MXPA99011495A

MXPA99011495A - 4"-substituted-9-deoxo-9a-aza-9a-homoerythromycin a derivatives

Info

Publication number: MXPA99011495A
Application number: MXPA/A/1999/011495A
Authority: MX
Inventors: Kaneko Takushi; Scott Bronk Brian; Anthony Letavic Michael; Vera Yang Bingwei; Cheng Hengmiao; Alan Glazer Edward
Original assignee: Scott Bronk Brian; Alan Glazer Edward; Kaneko Takushi; Anthony Letavic Michael; Pfizer Products Inc; Vera Yang Bingwei
Priority date: 1997-06-11
Filing date: 1999-12-09
Publication date: 2001-05-17

Abstract

Estáinvención se refiere a compuestos de fórmula (Ver Fórmula) y a sales farmacéuticamente aceptables de los mismos;los compuestos de fórmula I son agentes antibacterianos que pueden usarse para tratar diversas infecciones bacterianas y protozoarias;la invención también se refiere a composiciones farmacéuticas que contienen los compuestos de fórmula 1 y a procedimientos para tratar las infecciones bacterianas y protozoarias administrando los compuestos de fórmula 1;la invención también se refiere a procedimientos para preparar los compuestos de fórmula 1 y a los intermediosútiles para dicha preparación.

Description

DERIVATIVES OF 9-DESOXO-9A-AZA-9A-HOMOERITROMIC1NA A C-4"SUBSTITUTE BACKGROUND OF THE INVENTION This invention relates to novel substituted 9-deoxo-9a-aza-9a homo-cytochromin A C-4 derivatives which are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. It relates to pharmaceutical compositions containing the novel compounds and methods for the treatment of bacterial and protozoal infections in mammals, fish and birds, by administering the new compounds to mammals, fish and birds in need of 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 U.S. Patents 4,474,768 and 4,517,359, which are incorporated herein by reference in their entirety. to azithromycin and other macrolide antibiotics, the new macrolide compounds 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: R1 is H, hydroxy or methoxy; R2 is hydroxy; R 3 is C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, cyano, -CH 2 S (O) n R 8, wherein n is an integer ranging from 0 to 2, -CH 2 OR 8, -CH 2 N (OR9) R8, -CH2NR8R15, - (CH2) m- (C6-C10 aryl), or - (CH2) m (heteroaryl of 5-10 links), wherein m is an integer ranging from 0 to 4 and wherein the above R3 groups are optionally substituted with 1 to 3 R16 groups; or R2 and R3 are linked 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, C1-C10 alkyl, C2-C20 alkenyl, C2-C10 alkynyl, - (CH2) m- (ar! C6-C10) or - (CH2) m (heteroaryl of 5-10 links), where m is an integer ranging from 0 to 4, and in which the R5 groups above are optionally substituted with 1 to 3 R16 groups; each R6 and R7 is independently H, hydroxy, CrCd alkoxy, Ci-Cß alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CH2) m (C C-C-io aryl) or - (CH 2) m (heteroaryl 5-10 links), where m is an integer that varies from 0 to 4; each R8 is independently H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) qCR'I1R'l2 (CH2) rNR13R14, wherein q and r are each independently an integer ranging from 0 to 3, except that q and y are not both 0, - (CH2) m (C C-C-io) or - (CH 2) m (5-10-membered heteroaryl), where m is a integer ranging 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 linked to form a monocyclic or polycyclic saturated ring of 4-10 links or a 5-10 membered heteroaryl ring, wherein said heteroaryl and saturated 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, including optionally said saturated ring 1 or 2 double or triple carbon-carbon bonds and said saturated rings and heteroaryls being optionally substituted with 1 to 3 R 6 groups; each R9 and R10 is independently H or C-? -C6 alkyl; each R11, R12, R13 and R14 is independently selected from H, C1-C10 alkyl, - (CH2) m (C6-C10 aryl) and - (CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4 and in which the groups R11, R12, R13 and R14 above, except H, are optionally substituted with 1 to 3 R16 groups; or R11 and R13 are joined forming - (CH2) P-, where p is a number ranging from 0 to 3, such that a 4-7-membered saturated ring is formed which optionally includes 1 or 2 double or triple bonds carbon-carbon; or R13 and R14 are bonded to form a monocyclic or polycyclic saturated ring of 4-10 links 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; R15 is H, C1-C10 alkyl, C2-C2 alkenyl, or C2-C10 alkynyl, wherein the above R5 groups are optionally substituted with 1 to 3 substituents independently selected from halogen and -OR9; each R16 is independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R17, -C (O) OR17, -C (O) OR17, -OC (O) OR17, -NR6C (O) R7 , -C (O) NR6R7, -NR6R7, hydroxy, C? -C6 alkyl, C? -C6 alkoxy, - (CH2) m (C6-C? 0 aryl) and - (CH2) m (5-10 heteroaryl) links), 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 (O) R17, -C (O) OR17, -C (O) OR17, -OC (O) OR17, -NR6C (O) R7, -C (O) NR6R7, -NR6R7, hydroxy, C? -C6 alkyl, and alkoxy C C6; each R 17 is independently selected from H, Ci-C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 10 alkynyl) - (CH 2) m- (C 6 -C 0 aryl) and - (CH 2) m (heteroaryl 5- 10 links), where m is an integer that varies from 0 to 4; provided 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 CH2NR15R8, -CH2SR8 and R4 is H. Other preferred compounds of formula 1 include those in which R1 is hydroxy, R2 is hydroxy, R3 is -CH2NR15R8, R4 is ^ HHH are each selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl and C 2 -C 0 alkynyl, wherein said groups R 15 and R 8, except H, are optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen and CrC6 alkoxy. Specific preferred compounds having the above general structure include those in which R15 is 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-propinyl, sec-butyl, fer-butyl and n-hexyl. Other preferred compounds of formula 1 include those in which R1 is hydroxy, R2 is hydroxy, R3 is CH2NHR8, R4 is H, and R8 is - (CH2) m (C ar-C-io aryl), wherein m is a 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 R 1 is hydroxy, R 2 is hydroxy, R 3 is -CH 2 NR 15 R 8, R 4 is H, and R 15 and R 8 are linked to form a saturated ring. Preferred specific compounds having the above general structure include those in which R6 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 CH2NH15R8, R4 is H, and R15 and R8 are bonded to form a heteroaryl ring optionally substituted with 1 or 2 C-i-Cß alkyl groups. Preferred specific compounds having the above general structure include those in which R15 and R8 are linked to form a pyrrolidino, triazolyl or imidazolyl ring, wherein said heteroaryl groups are optionally substituted with 1 or 2 methyl groups.

Other preferred compounds of formula 1 include those in which R1 is hydroxy, R2 is hydroxy, R3 is -CH2SR8, R4 is H, and R8 is selected from C1-C10 alkyl, C2-C20 alkenyl, and C2-C alkynyl? , wherein said R8 groups are optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen and C-? -C6 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 wherein 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 10 alkynyl, wherein said 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 CTCT alkoxy. Preferred specific compounds having the above general structure include those in which R3 is methyl, allyl, vinyl, ethynyl, 1-methyl-1-propenyl, 3-methoxy-1-propynyl, 3-dimethylamino-1-propynyl, -pyridylethynyl, 1-propynyl, 3-hydroxy-1-propynyl, 3-hydroxy-1-propenyl, 3-hydroxypropyl, 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 R 1 is hydroxy, R 2 is hydroxy, R 4 is H, and R 3 is - (CH 2) m (heteroaryl of 5-10 links), wherein m is a varying integer from 0 to 4. Preferred specific compounds having the above general structure they 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 I include those in which R 1 is hydroxy, R 2 is hydroxy, R 4 is H, and R 3 is - (CH 2) m (Ce-Cι aryl), wherein m is a varying integer 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 which R2 and R3 are linked to form an oxazolyl ring as shown below. where R is as defined above. Specific compounds of formula include those in which R3 are selected from the following: wherein X3 is O, S or -N (R15) -, and the group -OR9 can be attached to any avble carbon of the phenyl group. The invention also relates to 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 formula I 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 administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The term "treatment", as used herein, unless otherwise indicated, includes the treatment or prevention of 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)" and "protozoan infection (s)" includes bacterial infections and protozoal infections that are they produce in mammals, fish and birds, as well as disorders related to bacterial infections and protozoal infections that can be treated or avoided by administering antibiotics, such as the compounds of the present invention. Said bacterial infections and protozoal infections, and disorders related to such infections include the following: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis, related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp .; pharyngitis, rheumatic fever and glomerulonephritis associated with infection by Streptococcus pyrogenes, streptococci of groups C and G, Clostridium diphtheriae or Actinobacillus haemoluticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis and puerperal fever related to Staphylococcus aureus infection, coagulase-positive Staphylococci (ie, S. epidermis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, groups of CF streptococci (minute colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; urinary tract infections 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 Neisseria gonorrheae; diseases caused by toxins related to infection by S. aureus (intoxicated foods and toxic shock syndrome) or streptococci of groups A, B and C; ulcers related to infection by Helycobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to Borrelia burgdoríeri infection; conjunctivitis, keratitis and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhea, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae or Listeria spp .; Mycobacterium avium disseminated complex (MAC) related to infection by Mycobacterium avium or Mycobacterium intracellulare; gastroenteritis related to Campylobacter jejuni infection; intestinal protozoa related to infection by Cryptosporidium spp., odontogenic infection related to viridans streptococcal infection; persistent cough related to Bordetella pertussis infection; gaseous 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.); mastitis of dairy cows related to infection by S. aureus, S. uberis, S. agalactiae, S. dysgalactiae, Klebsiella spp., Corynebacterium or Enterococcus spp .; the 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 infections (eg, neosporium); urinary tract infection in dogs and cats related to E. coli infection; infections of the skin and white tissues 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 infection by Alcaligenes spp. ., Bacterioides spp, Clostridium spp., Enterobacter spp., Eurobacterium, 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 J. P. Sanford et al., "The Sanford Guide To Antimicrobial Therapy". 26th edition (Antimicrobial Therapy, Inc., 1996). The present invention also relates to a process for the preparation of the above compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R3 is -CH2S (O) nR8, -CH2OR8 or -CH2NR8R15, wherein n, R15 and R8 are as defined above, provided that R is not H when R is -CH2S (O) nR comprising the treatment of a compound of formula wherein 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 the oxidation of the substituent -SR8 forming - S (O) R8 or -S (O) 2R8. In another aspect of the above preparation process of the compound of formula 1, or a pharmaceutically acceptable salt thereof, the above compound of formula 5 is prepared by treating a compound of formula wherein R1 and R4 are as defined above, with (CH3) 3S (O) nX2, wherein n is 0 or 1, and X2 is halogen, -BF4 or -PF6 preferably iodo or -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 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 4 and 5, which, as indicated above, are useful for the preparation of the above compounds 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 fluoro, chloro, bromo or iodo. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having linear, cyclic or branched moieties or mixtures thereof. same. It is assumed that when speaking of cyclic moieties, at least three carbons must be present in said alkyl. Such cyclic moieties are cyclopropyl, cyclobutyl and cyclopentyl. The term "alkoxy", as used herein, unless otherwise indicated, includes the groups - (O) -alkyl in which, "alkyl" is as defined above. The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl or naphthyl. The term "heteroaryl" of 5-10 links ", as used herein, unless otherwise indicated, includes aromatic heterocyclic groups containing one or more heteroatoms, each selected from O, S and N, in which each heterocyclic group has 5-10 atoms in its ring system Examples of heteroaryl groups of 5-10 appropriate links are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, (1, 2,3) - and (1 , 2,4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl and thiazolyl The phrase "pharmaceutically acceptable salt (s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention The compounds of the present invention which are basic in nature may form a wide variety of salts with various inorganic and organic acids. Acids which can be used to prepare the pharmaceutically acceptable acid addition salts of said basic compounds of the present invention are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as hydrochloride salts, Hydrobromide hydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate , benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie, 1, V-methylene-b] - (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 that are acidic in nature, they can form basic salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or 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 compositions pharmaceuticals and treatment procedures that can use or contain them. The present invention includes the compounds of the present invention and pharmaceutically acceptable salts thereof, wherein one or more hydrogen atoms, carbon and other atoms are substituted by their isotopes. Said compounds may be useful as research or diagnostic tools in pharmacokinetic studies of metabolism and in binding assays.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention can be prepared according to the following schemes 1-3 and the following description.

SCHEME 1 SCHEME 1 (CONTINUED) SCHEME 2 SCHEME 3 SCHEME 3 (CONTINUED) SQUEMA 3 (CONTINUED) The compounds of the present invention are prepared easily. With reference to the schemes illustrated above, the starting compound of formula 2 can be prepared according to procedures familiar to those skilled in the art, including one or more of the synthetic procedures described in U.S. Patents 4,474,768 and 4,517. .359, cited above. In step 1 of scheme 1, the C-2 'hydroxy group can be selectively protected by treating the compound of formula 2 with one equivalent of acetic anhydride in dichloromethane in the absence of an external base to give the compound of formula 3 in which R4 It 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 C-2 'hydroxy can also be protected with other protecting groups familiar to those skilled in the art, such as the benzyloxycarbonyl group (Cbz). The amino group C-9a may also require protection before other synthetic modifications are made. Suitable protecting groups for the amino moiety are the Cbz and t-butoxycarbonyl groups (Boc). To protect the amino group C-9a, the macrolide can be treated with t-butyl dicarbonate in anhydrous tetrahydrofuran (THF) or benzyloxycarbonyl N-hydroxysuccinimide ester or benzyl chloroformate to protect the amino group as its t-butyl carbamate or of benzyl. Both the amino C-9a 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 removed by acid treatment and the group Cbz can be removed by conventional catalytic hydrogenation. In the following description, it is assumed that the C-9a amino moiety, as well as the C-2 'hydroxy group, are protected and deprotected as deemed appropriate by those skilled in the art. In step 21 of scheme 1, the C-4 hydroxy group of the compound of formula 3 is oxidized to the corresponding ketone by procedures familiar to those skilled in the art, including one or more procedures described in the Journal of Antibiotics, 1988 , pages 1029-1047 For example, the ketone of formula 4 can be prepared with DMSO and an appropriate activating agent Typical reaction conditions for oxidation include: (a) oxidation of Moffatt using N-ethyl-N'- (N, N-dimethylaminopropyl) carbodiimide and DMSO in the presence of pyridinium trifluoroacetate, or (b) Swern oxidation in which the addition of DMSO in CH 2 Cl 2 is followed by the addition of triethylamine or, alternatively, trifluoroacetic anhydride and DMSO in CH2CI2, followed by the addition of triethylamine In step 3 of scheme 1, the compound of formula 4 is treated with R3MgX1 or R3-L1 and Mg (X1) 2, wherein X1 is halide, as chlorine or bromine, in a solvent such as THF, dimethyl ether ethylene glycol (DME), diisopropyl ether, toluene, diethyl ether or tetramethylethylenediamine (TMEDA), hexanes, or a mixture of two or more of the above solvents, preferably an ether solvent, at a temperature ranging from about -78 ° C to about the ambient temperature (20-25 ° C), giving the compound of Formula 1_, wherein R2 is hydroxy, R1, R3 and R4 are as defined above. Scheme 2 illustrates the preparation of the compounds of formula 1 by the use of an epoxy intermediate. In step 1 of scheme 2, the compound of formula 5 can be generated by two methods. In one of the processes (process A), the compound of formula 4 is treated with (CH 3) 3 S (O) X 2 is halogen, -BF 4 or -PF 6, preferably iodine, in the presence of a base such as potassium tert-butoxide, tert. sodium-sodium oxide, 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- eno, 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 methyl sulfoxide (DMSO) or a mixture of two or more of the above solvents , at a temperature in the range from about 0 ° C to about 60 ° C, giving the compound of formula 5, in which the following configuration of the epoxy radical predominates In a second procedure (method B), the compound of formula 4 is treated with (CH 3) 3 SX 2, wherein X 2 is halogen, -BF 4 or -P 6, preferably -BF 4, in the presence of a base such as potassium tert-butoxide, sodium ethoxide, sodium tert-butoxide, sodium hydride, 1, 1, 3,3-tetramethylguanidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5 -one, 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 -78 ° C to about 60 ° C, giving the compound of formula 5 in which the following configuration of the epoxy radical predominates.

In step 2 of scheme 2, the compound of formula 5 can be converted into a compound of formula 1 wherein R 2 is hydroxy and R 3 is a group that is attached to carbon C-4", through a methyl group, as when R3 is -CH2NR15R8 or -CH2S (O) nR8, wherein n, R15 and R8 are as defined above To prepare a compound of formula 1, wherein R3 is -CH2NR15R8, the compound of formula it 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 which varies 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 perchlorate, lithium tetrafluoroborate, pyridinium hydrochloride or a tetraalkylammonium 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 5 can be treated with a compound of formula HSR8 in the presence of K2CO3, Kl or sodium methoxide, in an aromatic solvent such as methanol, benzene or toluene at an ambient temperature up to approximately 120 ° C. If appropriate, the sulfur radical can be oxidized to -SO- or -SO2- according to procedures 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 group R8 are as defined above, the compound of formula 5 can be to treat with a compound of formula HS- (CH2) qCR11R12 (CH2) rNPhth, wherein NPhth represents phthalamido, and potassium iodide giving the compound of formula 1, wherein R3 is -CH2S (CH2) qCR11R12 (CH2) rNH2, after separating the phthalamido radical, which can be modified later if necessary. Using the same or an analogous procedure, 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 5 with a compound of formula HNR9 (CH2 ) qCR11R12 (CH2) rNR13R14 or a compound of formula H2N- (CH2) qCR11R12 (CH2) r-NH2 followed by a reductive alkylation of the nitrogen atoms. Using the same or an analogous procedure, a compound of the formula wherein R3 is -CH2OR8 and R8 is as defined above, can be prepared by treating a compound of formula 5 with a compound of formula HOR8. Scheme 3 illustrates the preparation of the compounds of formula 1 wherein R2 and R3 are linked to form an oxazolyl radical. In step 1 of scheme 3, the compound of formula 5 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 6. In step 2 of scheme 3, the compound of formula 6 can be converted to the corresponding amine of formula 7 by conventional catalytic hydrogenation. Preferably, said hydrogenation is done using Pd (10% on carbon) powder under H2 (101.3 kPa) atmosphere. The resulting amine of formula 7 can be converted to different compounds of formula 1, wherein R3 is -CH2NR15R8 using conventional synthetic procedures, such as a reductive amination. In step 3 of scheme 3, the compound of formula 7 can be converted to the compound of formula 1, wherein R2 and R3 are attached as shown, treating the compound of formula 7 with a compound of formula R5-CN, R5-C = N (OCH3), R5-C = N (OC2H5), R5-C (O) CI, or R5-CO2H, wherein R5 is as defined above, except that it is not NH2, in the presence or in the absence of an acid, such as HCl or a Lewis acid, such as ZnCI2 or BF4Et3O or a base, such as NaOH or TEA, in a solvent such as THF, a chlorinated hydrocarbon (such as CH2Cl2 or chlorobenzene), at a temperature ranging from about room temperature to reflux. Alternatively, the compound of formula 7 can be prepared as indicated in steps 4 and 5 of scheme 3. In step 4 of scheme 3, the compound of formula 7 is treated with thiocarbonyldiimidazole in methylene chloride at a temperature ranging from about 0 ° C to room temperature, giving the compound of formula 13. In step 5 of scheme 3, the compound of formula 13 is treated with R5-X1, wherein X1 is halide, such as bromine or iodine, and a base, such as sodium methoxide in a solvent such as methanol or acetone or a mixture of the two solvents, 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, an alcohol), separating the diastereoisomers and converting (eg, hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.

The use of all these isomers, including the diastereomeric mixtures and the pure enantiomers is considered part of the invention. The compounds of the present invention which are basic in nature can form a wide range of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to mammals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter into the pharmaceutically acceptable salt. 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. After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired salt can also be precipitated in a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution. The compounds of the present invention which are acidic in nature, can form 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 simply to a pharmaceutically acceptable salt according to a procedure analogous to that described with reference to conversion of pharmaceutically acceptable acid addition salts into pharmaceutically acceptable salts. Examples of basic salts are the alkali metal or alkaline earth metal salts and, especially, the sodium, amine and potassium salts. All these salts can be prepared by conventional techniques. The chemical bases that are used as reagents for preparing the pharmaceutically acceptable basic salts of this invention are those that form non-toxic base salts with the acidic compounds of the present invention. Said non-toxic basic salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, various cations of amines, etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired 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. Alternatively, they can also be prepared by mixing lower alkane solutions of the acidic compounds and the desired alkali metal alkoxide and then evaporating Dry the resulting solution in the same manner as before. In any case, stoichiometric amounts of reagents are preferably used in order to ensure the completion of the reaction and that the maximum yields of the desired final product are obtained. The antibacterial and antiprotozoal activity of the compounds of the present invention against pathogenic bacteria and protozoa is demonstrated by the ability of the compounds to inhibit the growth of defined strains of human pathogens (test I) or animals (assay II and III).

Assay I Assay I, described below, utilizes conventional methodology and interpretation criteria and is designed to provide guidance for chemical modifications that may result in compounds that circumvent defined mechanisms of macrolide resistance. In trial I, a group 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 group allows to determine the chemical structure / activity relation with respect to the pharmacological potency, spectrum of activities and structural elements or modifications that may be necessary to obviate the mechanisms of resistance. The bacterial pathogens that make up the selection group are presented in the following table. In many cases, both the parental strain susceptible to macrolides as the strain resistant to macrolides derived from it, to obtain a more accurate assessment of the ability of the compounds to circumvent the resistance mechanism. Strains containing genes with the designation ermA / ermB / ermC are resistant to macrolide antibiotics, lincosamides and streptogramin B due to modifications (methylation) of 23S rRNA molecules by an Erm methylase, so they generally prevent union of the three structural classes. Two types of macrolide entry mechanism have been described; msrA codes for a component of a system of the staphylococcal input mechanism that prevents the entry of macrolides and streptogramins, whereas mefA / E codes for a transmembrane protein that seems to allow only the macrolides to pass. Inactivation of macrolide antibiotics may occur, being able to be measured by a phosphorylation of the 2'-hydroxyl (mph) or by cleavage of the macrocyclic lactone (esterase). The strains can be characterized using the technology of the polymerase chain reaction (PCR) and / or sequencing the determinant 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 Chemoterapi, 40 (11), 2562-2566 (1996). The assay is performed in microtiter trays and is interpreted according to the Performance Standards guidelines of Antimjcrobial Disk Susceptibility Test-Sixth Edition: Approved Standards. published by the National Committee for the Patterns of Clinical Laboratories (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.

Test II This test is based on the procedure of liquid dilution in microtiter format. A single colony of P. multocida (strain 59A 067) is inoculated into 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 dilutions 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 by 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 that shows a 100% inhibition of the growth of P. multocida as determined by comparison with a non-inoculated control.

Test lll This assay is based on the agar dilution procedure 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 previously grown P. haemolytica culture is inoculated in 3 ml of broth Fresh IHB and incubate 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 are 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 P. haemolytica culture is inoculated on BHI agar plates containing various concentrations of the test compound using a Steers replicator and incubated for 18 hours at 37 ° C. The initial concentrations of the test compound vary from 100 to 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, generally carried out in mice. The mice are housed in cages (10 per cage) at the time of their arrival and are allowed to acclimate for a minimum of 48 hours before using them. The animals are inoculated intraperitoneally with 0.5 ml of a bacterial suspension with 3 x 10 3 CFU / ml (P. multocida strain 59A 006). Each experiment has at least 3 non-medicated control groups including one infected with an infection dose caused by 0.1 X and two infected with a dose of infection provoked 1X; an infection data set caused by 10X can also be used. Generally, all mice in a given study can become infected in 30-90 minutes, especially if a repeating syringe (such as a Comwall® syringe) is used to administer the dose. Thirty minutes after the infection started, the treatment with the first compound is administered. It may be necessary for a second person to start the compound administration if all animals have not yet been infected 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 induced infection. 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 model of P. multocida continues for 96 hours (four days) after the infection caused. The DP50 dose is a calculated dose in which the compound tested protects 50% of a group of mice from mortality due to bacterial infection that would be lethal in the absence of pharmacological treatment. The compounds of formula _ and the pharmaceutically acceptable salts thereof (hereinafter "the active compounds") are 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 (i.e. from 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 particular 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, variations occur depending on the species of mammal, fish or bird treated and their individual response to said medicament, 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 more appropriate, while in other cases higher doses may be used without causing any harmful side effects, assuming that said higher doses are first divided 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 especially, Active compounds can be administered in a wide range of different dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, dragees, tablets to dissolve in the mouth, hard candies, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents, etc. Also, the oral pharmaceutical compositions may be sweetened and / or flavored appropriately. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, may be used 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 gum arabic. In addition, 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 the gelatin capsules; the Preferred materials in this sense 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 so desired, also with emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions of an active compound in sesame or in peanut oil or in aqueous propylene glycol can be employed. Aqueous solutions should be suitably buffered (preferably at a pH above 8) if necessary, obtaining first an isotonic liquid diluent. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily done by conventional pharmaceutical techniques well known to those skilled in the art. In addition, it is also possible to administer the active compounds of the present invention topically and this can be done by creams, gelatins, gels, pastes, patches, ointments 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 are They can be administered in animal feed or orally in the form of a potion. 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 attached to soluble polymers as vehicles of the drug to direct it to a target. Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenyl, polyhydroxyethylaspartamide-phenol or polyethyleneoxide 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, poly (lactic acid), poly (glycolic acid), copolymers of poly (lactic acid) and poly (lactic acid). glycolic acid), epsilon caprolactone, poly (hydroxybutyric acid), polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic copolymers of hydrogels block. The following examples further illustrate the process 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 1-32 have the following general formula 8 ^ the substituents R being indicated in the following table. The compounds were prepared as described in the following preparations 1-7. In the table, the performance data and the mass spectra ("Spec.Masses") refer to the final product.

PREPARATION PROCEDURES FOR TABLE 1 With reference to the scheme illustrated above, the compound of formula 1 was mixed, wherein R is H and R 4 is H (25 g (34.01 mmol, 1.0 equivalent)) in a solution with phenol red in 250 ml of THF and 125 ml of water. To this pink solution, 29 ml (204.1 mmol, 6.0 equivalents) of chlorofomiato and benzyl and 2N NaOH were added slowly, maintaining the basic solution. The reaction was allowed to stir at room temperature overnight. The reaction mixture was concentrated to remove THF and the aqueous phase was adjusted to pH 9.5 and extracted with 3 x 500 mL EtOAc. The combined organic layers were washed with 500 ml of brine and then dried over Na2CO3. Filtration, concentration of the filtrate and drying gave a crude material. Further purification was performed by column chromatography (100% CH2CI2 to remove the impurities and then 5% MeOH / CH2Cl2 to separate the product) to provide 32.6 g (96%) of a yellowish solid which was the compound of formula H, wherein R and R4 were both Cbz (MS (FAB) m / z 1003). 32.6 g (32.49 mmol, 1.0 equivalents) of this product were dissolved in 216.6 ml of CH2CI2 and 27.3 ml of DMSO. To this solution, 21.2 g (1 10.5 mmol, 3.4 equivalents) of EDC and 24.1 g (124.8 mmol, 3.8 equivalents) of PTFA were added. After stirring overnight, the reaction was quenched with 150 ml of water and the pH was adjusted to 9.5 by the addition of 2N NaOh. The organic layer was extracted 3 x 150 ml with CH 2 Cl 2 and dried over Na 2 SO 4. The filtration, Concentration of the filtrate and drying gave a crude yellow oil. Further purification on a silica gel column (2% MeOH / CHCl3) provided 25.6 g (79%) of a yellowish solid which was the compound of formula V ?, in which both R and R4 were Cbz. 14 g (13.98 mmol, 1.0 equivalents) of the compound of formula 1_2_ were prepared as described above, in 1 liter of 2-propanol and 14 g of 10% Pd / C were added. The mixture was hydrogenated at 344. 8 kPa for three days. 14 g of 10% Pd / C were added to the reaction and allowed to stir for another day. This was repeated again and stirred for another day. The catalyst was removed by filtration through Celite® and a minimum washing of 2-propanol, providing 4.8 g (47%) of the compound of formula 12, wherein both R and R4 were H (MS (APCi) m / z 734). 6.7 g (169.17 mmol, 6.2 equivalents) of NaH (60% in oil dispersion) were washed twice with 150 ml of hexanes to remove the mineral oil. The solid was diluted in 335 ml of DMSO and 38.4 g (174.62 mmol, 6.4 equivalents) of Me3SOI were added in three portions. The solution was stirred for one hour or until it became clear. 20 g (27.29 mm? L, 1.0 equivalents) of the compound of formula 12, in which R and R4 were H, were dissolved in 200 ml of THF. The acetone was passed through a cannula into the reaction flask and allowed to stir for 20 minutes. The reaction was quenched with 500 mL of saturated NaHCO3, extracted 4 x 500 mL with EtOAc and dried over Na2SO4. Filtration, filtrate concentration and drying provided the crude oil. Further purification on 750 g of silica gel (5% MeOH / CHCl 3, 0.3% NH 4 OH) provided 8.8 g (43%) of a white solid which was the compound of formula 13 (MS (TS) m / z 747 ).

PREPARATION 1 250-500 mg of the above compound of formula 13 were dissolved in 1-2 ml of an amine corresponding to the substituent R specified in table 1. A catalytic amount (20 mg) of pyridinium hydrochloride was added and the solution was heated to 50.degree. -85 ° C for one to seven days. The reaction was treated by quenching with 50 mL of saturated NaHCO3, extracted with 3 x 50 mL of CH2Cl2, and dried over Na2SO4. Filtration, concentration of the filtrate and drying gave an oil or a crude solid. Further purification on a column of silica gel (2-4% MeOH / CHCl3, 0.2% NH4OH) provided the final product.

PREPARATION 2 200-500 mg of the above compound of formula 3 were dissolved in 1-2 ml of an amine corresponding to the substituent R specified in table 1 in a hermetically sealed tube. A catalytic amount (20 mg) of pyridinium hydrochloride was added and the solution was heated at 50-75 ° C for one to five days. The reaction was treated by quenching it with 50 ml of Saturated NaHCO3, extracted with 3 x 50 ml of CH2Cl2, and dried over Na2SO4. Filtration, concentration of the filtrate and drying gave an oil or a crude solid. Further purification on a column of silica gel (2-4% MeOH / CHCl3, 0.2% NH4OH) provided the final product.

PREPARATION 3 100 mg of the above compound of formula 13 was dissolved in MeOH / H 2 O (8: 1). Sodium azide (7 equivalents) and ammonium chloride (5.5 equivalents) were added and the solution was heated at 60 ° C for two days. The reaction was treated by quenching with 50 mL of saturated NaHCO3, extracted with 3 x 50 mL of CH CI2. and dried over Na2SO4. Filtration, concentration of the filtrate and drying gave an oil or a crude solid. Further purification on a column of silica gel (2% MeOH / CHCl3, 0.2% NH4OH) provided the final product.

PREPARATION 4 150-250 mg of the above compound of formula 1_3 were dissolved in 1-2 ml of MeOH / H2O or MeOH. To this was added the heteroaromatic reagent corresponding to the substituent R specified in the table 1 (10-50 equivalents) and a catalytic amount (20 mg) of pyridinium hydrochloride. The reaction mixture was heated at 45-50 ° C for one to three days.

The reaction was then quenched with 100 mL of saturated NaHCO3, extracted with 3 x 25 mL of CH2Cl2, dried over Na2S4, filtered and concentrated to a solid. The solid was redissolved in 100 mL of EtOAc and washed with 3 x 25 mL of 2N NaOH to remove excess reagent. Further purification on a column of silica gel (2-5% MeOH / CHCl 3, 0.2% NH 4 OH) provided the final product.

PREPARATION 5 50 mg of the above compound of formula 13 was dissolved in 1 ml of an amine corresponding to the substituent R specified in table 1. A small teaspoon of neutral alumina was added and the mixture was stirred at room temperature for seven days. The reaction was treated by filtering through Celite® (diatomaceous earth) and concentrated to a crude solid. Further purification on a column of silica gel (5% MeOH / CHCl3, 0.2% NH4OH) provided the final product.

PREPARATION 6 270 mg of the above compound of formula 13 were dissolved in 4 ml of benzene. To this was added K2CO3 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 NaHCO3, extracted with 3 x 25 mL of CH2Cl2, dried Na2S? 4 was added, filtered and concentrated to a solid. Further purification on a column of silica gel (2% MeOH / CHCl3, 0.2% NH4OH) provided the final product.

PREPARATION 7 250 mg of the above compound of formula 13 were dissolved in 0.5 ml of bis (2-hydroxyethyl) amine and 2 ml of 2-propanol in a sealed tube. A catalytic amount (20 mg of pyridinium hydrochloride was added and the solution was heated at 75 ° C for seven days.) The reaction was treated quenching with 50 ml of saturated NaHCO3., extracted with 3 x 50 ml of CH2Cl2 and dried over NaS? 4. Filtration, concentration of the filtrate and drying gave an oil or a crude solid. Further purification on a column of silica gel (2% MeOH / CHCl3, 0.2% NH4OH) provided the final product. Examples 33-68 below describe the preparation of compounds having the general structure of formula 9 below, wherein R is as defined in the examples.

EXAMPLE 33 To a solution of the compound of formula 4, in which R4 is H (0.059 g, 0.08 mmol) in THF (2 ml) at 0 ° C, allylmagnesium bromide in Et2 (1.0 M, 0.5 ml) was added. After 2 hours at 0 ° C, stirring was continued at room temperature for 12 hours. The reaction was diluted with a saturated aqueous sodium bicarbonate solution (10 ml) and EtOAc (20 ml). After separating, the aqueous layer was washed with EtOAc (2 x 15 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (20 ml) and brine (25 ml), dried over Na2SO and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 10: 89: 1) yielded 0.011 g (18% yield) of the compound of formula 9, wherein R is allyl: MS: 776 (TS) EXAMPLE 34 To a solution of the compound of formula 4, in which R4 is H (0.059 g, 0.08 mmol) in DME (3 ml) at 0 ° C, vinylmagnesium bromide in THF (1.0 M, 0.56 ml) was added. After stirring at 0 ° C for 1 hour and at room temperature for 1 hour, the reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate (10 ml) and EtOAc (10 ml). After separating, the aqueous layer was washed with EtOAc (3 x 10 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (15 ml) and brine (20 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1) gave 0.016 g (26% yield) of the compound of formula 9, wherein R is vinyl: MS: 762 (FAB).

EXAMPLE 35 To a flask containing MgCl2 (0.095 g, 1 mmol) and DME (1 mL) at 0 ° C was added 2-thienyl lithium (1.0 M, 1.0 mL). After 0.5 hours a solution of the compound of formula 4 was introduced, in which R4 is H (0.073 g, 0.1 mmol) in DME (2 ml) and stirring was continued at 0 ° C for 1 hour, and then a room temperature for 0.5 hours. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate (10 ml) and EtOAc (15 ml). After separating, the aqueous layer was washed with EtOAc (3 x ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (15 ml) and brine (20 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1) provided 0.012 g (15% yield) of the compound of formula 9, wherein R is 2-thienyl: MS: 817 (TS).

EXAMPLE 36 To a solution of the compound of formula 4, in which R4 is H (0.147 g, 0.2 mmol) in DME (10 ml) at 0 ° C, ethynylmagnesium bromide in THF (0.5 M, 2.8 ml) was added. After stirring at 0 ° C for 1 hour and at room temperature for 1 hour, the reaction mixture was diluted with water (20 ml) and EtOAc (35 ml). After separating, the aqueous layer was washed with EtOAc (3 x 25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (30 ml) and brine (30 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 10: 89: 1) provided 0.068 g (45% yield) of the compound of formula 9, wherein R is ethynyl: MS: 759 (API).

EXAMPLE 37 To a solution of the compound of formula 4, in which R4 is H (0.220 g, 0.3 mmol) in DME (15 ml) at 0 ° C was added 1-methyl-1-propenylmagnesium bromide in THF (0.5 M, 4.2 ml). After stirring at room temperature for 3 hours, the reaction mixture was diluted with a saturated solution of sodium bicarbonate (20 ml) and EtOAc (30 ml). After separating, the aqueous layer was washed with EtOAc (3 x 10 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (25 ml) and brine (30 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH OH (6: 93: 1 to 10: 89: 1) yielded 0.068 g (26% yield) of the compound of formula 9, wherein R is 1-methyl- 1 -propenyl: MS: 790 (API).

EXAMPLE 38 To a solution of butylmagnesium bromide in THF (2.0 M, 1.0 ml) at 0 ° C was added a solution of methylpropargyl ether (0.154 g, 0.2 mol) in DME (3 ml). After stirring at 0 ° C for 0.5 hour, a solution of the compound of formula 4 was added, wherein R4 is H (0.147 g, 0.2 mol) in DME (7 ml). After stirring at 0 ° C for 0.5 hour and at room temperature for 4 hours, the reaction mixture was diluted with water (20 ml) and EtOAc (25 ml). After separating, the aqueous layer was washed with EtOAc (3 x ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (20 ml) and brine (25 ml), dried over Na2SO4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 10: 89: 1) provided 0.081 g (50% yield) of the compound of formula 9, wherein R is 3-methoxy-1 -propynyl: MS: 803 (API).

EXAMPLE 39 To a solution of methylmagnesium bromide in Et 2 O (3.0 M, 1.8 ml) at 0 ° C was added a solution of 1-dimethylamino-2-propyne (0.154 g, 0.2 mol) in THF (5 ml). After stirring at 0 ° C for 6 hours, a solution of the compound of formula 4 was added, wherein R13 is H (0.147 g, 0.2 mol) in DME (10 ml) at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (40 ml) and EtOAc (50 ml). After separating, the aqueous layer was washed with EtOAc (3 x 50 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: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 8:91: 1) afforded 0.140 g (57% yield) of the compound of formula 9, wherein R is 3-dimethylamino-1 -propynyl: MS: 817 (API).

EXAMPLE 40 To a solution of methylmagnesium bromide in Et 2 O (3.0 M, 1.8 ml) and DME (1 ml) at 0 ° C was added a solution of 2-ethynylpyridine (0.186 g, 1.8 mol) in DME (2 ml). After stirring at 0 ° C for 1 hour and at room temperature for 1 hour, a solution of the compound of formula 4 was added, in which R 4 is H (0.1 10 g, 0.15 mol) in DME (7 ml) at room temperature . After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (20 ml) and EtOAc (40 ml). After separating, the aqueous layer was washed with EtOAc (3 x 30 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: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 10: 89: 1) afforded 0.066 g (53% yield) of the compound of formula 9, wherein R is 2-pyridylethynyl: MS : 836 (API).

EXAMPLE 41 To a round bottom flask containing MgBr2 (0.552 g, 3.0 mmol) and propynyl lithium (0.069 g, 1.5 mmol) at 0 ° C was added THF (5 mL). After 4 hours, a solution of the compound of formula 4, in which R 4 is H (0.1 10 g, 0.15 mmol) in DME (10 ml) was introduced at room temperature and He continued with the agitation for 3 hours. The reaction mixture was diluted with water (30 ml) and EtOAc (30 ml). After separating, the aqueous layer was washed with EtOAc (3 x 40 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: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 7: 92: 1) provided 0.060 g (52% yield) of the compound of formula 9, wherein R is 1-propynyl: MS : 817 (API): EXAMPLE 42 To a solution of methylmagnesium bromide in Et 2 O (3.0 M, 0.6 ml) at 0 ° C was added a solution of propargyl alcohol (0.346 g, 0.286 g, 2.25 mmol) in THF (5 ml). After stirring at 0 ° C for 3 hours, a solution of the compound of formula 4, wherein R 4 is H (0.1 10 g, 0.15 mmol) in DME (10 ml) was added at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (35 ml) and EtOAc (50 ml). After separating, the aqueous layer was washed with EtOAc (3 x 40 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 (6: 93: 1 to 15: 84: 1) provided 0. 038 g (32% yield) of the compound of formula 9, wherein R is 3-hydroxy-1-propynyl: MS: 790 (API).

EXAMPLE 43 Palladium catalyst (20 mg, 10% Pd / C) was added to a solution of the compound of example 42 is isopropanol (8 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Filtration of an aliquot of the reaction mixture in Celite® and concentration in vacuo afforded the compound of formula 9 in which R is 3-hydroxy-1 -propenyl: MS: 791 (API).

EXAMPLE 44 Palladium catalyst (20 mg, 10% Pd / C) was added to the solution obtained in Example 43 and the reaction vessel was flushed with hydrogen (344.8 kPa) and stirred at room temperature for 48 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2; NH 4 OH (6: 93: 1 to 8:91: 1) afforded 0.018 g (57% yield) of the compound of formula 9 wherein R is 3-hydroxypropyl: MS: (API).

EXAMPLE 45 Palladium catalyst (15 mg, 10% Pd / C) was added to a solution of the title compound of Example 38 in isopropanol (8 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Filtration of an aliquot of the reaction mixture in Celite® and concentration in vacuo afforded the compound of formula 9 in which R is 3-methoxy-1 -propenyl: MS: 806 (API).

EXAMPLE 46 Palladium catalyst (15 mg, 10% Pd / C) was added to the rest of the solution obtained in Example 45 and the reaction vessel was flushed with hydrogen (344.8 kPa) and stirred at room temperature for 48 hours. . The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 7: 92: 1) provided 0.017 g (73% yield) of the compound of formula 9 wherein R is 3-methoxypropyl: MS: 808 (API).

EXAMPLE 47 To a solution of the compound of formula 4, in which R4 is benzyloxycarbonyl (0.520 g, O. mm mol) in DME (6 ml) and TMEDA (2 ml) at -40 ° C, propynyl lithium (0.414 g, 9.0) was added. mmol). After stirring at -40 ° C for 2.5 hours, the reaction mixture was diluted with saturated aqueous ammonium chloride solution (30 ml) and EtOAc (30 ml). After separating, the aqueous layer was washed with EtOAc (3 x 10 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (25 ml) and brine (30 ml), dried over Na2SO and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH4OH (4: 95.6: 0.4 to 6: 93.6: 0.4) gave 0.157 g (29% yield) of the diastereomer eluting most rapidly, together with 0.071 g ( 13% yield) of the diastereomer that eluted more slowly and 0.070 g (13% yield) of a mixture of diastereoisomers. A solution of the diastereomer eluting most rapidly (0.157 g, 0.17 mmol) in MeOH (5 ml) was allowed to stir at 30 ° C for 6 days. After concentration in vacuo, chromatography on silica gel with MeOH: CH2Cl2: NH4OH (4: 95.6: 0.4 to 6: 93.6: 0.4) gave 0.102 g (78% yield) of the compound of formula 9 in the that R is 1-propynyl according to the following configuration on carbon C-4"(MS: 774 (API)).

A solution of the diastereomer that eluted more slowly (0.071 g, 0.078 mmol) in MeOH (3 ml) was allowed to stir at 30 ° C for 6 days. After concentrating in vacuo, chromatography on silica gel with MeOH: CH2Cl2: NH4OH (4: 95.6: 0.4 to 6: 93.6: 0.4) gave 0.041 g (68% yield) of a material identical to that described by the compound of Example 41 which corresponds to the compound of formula 9 in which R is 1-propynyl according to the following configuration in carbon C-4"(MS: 774 (API)): EXAMPLE 48 To a suspension of trimethylsulfonium tetrafluoroborate (1.03 g, 6.3 mmol.) In THF (40 mol) at -10 ° C was added KHMDS (1.20, 6.0 mmol).

After stirring below 0 ° C for 0.5 hour, the reaction vessel was cooled to -78 ° C and a solution of the compound of formula 4 in which R13 is benzyloxycarbonyl (2.60 g, 3 mmol) in DME was added. (10 ml). After 0.5 hours, the reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (40 ml) and EtOAc (50 ml). After separating, the aqueous layer was washed with EtOAc (3 x 30 ml). The combined organic extracts were washed with brine (40 ml), dried over NA2S4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH4OH (2: 97.6: 0.4 to 4: 95.5: 0.4) provided 0.834 g (32% yield) of the compound of formula 5, wherein R4 is benzyloxycarbonyl : MS: 881 (API).

EXAMPLE 49 A solution of the compound of Example 48 (0.176 g, 0.2 mmol) in MeOH (5 mL) was allowed to stir at 50 ° C for 4 days. After concentrating, chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 HH (4: 95.6: 0.4 to 6: 93.5: 0.4) gave 0.107 g (72% yield) of the compound of formula 5 in which R4 is hydrogen and the epoxide radical at C-4 '' has the following configuration (MS: 74 (API)): EXAMPLE 50 A solution of the compound of Example 48 (0.176 g, 0.2 mmol), potassium iodide (2.32 g, 14 mmol) and cyclopropylamine (2.43 mL, 2.00 g, 35 mmol) in MeOH was allowed to stir at 50 ° C for 2 days. ml). After concentrating, the residue was dissolved in water (50 ml) and EtOAc (100 ml). After separating, the aqueous layer was washed with EtOAc (3 x 50 mL). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (50 ml) and brine (40 ml), dried over Na2SO4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (4: 95.6: 0.4 to 6: 93.5: 0.4) gave 0.377 g (69% yield) of the compound of formula 9, wherein R is cyclopropylamomethyl according to the following configuration in carbon C-4 '' (MS: 805 (API)): EXAMPLE 51 A solution of the compound of Example 48 (0.176 g, 0.2 mmol), tetrabutylammonium iodide (0.739 g, 2.0 mmol) and butylamine (0.395 mL, 0.293 g, 4 mmol) in MeOH was allowed to stir at 50 ° C for 2 days. (5 ml). After concentrating, the residue was dissolved in water (20 ml) and EtOAc (20 ml). After separating, the aqueous layer was washed with EtOAc (3 x 20 ml). The combined organic extracts were washed with brine (40 ml), dried over Na2SO and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2CL2NH4OH (4: 95.6: 0.4 to 6: 93.5: 0.4) afforded 0.088 g (54% yield) of the compound of formula 9, wherein R is propylaminomethyl according to following configuration on carbon C-4 '' (MS: 821 (API)): EXAMPLE 52 To a solution of a compound of formula 4 in which R 4 is benzyloxycarbonyl and the hydrogen bonded to nitrogen C-9a is substituted by benzyloxycarbonyl (0.500 g, 0.499 mmol) in THF (15 ml) at 0 ° C was added methylmagnesium bromide in Et2O (3.0 M, 1.2 ml). After 20 minutes the reaction was diluted with EtOAc (30 ml) and water (50 ml). After separating, the aqueous layer was washed with EtOAc (3 x 35 ml). The combined organic extracts were washed with 10% aqueous sodium bicarbonate solution (100 ml) and brine (120 ml), dried over Na2SO and concentrated in vacuo to give 0.500 g (98% yield) of an off-white foam. (MS: 1017, 845 (API)). Palladium catalyst (0.250 g, 10% Pd / C a) was added to a solution of the compound described above (0.500 g, 0.491 mmol) in isopropanol (50 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 48 hours. Additional palladium catalyst (0.250 g, 10% Pd / C) was added and the hydrogenation was continued at 344.8 kPa for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. The resulting oil was dissolved in isopropanol (50 ml), palladium catalyst (0.312 g) was added., Pd at 10% / C) and hydrogenation was continued at 344.8 kPa for 24 hours. Additional palladium catalyst (0.170 g, 10% Pd / C) was added and the hydrogenation was continued at 344.8 kPa for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (8:91: 1 to 10: 89: 1) afforded 0.120 g (33% yield) of the compound of formula 9 in which R is methyl according to the following configuration in carbon C-4"(MS: 749 (API)).

EXAMPLE 53 To a solution of a compound of formula 4 in which R 4 is benzyloxycarbonyl and hydrogen bonded to nitrogen C-9a is substituted by benzyloxycarbonyl (0.101 g, 0.101 mmol) in THF (2 ml) at -78 ° C was added phenylmagnesium bromide in THF (1.01 M, 1.0 ml). After 15 minutes, stirring was continued at 0 ° C for 1 hour and then at room temperature for 12 hours. The reaction was diluted with a 10% aqueous solution of sodium bicarbonate (10 ml) and EtOAc (20 ml). After separating, the aqueous layer was washed with EtOAc (3 x 15 ml). The combined organic extracts were washed with 10% aqueous sodium bicarbonate solution (20 ml) and brine (25 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH4OH (5: 94: 1 to 25: 74: 1 afforded 0.048 g (45% yield) of a white foam (MS: 1080 (LSIMS)). palladium (0.024 g, 10% Pd / C) to a solution of the compound described above (0.024 g, 0.022 mmol) in methanol (15 ml) The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH? H (5: 94.5: 1 to 10: 89: 1) afforded 0.010 g (28% yield) of the compound of formula 9 in which R is phenyl: MS : 81 1 (LSIMS).

EXAMPLE 54 To a solution of the starting compound used in Example 53 (0.300 g, 0.30 mmol) in THF (3 mL) at 0 ° C was added n-butylmagnesium chloride in THF (2.0 M, 1.5 mL). After 20 minutes, the reaction was diluted with water and EtOAc (20 ml). After separating, the aqueous layer was washed with EtOAc (3 x 50 ml). The combined organic extracts were washed with a 10% aqueous solution of sodium bicarbonate (50 ml) and brine (55 ml), dried over Na2S? and concentrated in vacuo provided 0.295 g (93% yield) of a whitish foam (MS: 1060 (FAB)). Palladium catalyst (0.087 g, 10% Pd / C) was added to a solution of the compound described above (0.087 g, 0.082 mmol) in isopropanol (15 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Additional palladium catalyst (0.087 g, 10% Pd / C) was added and the hydrogenation was continued at 344.8 kPa for 60 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2CL2: NH4OH (5: 94.5: 0.5 to 10: 89: 1) yielded 0.010 g (28% yield) of the compound of formula 9 wherein R is n-butyl: MS: 792 (API).

EXAMPLE 55 To a solution of the starting compound used in Example 53 (0.200 g, 0.20 mmol) in THF (2 mL) at 0 ° C was added ethylmagnesium bromide in THF (1.0 M, 2.0 mL). After 20 minutes, the reaction was diluted with water and EtOAc (20 ml). After separating, the aqueous layer was washed with EtOAc (3 x 30 ml). The combined organic extracts were washed with a 10% aqueous solution of sodium bicarbonate (50 ml) and brine (55 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica with MeOH: CH2CL2: NH4OH (5: 94.5: 0.5 to 20: 79: 1) provided 0.079 g (38% yield) of a white foam (MS: 1033 (MSIMS)). Palladium catalyst (0.035 g, 10% Pd / C) was added to a solution of the compound described above (0.079 g, 0.077 mmol) in ethanol (20 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Additional palladium catalyst (0.036 g, 10% Pd / C) was added and the hydrogenation was continued at 344.8 kPa for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo affording 0.056 g (96% yield) of the compound of formula 9 wherein R is ethyl: MS: 763 (TS).

EXAMPLE 56 To a solution of the starting compound used in Example 53 (0.300 g0.30 mmol) in THF (3 ml) at 0 ° C was added isopropenylmagnesium chloride in THF (0.5 M, 6.0 ml). After 20 minutes, the reaction was diluted with water and EtOAc (20 ml). After separating, the aqueous layer was washed with EtOAc (3 x 30 ml). The combined organic experts were washed with a 10% aqueous solution of sodium bicarbonate (50 ml) and brine (55 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2CL2: NH4OH (3:96, 9: 0.1 to 20:79, 9: 0.1) gave 0.063 g (20% yield) of a white foam (MS: 1045 (LSIMS)) . Palladium catalyst (0.075 g, 10% Pd / C) was added to a solution of the compound described above (0.150 g, 0.165 mmol) in ethanol (30 mL). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Additional palladium catalyst (0.075 g, 10% Pd / C) was added and the hydrogenation was continued at 344.8 kPa for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2CL2: NH4OH (6: 93: 1 to 10: 89: 1) provided 0.024 g (19% yield) of the compound of formula 9 in which R is isopropenyl: MS 775 (TS ).

EXAMPLE 57 To a solution of the starting compound used in Example 53 (0.750 g, 0.75 mmol) in THF (12 ml) at 0 ° C was added allylmagnesium chloride in THF (2.0 M, 3.0 ml). After 15 minutes, the reaction was diluted with water and EtOAC (40 mL). The combined organic extracts were washed with a 10% aqueous solution of sodium bicarbonate (100 ml) and brine (100 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH4OH (6: 93: 1 to 15: 84: 1) gave 0.530 g, (68% yield) of an off-white foam (MS: 1044, 910 (API)). Palladium catalyst (0.175 g, 10% Pd / C) was added to a solution of the compound described above (0.350 g, 0.335 mmol) in isopropane (100 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Additional palladium catalyst (0.150 g, 10% Pd / C) was added and the hydrogenation was continued at 344.8 kPa for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on Silica gel with MeOH: CH2CL2: NH4OH (6: 93: 1 to 10: 89: 1) yielded 0.148 g (57% yield) of the compound of formula 9 in which R is propy: MS: 778 ( API).

EXAMPLE 58 To a solution of the starting compound used in Example 53 (0.750 g, 0.75 mmol) in THF (12 mL) at 0 ° C was added allylmagnesium chloride in THf (2.0 M, 3.0 mL). After 15 minutes, the reaction was diluted with water and EtOAc (40 mL). After separating, the aqueous layer was washed with EtOAc (3 x 50 ml). The combined organic extracts were washed with a 10% aqueous solution of sodium bicarbonate (100 ml) and brine (100 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH4OH (6: 93: 1 to 15: 84: 1) gave 0.530 g (68% yield) of an off-white foam (MS: 1044 (API)). A solution of the compound described above (0.104 g, 0.100 mmol) and (1 S) - (+) - 10-camphorsulfonic acid (0.046 g, 0.200 mmol) in MeOH (4 mL) was cooled to -78 ° C and reached treated with ozone until it was persistent an intense blue color. The reaction was purged with oxygen, dimethyl sulfide (0.13 ml, 1.76 mmol) and pyridine (0.20 ml, 2.42 mmol) were added and stirring was continued for 12 hours. CH 2 Cl 2 (30 ml) and 10% aqueous sodium bicarbonate solution (10 ml) were added, the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 30 ml). The combined organic extracts were washed with a 10% aqueous solution of sodium bicarbonate (50 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: 1 to 10: 89: 1) gave 0.024 g (23% yield) of a whitish foam (MS: 912 (API)). To a solution of the compound described above (0.022 g, 0. 024 mmol) in MeOH (1 mL) was added sodium borohydride (0.001 g, 0.024 mmol). Additional sodium borohydride (0.004 g, 1.00 mmol) was added over a period of 3 hours. The reaction mixture was diluted with CH CI2 (30 ml) and 10% sodium bicarbonate solution (20 ml). After separating, the aqueous layer was extracted with CH2Cl2 (3 x 30 ml). The combined organic extracts were washed with 10% aqueous sodium bicarbonate solution (50 ml) and brine (50 ml), dried over Na 2 SO 4 and concentrated in vacuo affording 0.022 g (100% yield) of a yellow foam. (MS: 914 (API)). Palladium catalyst (0.012 g, 10% Pd / C) was added to a solution of the compound described above (0.022 g, 0.024 mmol) in isopropanol (10 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours.

Additional palladium catalyst (0.020 g, 10% Pd / C) was added and the hydrogenation was continued at 344.8 kPa for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH4OH (8:91: 1 to 10: 89: 1) provided 0. 005 g (23% yield) of the compound of formula 9 wherein R is 2-hydroxyethyl: MS: 779 (API).

EXAMPLE 59 To a solution of the starting compound used in Example 53 (0.750 g, 0.75 mmol) in THF (12 ml) at 0 ° C was added allylmagnesium chloride in THF (2.0 M, 3.0 ml). After 15 minutes, the reaction was diluted with water and EtOAc (40 mL). After separating, the aqueous layer was washed with EtOAc (3 x 50 ml). The combined organic extracts were washed with a 10% aqueous solution of sodium bicarbonate (100 ml) and brine (100 ml), dried over Na 2 SO 4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH4OH (6: 93: 1 to 15: 84: 1) gave 0.530 g (68% yield) of an off-white foam (MS: 1044 (API)). A solution of the compound described above (0.104 g, 0.100 mmol) and (1 S) - (+) - 10-camphorsulfonic acid (0.046 g, 0.200 mmol) in MeOH (4 mL) was cooled to -78 ° C and reached treated with ozone until it was persistent an intense blue color. The reaction was purged with oxygen, dimethyl sulfide (0.13 ml, 1.76 mmol) and pyridine (0.20 ml, 2.42 mmol) were added and stirring was continued for 12 hours. CH 2 Cl 2 (30 ml) and 10% aqueous sodium bicarbonate solution (10 ml) were added, the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (3 x 30 ml). The combined organic extracts were washed with a 10% aqueous solution of sodium bicarbonate (50 ml) and brine (50 ml), dried over Na2SO2 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH4OH (6: 93: 1 to 10: 89: 1) gave 0.024 g (23% yield) of a whitish foam (MS: 912 (API)). Palladium catalyst (0.040 g, 10% Pd / C) was added to a solution of the compound described above (0.057 g, 0.063 mmol) in isopropanol (15 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Additional palladium catalyst (0.040 g, 10% Pd / C) was added and the hydrogenation was continued at 344.8 kPa for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 10: 89: 1) afforded 0.010 g (15% yield) of the compound of formula 9 wherein R is formylmethyl: MS: 777 ( API).

EXAMPLE 60 To a solution of 2-bromopyridine (0.474 g, 3.0 mmol) in THF (5 mL) at -78 ° C was added n-butyllithium (3.0 M, 1.2 mL) at -78 ° C. After 40 minutes, the solution was transferred through a cannula cooled with a dry ice jacket to a flask containing MgCl 2 (0.428 g, 4.5 mmol) and ether (4 mL) at -78 ° C. After 15 minutes, a solution of a compound of formula 4 in which R4 is benzyloxycarbonyl (0.260 g, 0.3 mmol) in THF (3 ml) was introduced at -78 ° C and stirring was continued allowing the reaction to warm to room temperature for several hours, after 3.5 hours, the reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (20 ml) and EtOAc (30 ml). After separating, the aqueous layer was washed with EtOAc (3 x 50 ml). The combined organic extracts were washed with 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: CH 2 Cl 2: NH 4 OH (6: 93.3: 0.7 to 10: 89: 1) gave 0.023 g (yield of 9.5%) of the compound of formula 9 in which R is 2-pyridyl: MS: 812 (API).

EXAMPLE 61 To a round bottom flask containing n-butyllithium (3.0 M, 1.62 ml) in diethyl ether (15 ml) at -78 ° C was added cooled 3-bromopyridine (-78 ° C) (0.790 g, 5 mmol). ) through a cooled cannula with a dry ice jacket. Stirring was continued at -78 ° C for 35 minutes. A suspension of diethyl MgBr 2 -etherate (0.1 14 g 0.440 mmol) in diethyl ether (3 ml) was added at -78 ° C through a cannula cooled with a dry ice jacket to the 3-pyridyl-lithium solution. . A solution of the compound of formula 4 in which R 4 is benzyloxycarbonyl (0.347 g, 0.400 mmol) in diethyl ether (3 ml) at -78 ° C was introduced through a cannula. Stirring was continued at -78 ° C for 2 hours and it was allowed to slowly warm up to 0 ° C for 3 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (20 ml) and EtOAc (30 ml). After separating, the aqueous layer was washed with EtOAc (3 x 50 ml). The combined organic extracts were washed with saturated 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 (4:95, 4: 0.6 to 20: 79: 1) gave 0.075 g (26% yield) of a white foam (MS: 947, 812 (API)) . Palladium catalyst (0.073 g, 10% Pd / C) was added to a solution of the compound described above (0.073 g, 0.077 mmol) in isopropanol (30 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 48 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 8:91: 1) afforded 0.032 g (51% yield) of the compound of formula 9 wherein R is 3-pyridyl: MS: 812 (API).

EXAMPLE 62 To a solution of methylmagnesium bromide in diethyl ether (3.0 M, 1.8 ml) at 0 ° C was added a solution of 5-hexinonitrile (0.63 ml, 6.00 mmol) in THF (5 ml). After stirring at 0 ° C for 6 hours, a solution of the compound of formula 4 in which R 4 is H (0.220 g, 0.300 mmol) in DME (10 ml) was added and stirring was continued at 0 ° C for 0.5 hours , and then at room temperature for 4 hours. The reaction mixture was diluted with water (20 ml) and EtOAc (25 ml), the layers were prepared and the layer was washed aqueous with EtOAc (3 x 20 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (20 ml) and brine (25 ml), dried over Na2SO4 and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 10: 89: 1) provided 0.035 g (14% yield) of the compound of formula 9 wherein R is 6-cyano-1- pentinyl: MS: 827 (API).

EXAMPLE 63 To a solution of the compound of Example 49, except that R is benzyloxycarbonyl, (0.101 g, 0.1 15 mmol) in DME (3 mL) was added LiAIH4 (1.0 M, 2.1 mL), dropwise. After 10 minutes, the reaction mixture was treated sequentially with water (0.044 ml), 15% NaOH solution (0.044 ml) and water (0.132 ml), and then stirred at room temperature for 0.5 hours, the mixture was diluted with EtOAc (20 ml) and water (20 ml) and water (20 ml). After separating, the aqueous layer was extracted with EtOAc (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: CH 2 Cl 2: NH 4 OH (3:96, 5: 0.5 to 3.5: 95: 0.5) provided 0.042 g (yield 49%) of the compound of formula 9 wherein R is methyl according to the following configuration at carbon C-4": (MS: 749 (API)).

EXAMPLE 64 To a solution of 1-methylimidazole (0.41 g, 4.99 mmol) in THF (5 mL) at -78 ° C was added n.-butyl lithium (2.5 M, 2.02 mL). After 45 minutes at -78 ° C, the solution was added through a cannula to a flask containing MgCl 2 (0.71 g, 7.49 mmol) and THF (5 ml) at 0 ° C. After 1.5 hours at 0 ° C, a solution of the starting compound used in example 53 (0.500 g, 4.99 mmol) in DME (2 ml) was introduced and stirring was continued at 0 ° C for 1 hour. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (100 ml) and EtOAc (100 ml). After separating, the aqueous layer was washed with EtOAc (3 x 100 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 to give 0.660 g of a yellow foam (MS: 949 (API)). Palladium catalyst (0.700 g, 10% Pd / C) was added to a solution of the compound described above in sopropane! (60 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Additional palladium catalyst (0.500 g.Pd at 10% / C) was added and the hydrogenation was continued at 344.8 kPa for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (1: 98: 1 to 8:91: 1) gave 0.052 g (13% yield) of the compound of formula 9 wherein R is 1-methylimidazole-2 It: MS: 816 (API).

EXAMPLE 65 To a solution of furan (0.34 g, 4.99 mmol) in THF (5 mL) at -78 ° C was added n-butyllithium (2.5 M, 1.98 mL). After 0.5 hours at -78 ° C, the solution was added to a flask containing MgCl2 (0.71 g, 7.49 mmol) and THF (5 ml) at 0 ° C. After 1.5 hours at 0 ° C, a solution of the starting compound used in example 53 (0.500 g, 4.99 mmol) in DME (2 ml) was introduced and stirring was continued at 0 ° C for 1 hour and then at room temperature. environment for 1 hour. The reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (100 ml) and EtOAc (100 ml). After separating, the aqueous layer was washed with EtOAc (3 x 100 ml). The combined organic extracts were washed with a saturated aqueous sodium bicarbonate solution (100 ml), and brine (100 ml), dried over Na2SO and concentrated in vacuo. Chromatography on silica gel with MeOH: CH2Cl2: NH4OH (1: 98: 1 to 8:91: 1) gave 0.096 g (yield of 24%) of a white foam (MS: 935 (API)).

Palladium catalyst (0.100 g, 10% Pd / C) was added to a solution of compound described above in isopropanol (15 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 72 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (1: 98: 1 to 8:91: 1) gave 0.053 g (13% yield) of the compound of formula 9 wherein R is 2-furyl: MS: 802 (API).

EXAMPLE 66 To a solution of N-methylpyrrole (0.184 g, 2.31 mmol) in THF (4 mL) at -78 ° C was added n.-butyl lithium (2.5 M, 0.93 mL). The solution was heated to room temperature for 1 hour and then added through a cannula to a flask containing MgCl (0.329 g, 3.46 mmol) and Et2O (4 mL) at room temperature. After 1 hour, a solution of compound of formula 4 in which R 4 is benzyloxycarbonyl (0.200 g, 0.231 mmol) in THF (2 ml) was introduced and stirring was continued at room temperature for 45 minutes. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate (50 ml) and EtOAc (50 ml). After separating, the aqueous layer was washed with EtOAc (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 S 4 and concentrated in vacuo yielding 0.293 g of a yellow foam (MS: 949 (API)). Palladium catalyst (0.324 g, 10% Pd / C) was added to a solution of the compound described above in isopropanol (30 ml). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Additional palladium catalyst (0.300 g, 10% Pd / C) was added and the hydrogenation was continued at 344.8 kPa for 24 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Chromatography on silica gel with MeOH: CH 2 Cl 2: NH 4 OH (6: 93: 1 to 8:91: 1) afforded 0.033 g (18% yield) of the compound of formula 9 in which R is 1-methyl-2-pyrrolyl : MS: 814 (API).

EXAMPLE 67 To a solution of the doped compound prepared as described in example 39 (0.480 g) in isopropanol (40 ml) was added platinum oxide (0.115 g, 0.505 mmol). The reaction vessel was cleaned and filled with hydrogen (344.8 kPa) and stirred at room temperature for 24 hours. Filtration of an aliquot of the reaction mixture through Celite® and concentration in vacuo afforded the compound of formula 9 wherein R is 3-dimethylamino-1 -propenyl: MS 819 (API).

EXAMPLE 68 Platinum oxide (0.076 g, 0.335 mmol) was added to the solution obtained from example 67 and the reaction vessel was flushed with hydrogen (344.8 kPa) 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 OH (4: 95: 1 to 6: 93: 1) provided 0.069 g (15% yield) of the compound of formula 9 wherein R is 3-dimethylpropyl: MS 821 (API).

TABLE 2 The compounds of examples 69-81 have the general structure of formula 1Q_ below with the substituents R indicated in the table. The compounds of Examples 69-82 were prepared following the procedures of Examples 50 and 51, cited above, with the reaction period specified in the following table. In the table, the performance data and mass spectrum ("Esp. Masas") refer to the final product.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula or one of the pharmaceutically acceptable salts thereof, wherein: R is H, hydroxy or methoxy; R2 is hydroxy; R3 is C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 10 alkynyl, cyano, -CH 2 S (O) n R 8, wherein n is an integer ranging from 0 to 2, -CH 2 OR 8, -CH 2 N (OR9) R8, -CH2NR8R15, - (CH2) m- (C6-C10 aryl), or - (CH2) m (heteroaryl of 5-10 links), wherein m is an integer ranging from 0 to 4 and wherein the above R3 groups are optionally substituted with 1 to 3 R16 groups; or R2 and R3 are linked 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, C1-C10 alkyl, C2-C10 alkenyl, - (CH2) m- (C-C-io aryl) or - ( CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and in which the above R5 groups are optionally substituted with 1 to 3 R16 groups; each R6 and R7 is independently H, hydroxy, Ci-C alco alkoxy, C?-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CH2) m (C6-C10 aryl) or - (CH2) m (heteroaryl 5-10 links), where m is an integer that varies from 0 to 4; each R 8 is independently H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, or - (CH 2) qCR 11 R 12 (CH 2) NR 13 R 14, wherein q and r are each independently a varying integer from 0 to 3, except that q and y are not both 0, - (CH2) m (C6-C10 aryl) or - (CH2) m (5-10-membered heteroaryl), where m is an integer ranging 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 linked to form a saturated monocyclic or polycyclic ring of 4-10 links or a 5-10 membered heteroaryl ring, wherein said saturated heteroaryl and sy ring 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 groups R16; each R9 and R10 is independently H or C-? -C6 alkyl; each R11, R12, R13 and R14 is independently selected from H, C1-C10 alkyl, - (CH2) m (C6-C6o aryl) and - (CH) m (5-10-membered heteroaryl), wherein m is an integer ranging from 0 to 4 and in which the groups R11, R12 R13 and R14 above, except H, are optionally substituted with 1 to 3 R16 groups; or R11 and R13 are joined forming - (CH) P-, where p is an integer ranging from 0 to 3, such that a saturated ring of 4-7 links is formed which optionally includes 1 or 2 double or triple carbon-carbon bonds; or R13 and R14 are joined to form a monocyclic or polycyclic saturated ring of 4-10 links 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; R15 is H, C1-C10 alkyl, C2-C10 alkyl or C2-C10 alkynyl, wherein the above R15 groups are optionally substituted with 1 to 3 substituents independently selected from halogen and -OR9; each R16 is independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R17, -C (O) OR17, -C (O) OR17, -OC (O) OR17, -NR6C (O) R7 , -C (O) NR6R7, -NR6R7, hydroxy, C ^ Ce alkyl, C ^ Ce alkoxy, - (CH2) m (C6-C10 aryl) and - (CH2) m (5-10 membered heteroaryl), in 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 (O) R17, - C (O) OR17, -C (O) OR17, -OC (O) OR17, -NR6C (O) R7, -C (O) NR6R7, -NR6R7, hydroxy, C? -C6 alkyl and C? -C6 alkoxy; each R17 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) m- (C6-C10 aryl) and - (CH2) m (5-10 membered heteroaryl), where m is an integer that varies from 0 to 4; provided that R8 is not H when R3 is -CH2S (O) nR8.

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

3. The compound according to claim 2, wherein R1 is hydroxy, R2 is hydroxy, R3 is -CH2NR15R8 or -CH2SR8.

4. The compound according to claim 3, wherein R3 is -CH2NR15R8, and R15 and R8 are independently selected from H, alkyl C1-C10, C2-C10 alkenyl and C2-C10 alkynyl, in which the above groups R15 and R8, except H, are optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen and C6-C6 alkoxy.

5. The compound according to 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-propynyl, sec-butyl, tere-butyl and n-hexyl.

6. The compound according to claim 2, wherein R1 is hydroxy, R2 is hydroxy, R3 is -CH2NHR8 and R8 is - (CH2) m- (C6-C10 aryl), wherein m is an integer that It varies from 0 to 4.

7. - The compound according to claim 6, wherein R8 is phenyl or benzyl.

8. The compound according to claim 2, wherein R1 is -hydroxy, R2 is hydroxy, R3 is CH2NR15R8, and R15 and R8 are bonded to form a saturated ring of 4-10 links.

9. The compound according to claim 8, wherein R15 and R8 are linked to form a piperidino, trimethylenimino or morpholino ring.

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

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

12. The compound according to claim 2, wherein R1 is hydroxy, R2 is hydroxy, R2 is hydroxy, R3 is -CH2SR8, and R8 is selected from C1-C10 alkyl, C2-C10 alkenyl and C2-C10 alkynyl, wherein said R8 groups are optionally substituted with 1 or 2 substituents independently selected from hydroxy, halogen and Ci-Cβ alkoxy.

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

14. - The compound according to claim 2, wherein R1 is hydroxy, R2 is hydroxy and R3 is selected from C1-C10 alkyl, C2-C10 alkenyl, said R3 groups being optionally substituted with 1 or 2 substituents independently selected from hydroxy, - C (O) R 17, -NR 6 R 7, halogen, cyano, azido, 5-10 membered heteroaryl and C 1-6 alkoxy.

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

16. The compound according to claim 2, wherein R is hydroxy, R3 is - (CH2) m (heteroaryl of 5-10 links), wherein m is an integer ranging from 0 to 4.

17- . The compound according to claim 16, wherein R3 is 2-thienyl, 2-pyridyl, 1-methyl-2-imidazolyl, 2-furyl or 1-methyl-2-pyrrolyl.

18. The compound according to claim 2, wherein R1 is hydroxy, R2 is hydroxy and R3 is - (CH2) m (C6-C? 0 aryl), wherein m is an integer ranging from 0 to 4.

The compound according to claim 18, wherein R3 is phenyl.

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

21. - The compound according to 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 according to claim 1 and a pharmaceutically acceptable carrier.

23. The use of a compound according to claim 1 for the manufacture of a medicament for treating for the treatment of a bacterial infection or a protozoal infection in a mammal, fish or bird comprising administering said mammal, fish or bird a therapeutically effective amount of a compound according to claim 1.

24. - A process for preparing a compound of formula or a pharmaceutically acceptable salt thereof, wherein: R1 is H, hydroxy or methoxy; R2 is hydroxy; R3 is C1-C10 alkyl, C2-C2 alkenyl, C2-C10 alkynyl, cyano, -CH2S (O) nR8, wherein n is an integer ranging from 0 to 2, -CH2OR8, -CH2N (OR9 ) R8, -CH2NR8R15, - (CH2) m- (C6-C? 0 aryl), or - (CH2) m (5-10-membered heteroaryl), wherein m is an integer ranging from 0 to 4 and wherein the above R3 groups are optionally substituted with 1 to 3 R16 groups; or R2 and R3 are linked 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, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) m- (C6-C aryl ? 0) or - (CH2) m (5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and in which the above R5 groups are optionally substituted with 1 to 3 R16 groups; each R6 and R7 is independently H, hydroxy, C-C- alkoxy, C6-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, - (CH2) m (C6-C6-aryl) or - (CH2) m (heteroaryl 5-10 links), where m is an integer that varies from 0 to 4; each R 8 is independently H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 8 alkynyl, or - (CH 2) qCR 11 R 12 (CH 2) r-NR 13 R 14, wherein q and r are each independently an integer that varies from 0 to 3, except that q and y are not both 0, - (CH2) m (aryl Cß-C-io) or - (CH2) m (heteroaryl of 5-10 links), where m is an integer ranging 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 linked to form a monocyclic or polycyclic saturated ring of 4-10 links or a 5-10 membered heteroaryl ring, wherein said heteroaryl and saturated 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 C6-C6 alkyl; each R11, R12, R13 and R14 is independently selected from H, C? -C 0 alkyl, - (CH2) m (C-C-io aryl) and - (CH2) m (5-10-membered heteroaryl), 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 joined to form - (CH2) P-, where p is an integer ranging from 0 to 3, such that the 4-7-membered saturated ring is formed so that it optionally includes 1 or 2 double or triple carbon-carbon bonds; or R13 and R14 are joined to form a monocyclic or polycyclic saturated ring of 4-10 links 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 groups R16; R 15 is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl or C 2 -C 8 alkynyl, wherein the above R 15 groups are optionally substituted with 1 to 3 substituents independently selected from halogen and -OR 9; each R16 is independently selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R17, -C (O) OR17, -C (O) OR17, -OC (O) OR17, -NR6C (O) R7 , -C (O) NR6R7, -NR6R7, hydroxy, C? -C6 alkyl, CrC6 alkoxy, - (CH2) m (C6-C10 aryl) and - (CH2) M (5-10 membered heteroaryl), that m is an integer ranging from 0 to 4 and wherein said aryl and heteroaryl substituents are optionally selected from halogen, cyano, nitro, trifluoromethyl, azido, -C (O) R17, -C (O) OR17, -C ( O) OR17, -OC (O) OR17, -NR6C (O) R7, - C (O) NR 6 R 7, -NR 6 R 7, hydroxy, d-C 6 alkyl and C C β alkoxy; each R17 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl or C2-C20 alkynyl, - (CH2) m- (C5-C10 aryl) and - (CH2) m (5-10 link heteroaryl) ), where m is an integer that varies from 0 to 4; provided that R8 is not H when R3 is -CH2S (O) nR8; which comprises treating a compound of formula wherein 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 the formula -CH2SR8 is optionally oxidized to -CH2S (O) R8 or -CH2S (O) 2R8.

25. The process according to claim 24, wherein the compound of formula 5 is prepared by treating a compound of formula wherein R1 and R4 are as defined in claim 24, with (CH3) 3S (O) nX2, wherein n is 0 or 1, and X2 is halogen, -BF4 or -PF6, in the presence of a base.

26. The process according to 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: R1 is H, hydroxy or methoxy; and R4 is H, -C (O) R9, -C (O) OR9, -C (O) NR9R10 or a hydroxy protecting group, and each R9 and R10 is independently H or CiCß- 28 alkyl. formula or a pharmaceutically acceptable salt thereof, wherein: R1 is H, hydroxy or methoxy; and R 4 is H, -C (O) R 9, -C (O) OR 9, -C (O) NR 9 R 10 or a hydroxy protecting group, and each R 9 and R 10 is independently H or C 1 -C 6 alkyl