mg, 0.926 mmol). The solution was stirred for 10 minutes and cooled to 0 ° C. Methyl iodide (60 ml, 0.99 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred at room temperature for 7 hours. The organic solvent was removed. The product mixture was taken up in ethyl acetate and washed with 5% K2CO3, brine, dried over magnesium sulfate and concentrated to give the crude product. Chromatography on silica gel (CHCl3-MeOH-NH4OH = 97/3 / 0.1) gave the compound of formula 16, wherein R is methylthio as a white solid, 231 mg 80.277 mmol, yield 36%): FABMS: m / e 834 (MH +).

EXAMPLE 53 To a solution of the compound of formula 14 (250 mg, 0.321 mmol) in dichloroethane (10 ml) was added 2-thiophenecarboximidate hydrochloride (72 mg, 0.461 mmol), which was prepared by bubbling HCl gas through a solution of 2 g. -thiofen carbonitrile and ethanol (1.1 equivalent) for 2 hours and stirring at room temperature overnight. The suspension of the reaction mixture became clear by adding triethylamine (65 ml, 0.467 mmol). It was refluxed overnight. The product mixture was taken up in ethyl acetate and water, and the pH was adjusted to pH 9.5 and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate and concentrated to give the crude product. Chromatography on silica gel (CHCl3-MeOH-NH4OH = 99/1 / 0.1) gave the compound of formula 16, wherein R is 2-thienyl as a white solid, 92 mg (0.106 mmol, 33% yield): FABMS: m / e 870 (MH +).

EXAMPLE 54 ZnCl 2 (2 mg) was placed in a round bottom flask and heated until it was vacuum melted. After cooling to room temperature, a solution of the compound of formula 14 (236 mg, 0. 303 mmol) and 2-cyanopyridine (49 mg, 0.467 mmol) in chlorobenzene (10 ml).

The reaction mixture was heated to reflux overnight. Water was added and adjusted to pH 2. After separation, the aqueous layer was adjusted to pH 9.5 and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate and concentrated to give the crude product. Silica gel chromatography (CHCl3-MeOH-NH4OH = 98/2 / 0.1) gave the compound of formula 16, wherein R is 2-pyridyl as a white solid, 47 mg (0.054 mmol, yield 18%): FABMS: m / e 865 (MH +).

EXAMPLE 55 To a solution of the compound of formula 14 (383 mg, 0.492 mmol) in methanol (5 ml) was added dropwise a solution of cyanogen bromide (57 mg, 0.538 mmol) and sodium acetate (90 mg, 1.097 mmol) in methanol (5 ml). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the solid was taken up in ethyl acetate and water and the pH was adjusted to pH 9.5 with a 10% K2C03 solution. The organic extract was washed with brine, dried over magnesium sulfate and concentrated to give the crude product. Chromatography on silica gel (CHCl3-MeOH-NH4OH = 96/4 / 0.1) gave the compound of formula 16, wherein R is amino as a white solid, 124 mg (0.155 mmol, yield 31%): FABMS: m / e 803 (MH +). The following scheme illustrates the preparation of the compounds mentioned in the following Examples 56-63: EXAMPLE 56 A solution of compound of formula 17 (3 g, 3.7 mmol) in 30 ml of MeOH was heated at 50 ° C overnight with 2.25 g (37.5 mmol) of ethylenediamine and 6.21 g (37.1 mmol) of potassium iodide. The MeOH was evaporated from the resulting mixture and the residue was dissolved in CH2Cl2 and washed with brine. After drying over Na 2 SO 4, the CH CI 2 was evaporated at reduced pressure. The residue was chromatographed over SiO2 (5% MeOH-CH2Cl2-0.5% NH4OH-> 10% MeOH-CH2Cl2-1% NH4OH) giving 2.72 g (88%) of the compound of formula 18, wherein Y is -NH- : MS m / e 821 (M + 1).

EXAMPLE 57 A solution of the compound prepared in Example 56 (1.0 mg, 1.2 mmol), o-anisaldehyde (174 mg, 1.3 mmol) and sodium acetate (100 mg, 1.2 mmol) in 20 mL of CH 2 Cl 2 was stirred at room temperature for 1 hour . To this solution was added 388 mg (1.8 mmol) of sodium triacetoxyborohydride. After 2.5 hours of stirring at room temperature, the reaction mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. After drying over Na 2 SO 4, the organic solvent was removed. The residue was chromatographed twice over SiO2 (2% MeOH-CH2Cl2-0.2% NH4OH). The material was subsequently purified by preparative plates of Si02 (10% MeOH-CH2Cl2-1% NH4OH) to give 660 mg (58%) of the compound of formula 19, wherein Y is -NH-, Y1 is H and Y2 is 2 -methoxy-benzyl: MS m / e 940 (M + 1).

EXAMPLES 58-59 As analogous methods to that of Example 57, substituting o-anisaldehyde with p-trifluoromethylbenzaldehyde and p-phenoxybenzaldehyde, examples 58 and 59 respectively were prepared, wherein said compounds, having the general structure of formula 19, Y and Y1 were what is defined for the compound of example 57 and Y2 and are indicated below.

EXAMPLE 60 A solution of the compound prepared in Example 57 above (468 mg, 0.5 mmol), isobutyraldehyde (36 mg, 0.5 mmol) and sodium acetate (42 mg, 0.5 mmol) in 5 mL of CH2Cl2 was stirred at room temperature for 1.5 hours. To this solution was added 164 mg (0.77 mmol) of sodium triacetoxyborohydride. After stirring at room temperature for 0.5 hours, the reaction mixture was diluted with CH 2 Cl 2 and washed with a solution of NaHC 3 and brine. After drying over MgSO 4, the solvent was removed under reduced pressure. The residue was chromatographed on Si02 (4% MeOH-CH2Cl2-0.4% NH4OH) to give 256 mg (51%) of the compound of formula 19, wherein Y is NH-, Y1 is 2-methylpropyl and Y2 is 2-methoxy benzyl MS m / e 966 (M + 1).

EXAMPLE 61 A solution of the compound of formula 20 (522 mg, 0.65 mmol), 2-phthalidomidietanothio (1.08 g, 5.2 mmol) and potassium iodide (865 mg, 5.2 mmol) in 5 mL of MeOH was heated under N2 for 48 hours. The MeOH was then removed under reduced pressure and the residue was dissolved in CH2Cl2 and washed with a solution of NaCOH3 and brine. After drying over MgSO4, CH2Cl2 was removed under reduced pressure. The obtained residue was dissolved in 10 ml of EtOH and treated with 7.5 ml of hydrazine hydrate. After stirring at room temperature for 3 hours, the EtOH was removed under reduced pressure and the extract was extracted with CH2Cl2. The organic layer was washed with brine and dried over MgSO 4. A chromatography Si02 of the residue (4% MeOH-CH2Cl2-0.4% NH4OH -> 5% MeOH-CH2Cl2-0.5% NH4OH) gave 287 mg (53%) of the compound of formula 18, wherein Y is S: EM m / e 837 (M + 1).

EXAMPLE 62 Following a method analogous to that of example 57 and starting from the compound of example 60, a compound of formula 19 was obtained, in which Y is S, Y1 and Y2 are both 2-methoxybenzyl (yield 79%, EM m / e 957 (M + 1)) and a compound of formula 19, wherein Y is S, Y1 is H, and Y2 is 2-methoxybenzyl (yield 3%, Em m / e 1077 (M + 1)).

EXAMPLE 63 In a method analogous to that of example 60 and starting from the compound of formula 19, in which Y is S, Y1 is H and Y2 is 2-methoxybenzyl and propionaldehyde, the compound of formula 19 was obtained, wherein Y is S, Y1 is n-propyl, and Y2 is 2- methoxybenzyl with a yield of 70%, MS m / e 999 (M + 1). The following scheme illustrates the preparation of the compounds mentioned in the following Examples 64-72.

EXAMPLE 64 Starting from the compound of formula 12, the compound of formula 20 was prepared, wherein Y = NH using a procedure analogous to the procedure described in example 56 with a yield of 35%; MS m / e 821 (M + 1).

EXAMPLE 65 Using a procedure analogous to that described in example 63 and starting from the product of example 64, the compound of formula 21 was obtained, in which Y is NH, Y1 is H and Y2 is 2-methoxybenzyl, with a yield of M6%; MS m / e 942 (M + 1).

EXAMPLE 66 Using a procedure analogous to that described in example 63 and starting from the product of example 64 and p-trifluoromethylbenzaldehyde, the compound of formula 21 was obtained, in which Y is NH, Y1 is H and Y2 is 4-trifluoromethylbenzyl with a yield of 18%; MS m / e 980 (M + 1).

EXAMPLE 67 A solution of the product of Example 64 (145 mg, 0.18 mmol) and o-anisaldehyde (122 mg, 0.9 mmol) in 10 mL of EtOH was stirred at room temperature overnight. The EtOH was removed under reduced pressure and the residue was dissolved in 5 ml of MeOH. Sodium borohydride (34 mg, 0.9 mmol) was added and the mixture was stirred at room temperature for 2 hours. The MeOH was removed under reduced pressure and the residue was dissolved in CH 2 Cl 2 and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated. Chromatography on Si02 (5% MeOH-CH2Cl2-0.2% NH4OH) of the residue gave 104 mg (54%) of the compound of formula 2 _, wherein Y is NH, and Y1 and Y2 are 2-methoxybenzyl, the compound of Title; MS m / e 1061 (M + 1).

EXAMPLE 68 Following a procedure analogous to that of Example 61, the compound of formula 20 was obtained, in which Y is S, with a yield of 63%; MS m / e 838 (m + 1).

EXAMPLE 69 Following a procedure analogous to that of Example 57, the compound of formula 21 was prepared, in which Y is S, Y1 is H and Y2 is 2-methoxybenzyl, with a yield of 28%; MS m / e 958 (m + 1).

EXAMPLE 70 A solution of the product from Example 64 (80 mg, 0.1 mmol), o-anisaldehyde (136 mg, 1 mmol), sodium acetate (64 mg, 0.78 mmol) and sodium triacetoxyborohydride (64 mg, 0.3 mmol) was stirred at room temperature. ambient. The resulting solution was diluted with CH2Cl2 and washed with a saturated solution of Na2CO3 and brine. The organic layer was dried over K2CO3 and evaporated. The residue was chromatographed on a Si02 plate (2.5% MeOH-methyl-t-butyl ether 2.5% triethylamine) to give 20 mg (19%) of the compound of formula 21, wherein Y is S, and Y1 and Y2 are 2 -methoxybenzyl; MS m / e 1078 (M + 1).

EXAMPLE 71 A solution of the product of Example 70 (31 mg, 0.03 mmol), formaldehyde (37% aqueous solution, 83 μL, 1 mmol) and formic acid (18 μL, 0.47 mmol) in 2 mL of CHCl3 was heated at 61 ° C for 1 hour. The reaction mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. After drying over K2C02 the solvents were removed under reduced pressure. The residue was chromatographed on a SiO2 plate (2.5% MeOH-CH2Cl2-2.5%) triethylamine to give 14 mg (45%) of the compound of formula 21, wherein Y is S, Y1 is methyl and Y2 is 2-methoxy. benzyl; MS m / e 972 (M + 1).

EXAMPLE 72 A solution of the compound of formula 12 (380 mg, 0.5 mmol) and magnesium perchlorate (223 mg, 1 mmol) in 5 ml of MeOH was refluxed under N2 for 9 days. The MeOH was removed under reduced pressure and the residue was dissolved in CH 2 Cl 2 and washed with water and brine. The residue was chromatographed on Si02 (5% MeOH-CH2Cl2-0.5% NH4OH) to give 25 mg (6%) of the configuration indicated below (MS m / e 793 (M + 1)): The following scheme illustrates the preparation of the compounds mentioned in the following Examples 73-75.

EXAMPLE 73 A solution of the compound of formula 17 (500 mg, 0.62 mmol), sodium azide (80 mg, 1.23 mmol) and lithium perchlorate (135 mg, 1.27 mmol) in 5 ml of acetonitrile was refluxed for 4 days. After evaporation of the acetonitrile, the residue was dissolved in CH 2 Cl 2 and washed with water and brine. The CH2Cl2 layer was dried over MgSO4 and concentrated. The residue was dissolved in 5 ml of MeOH and refluxed overnight.

The residue obtained after evaporation of the solvent was chromatographed on SiO2 (4% MeOH-CH2Cl2-0-4% NH4OH) to give 218 mg (445) of the compound of formula 22; MS m / e 803 (M + 1).

EXAMPLE 74 A solution of the compound of formula 23 (250 mg, 0.311 mmol) in 15 ml of EtOH was hydrogenated in the presence of 30 mg of 10% Pd / C in a Parr shaker. After 2 hours at room temperature, the reaction mixture was filtered through Celite ™ and the solvent was removed under reduced pressure. The residue was chromatographed on Si02 (98% MeOH-CH2CI2-0.8% NH4OH) to give 140 mg (58%) of the compound of formula 23; MS m / e 777 (M + 1).

EXAMPLE 75 Following a procedure analogous to that of example 57 and using the compound of formula 26 as a starting material, the compound of formula 24 was prepared, in which Y1 is H and Y2 2-methoxybenzyl, with a yield of 43%; MS m / e 897 (M + 1).

Claims (28)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula or a pharmaceutically acceptable salt thereof, wherein: X is -CH (NR9R10) -, -C (O) -, C (= NOR9) -, -CH2NR9, or -N (C? -C? alkyl) CH2- wherein the first line of each of the above compounds X groups is attached to the carbon C-10 of the compound of formula 1 and the last line of each group is attached to the carbon C-8 of the compound of formula 1; R1 is H, hydroxy or methoxy; R is hydroxy; R3 is C1-C10 alkyl, C2-C-? Alkyl, C2-C10 alkynyl, cyano, CH2S (0) nR8, wherein n is an integer ranging from 0 to 2, CH2OR8, -CH2N (OR9) R8, -CH2NR8R15, - (CH2) m (C6-C10 aryl), or - (CH2) m (heteroaryl of 5-10 elements, wherein m is an integer ranging from 0 to 4 and in which the previous R3 groups are optionally substituted with 1 to 3 R16 groups: or R2 and R3 are joined to form an oxazolyl ring as shown below. R 4 is H, -C (0) -R 9, -C (0) OR 9, -C (0) NR 9 R 10 or a hydroxy protecting group; R5 is -SR8 '(CH2) nC (0) R8, wherein n is 0 or 1, CC? 0 alkyl, C2-C? Alkenyl, C2-C10 alkynyl, - (CH2) m (C6-C aryl) ? 0) or - (CH2) rt, (heteroaryl of 5-10 elements), wherein m is an integer ranging from 0 to 4, and in which the above R5 groups are optionally substituted with groups 1 to 3 R16 groups; each R6 and R7 is independently H, hydroxy, C -? - C6 alkoxy, d-C? alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CH2) m (C6-C? 0 aryl) or - (CH2) m (heteroaryl of 5-10 elements), wherein m is an integer ranging from 0 to 4; each R8 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) qCR11R12 (CH2) rNR13R14, wherein q and each are independently an integer ranging from 0 to 3 , except that q and r are not any of them 0, - (CH2) m (aryl C6-C-? o) or - (CH2) m (heteroaryl of 5-10 elements (), where m is integer that oscillates from 0 to 4 and in which the above R8 groups, except H, are optionally substituted with 1 to 3 R16 groups, or where R8 is -CH2NR8R15, R15 and R8 can be taken together to form a monocyclic saturated ring of 4-10 elements or a saturated polycyclic ring 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 including 1 or 2 double or triple carbon-carbon bonds and said saturated and heteroaryl rings being optional lly substituted with 1 to 3 R16 groups; each R 9 and R 10 is independently H or C 1 -C 2 alkyl; each R 11, R 12, R 13 and R 14 are independently selected from H, C 1 -C 10 alkyl, - (CH 2) m (C 1 -C 1 aryl) and - (CH 2) m (5-10 element heteroaryl), wherein m is an integer ranging from 0 to 4 and in which groups R11, R12, R13, and R14 above, except H, are all optionally substituted with 1 to 3 R + 16 groups; or R11 and R13 are taken together to form - (CH2) P-, wherein p is an integer ranging from 0 to 3, said ring being saturated with 4-7 elements such that it optionally includes 1 or 2 doubles or triple carbon-carbon bonds; or R13 and R14 are joined to form a saturated monocyclic or polycyclic ring of 4-10 elements or a 5-10 membered heteroaryl ring, wherein said saturated rings and heteroaryls 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 including 1 or 2 double or triple carbon-carbon bonds and said saturated rings and heteroaryls being optionally substituted with 1 to 3 R16 groups; R 15 is H, C 1 -C 12 alkyl, C 2 -C 10 alkenyl or C 2 -C 0 alkynyl, wherein the above R 15 groups are optionally substituted with 1 to 3 substituents independently selected from halo and -OR 9; each R16 is independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) R17, -C (0) OR17, -OC (0) OR17, -NR6C (0) R7, -C (0) NR6R7, -NR6R7, hydroxy, CrC6 alkyl, CrC6 alkoxy, - (CH2) m (aryl Ce-Cu,) and - (CH2) m (heteroaryl of 5-10 elements), wherein m is an integer ranging from 0 to 4 and wherein said aryl and heteroaryl substituents are optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, nitro, trifluromethyl, azido, --C (0) R17, -C (0) OR17, -OC (0) OR17, -NR6C (0) R7, -C ( 0) NR6R7, -NR6R7, hydroxy, C6 alkyl, C6 alkoxy; each R 17 is independently selected from 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) ), where m is an integer that ranges from 0 to 4; with the proviso that R8 is not H when R3 is CH2S (0) nR8.

2. The compound of claim 1, wherein R4 is H, acetyl or benzyloxycarbonyl.

3. The compound of claim 2, wherein R1 is hydroxy, R2 is hydroxy, R3 is -CH2NR1 R8 or -CH2SR8.

4. The compound of claim 3, wherein R3 is -CH2NR15R8 and R15 and R8 are independently selected from H, d-Cio alkyl, C1-C10 alkenyl, C2-C20 alkenyl, and C2-C10 alkynyl, in the that the above groups R15 and R8, except H, are optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen and Ci-Ce alkoxy.

5. The compound of claim 4, wherein R15 and R8 are each independently selected from H, methyl, ethyl, allyl, n-butyl, isobutyl, 2-methoxyethyl, cyclopentyl, 3-methoxypropyl, 3- ethoxypropyl, n-propyl, isopropyl, 2-hydroxyethyl, cyclopropyl, 2,2,2-trifluoroethyl, 2-propinyl, sec-butyl, fer-butyl and n-hexyl.

6. The compound of claim 2, wherein R1 is hydroxy, R2 is hydroxy, R3 is -CH2NHR8 and R8 is - (CH2) (aryl Ce-Cio), wherein m is an integer ranging from 0 to 4.

7 '.- The compound of claim 6, wherein R8 is phenyl or benzyl.

8. The compound of claim 2, wherein R 1 is hydroxy, R 2 is hβydroxy, R 3 is -CH 2 NR 15 R 8 and R 15 and R 8 together form a saturated ring of 4-7 elements.

9. The compound of claim 8, wherein R15 and R8 together form a piperidino, trimethylenimino or morpholino ring.

10. The compound of claim 2, wherein R1 is hydroxy, R2 is hydroxy, R3 is -CH2NR15R8 and R15 and R8 are taken together to form a 5-10 membered heteroaryl ring optionally substituted with 1 or 2 alkyl groups C2-Cß.

11. The compound of claim 10, wherein R15 and R8 are taken together to form a pyrrolidino, triazolyl or imidazolyl ring, wherein said heteroaryl groups are optionally substituted with 1 or 2 methyl groups.

12. The compound of claim 2, wherein R1 is hydroxy, R2 is hydroxy, R3 is -CH2SR8 and R8 is selected from C1-C10 alkyl, alkenyl C2-C ?o and C2-C- alqu 0 alkynyl, wherein said R8 groups are optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen and C Cß alkoxy.

13. The compound of claim 12, wherein R8 is methyl, ethyl or 2-hydroxyethyl.

14. The compound of claim 2, wherein R1 is hydroxy, R2 is hydroxy, R3 is selected from C1-C10 alkyl, C2-C20 alkenyl, and C2-C20 alkynyl, wherein said groups R3 are optionally substituted with 1 or 2 substituents independently selected from hydroxy, -C (0) R17, -NR6R7, halogen, cyano, azido, heteroaryl of 5-10 elements and alkoxy CI-CT.

15. The compound of claim 14, wherein R3 is methyl, allyl, vinyl, ethynyl, 1-methyl-propenyl, 3-methyxy-1-propynyl, 3-dimethylamino-1-propynyl, 2-pyridylethynyl, 1 - propynyl, 3-hydroxy-1-propynyl, 3-hydroxy-1-propynyl, 3-hydroxypropyl, 3-methoxy-1-propenyl, 3-methoxypropyl, 1-propynyl, n-butyl, ethyl, propyl, -hydroxyethyl, azidomethyl, forylmethyl, 6-cyano-1-pentynyl, 3-dimethylamino-1-propenyl or 3-dimethylaminopropyl.

16. The compound of claim 2, wherein R1 is hydroxy, R 2 is hydroxy and R 3 - (CH 2) m (Ce-Cι aryl), wherein m is an integer ranging from 0 to 4.

17. The compound of claim 16, wherein R 3 is 2-thienyl. , 2-pyridyl, 1-methyl-2-imidazolyl, 2-furyl or 1-methyl-2-pyrrolyl.

18. The compound of claim 2, wherein R1 is hydroxy, R 2 is hydroxy and R 3 is - (CH 2) m (C 6 -C 0 aryl), wherein m is an integer ranging from 0 to 4.

19. The compound of claim 18, wherein R 3 is phenyl.

20. The compound of claim 2, wherein R2 and R3 are taken together to form an oxazolyl ring as shown below

21. - The compound of claim 2, wherein R3 is selected from the following: wherein X3 is O, S or -N (R15) -, R9 and R15 are as defined in claim 1 and the -OR9 group can be attached to any available carbon of the phenyl group.

22. A pharmaceutical composition for the treatment of a bacterial infection or a protozoal infection in a mammal, fish or bird comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

23. The use of a compound of claim 1 in the manufacture of a medicament for treating a bacterial infection or a protozoal infection in a mammal, fish or bird.

24.- A method for the preparation of a compound of formula or a pharmaceutically acceptable salt thereof, wherein: X is -CH (NR9R10) -, -C (O) -, C (= NOR9) -, - CH2NR9, or -N (C6 alkyl) CH2- in the that the first line of each of the above groups X is attached to the carbon C-10 of the compound of formula 1 and the last line of each group is attached to the carbon C-8 of the compound of formula 1; R1 is H, hydroxy or methoxy; R2 is hydroxy; R3 is CiC-io alkyl, C2-C? Alkenyl, C2-C alqu alkynyl, cyano, -CH2S (0) nR8, wherein n is an integer ranging from 0 to 2, CH2OR8, -CH2N ( OR9) R8, -CH2NR8R15, - (CH2) m (C6.-c10 aryl), or - (CH2) m (heteroaryl of 5-10 elements, wherein m is an integer ranging from 0 to 4 and in those which the above R3 groups are optionally substituted with 1 to 3 R16 groups, or R2 and R3 are taken together to form an oxazolyl ring as shown below R 4 is H, -C (0) R 9, -C (0) OR 9, -CONR 9 R 10 or a hydroxy protecting group; R5 is -SR8, - (CH2) nC (0) R8, wherein n is 0 or 1, CrC10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) (C6-C6 aryl) or - (CH2) m (heteroaryl of 5-10 elements), wherein m is an integer ranging from 0 to 4, and in which the groups R5 above are optionally substituted with 1 to 3 groups R16; each R6 and R7 is independently H, hydroxy, CrC6 alkoxy, C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CH2) m (C6-C? 0 aryl) or - (CH2) m (heteroaryl) -10 elements), where m is an integer that ranges from 0 to 4; each R8 is independently H, CrC10 alkyl, C2-C? alkenyl, C2-C10 alkynyl, - (CH2) qCR11R12 (CH2) rNR13R14, wherein q and r are each independently an integer ranging from 0 to 3 , except that q and r are not any of them O, - (CH2) m (aryl C2-C? 0) or - (CH2) m (heteroaryl of 5-10 elements), where m is an integer that ranges from 0 to 4 and in which the above R8 groups, except H, are optionally substituted with 1 to 3 R16 groups; or when R8 is -CH2NR8R15, R15 and R8 can be taken together to form a saturated monocyclic ring or a 5-10 membered heteroaryl ring, where 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 including 1 or 2 double or triple carbon-carbon bonds and said saturated rings and heteroaryls being optionally substituted with 1 to 3 R16 groups; each R9 and R10 is independently H or CrC6 alkyl, each R11, R12, R13 and R14 is independently selected from H, C -? - C10 alkyl, - (CH2) m (C6-C? o aryl) and - (CH2) m (heteroaryl of 5-10 elements), wherein m is an integer ranging from 0 to 4 and in which the groups R11, R12, R13 and R14 above, except H, are all optionally substituted with 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, said saturated ring of 4-7 elements being formed in such a way that it optionally includes 1 or 2 double or triple carbon-carbon bonds; or R13 and R14 are taken together to form a saturated monocyclic or polycyclic ring of 4-10 elements or a 5-10 membered heteroaryl ring, wherein said saturated rings and heteroaryls 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 including 1 or 2 double or triple carbon-carbon bonds and said saturated rings and heteroaryls being optionally substituted with 1 to 3 R16 groups; R 15 is H, C 1 -C 10 alkyl, C 2 -C 20 alkenyl or C 2 -C 8 alkynyl, wherein the above R 15 groups are optionally substituted with 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, -OC (0) OR17, -NR6C (0) R7, -C (0) NR6R7 , -NR6R7, hydroxy, CrC6alkyl C6alkoxy, - (CH2) m (aryl Ce-Cio) and - (CH2) m (heteroaryl of 5-10 elements), wherein m is an integer ranging from 0 to 4 and wherein said aryl and heteroaryl substituents are optionally substituted with 1 or 2 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (0) R17, -C (0) OR17, -OC (0) OR17 , -NR6C (0) R7, -C (0) NR6R7, -NR6R7, .hydroxy, CrC6 alkyl, and C6Calkoxy; each R 17 is independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 2 -C 8 alkynyl, - (CH 2) m (C 6 -C 0 aryl) and - (CH 2) m (5-10 heteroaryl) elements), where m is an integer that ranges from 0 to 4; with the proviso that R8 is not H when R3 is -CH2S (0) nR8; comprising the treatment of a compound of formula wherein X, R1 and R4 are as defined above, with a compound of formula HOR8, HSR8 or HNR15R8, wherein n, R15 and R8 are as defined above, wherein if said compound of formula HSR8 is used, the resulting group R3 of formula -CH2SR8 is optionally oxidized to -CH2S (0) R8 or -CH2S (0) 2R8.

25. The method of claim 24, wherein the compound of formula 3 is prepared by treating a compound of formula wherein X, R1 and R4 are as defined in claim 24, with (CH3) 3S (0) nX2, wherein n is 0 or 1 and X2 is halogen, -BF4 or -PFβ, in the presence of a base .

26. The method of claim 25, wherein X2 is iodine or BF4 and said base is selected from potassium tert-butoxide, sodium 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 hexamethyldisilazide (KHMDS), potassium ethoxide and sodium methoxide.

27. - A compound of formula or a pharmaceutically acceptable salt thereof, wherein: X is -CH (NR9R10) -, -C (O) -, -C = (NOR9) -, -CH2NR9-, or -N- (alkyl d-Ce) , wherein the first line of each of the above groups X is attached to the carbon C-10 of the compound of formula 3 and the last line of each group is attached to the carbon C-8 of the compound of formula 3: R1 is hydroxy or methoxy; R 4 is H, -C (0) R 9, -C (0) OR 9, -C (0) NR 9 R 10 or a hydroxy protecting group; every R9 and R > 10 is independently H or CrC6 alkyl.

28. - A compound of formula or a pharmaceutically acceptable salt thereof, wherein: X is -CH (NR9R10) -, -C (O) -, C (= NOR9) -, -CH2NR9, or -N (C6 alkyl) CH2- wherein the first line of each of the foregoing groups X is attached to the carbon C-10 of the compound of formula 2 and the last line of each group is attached to the carbon C-8 of the compound of formula 2, with the proviso that X does not either -CH2N (CH3) - or -N (CH3) CH2) -; R1 is H, hydroxy or methoxy; R 4 is H, -C (0) -R 9, -C (0) OR 9, -C (0) NR 9 R 10 or a hydroxy protecting group; each R9 and R10 is independently H or C6 alkyl;