MXPA01007584A - Ketolide antibiotics - Google Patents

Abstract

This invention relates to compounds of formula (1) and to pharmaceutically acceptable salts and solvates thereof wherein X1, X2, R2, R8, R9, R10 and R11 are as defined herein. The compounds of formula (1) are antibacterial and antiprotozoal agents that may be used to treat various bacterial and protozoal infections and disorders related to such infections. The invention also relates to pharmaceutical compositions containing the compounds of formula (1) and to methods of treating bacterial and protozoal infections by administering the compounds of formula (1).

Description

ANTIBIOTICS CETO IDOS BACKGROUND OF THE INVENTION This invention relates to new macrolide derivatives which are useful as antibacterial and antiprotozoal agents in mammals, including humans, as well as in fish and birds. This invention further relates to pharmaceutical compositions containing the novel compounds and to methods of treating 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. Other macrolide antibiotics are described and claimed in the published PCT International Application WO 98/56800 (published December 17, 1998), which designates the United States; U.S. Patent 5,527,780, issued June 18, 1996; United States provisional application number 60/101263 (filed September 22, 1998) (file number of agent PC 10406); U.S. Provisional Patent Application No. 60/111728 (filed December 10, 1998) (file number of Agent PC 10494); published PCT application WO 98/01546 (published January 15, 1998); published PCY application WO 98/01571 (published January 15, 1998); published European patent application number 949268 (published October 13, 1999); and U.S. Patent 5,747,467 (issued May 5, 1998). Each of the patents and patent applications of the United States, and previous European and PCT international patent applications are hereby incorporated by reference in their entirety. Like azithromycin and other macrolide antibiotics, the new macrolide compounds of the present invention possess activities against various bacterial and protozoal infections as described below.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula and pharmaceutically acceptable salts and solvates thereof, wherein: X1 is O, -CR-R5- or -NR4-; X2 is = O or = NOR1; R1 is H or C1-C10 alkyl, with from 1 to 3 carbon atoms of said alkyl optionally replaced by a heteroatom selected from O, S and -N (R4) -, and said alkyl being optionally substituted with 1 to 3 selected substituents independently of the group consisting of -C- (O) O (C-rdo alkyl), C-1-C10 alkoxy, C1-C10 alkanoyl, halogen, nitro, cyano, 4- to 10-membered heterocyclyl, C1-C10 alkyl, - NR4R5, C6-C10 aryl, -S (O) n (C1-C10 alkyl), where n is an integer ranging from 0 to 2 and -SO2NR4R5; R2 is - (CR4R5) n (4 to 10 membered heterocycle) or - (CRR5) n (C6-C10 aryl), where n is an integer from 0 to 6, with 1 to 3 R or R groups of the portion - (CR 4 RGD5) Xn- of the above R groups optionally substituted with a halogen substituent, and the heterocyclic and aryl portions of the above R2 groups being optionally substituted with 1 to 4 R3 groups; each R 3 is independently selected from halogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C 1 -C 1 alkoxy, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl. -C (O) R6, -C (O) OR6, OC (O) R6, -NR6C (0) R7, -NR6C (0) NR1R7, -NR6C (0) OR7, -C (0) NR6R7, -NR6R7 , NR6OR7, -SO2-NR6R7, -S- (O) j (CrC6 alkyl), where j is an integer from 0 to 2, - (CR1R2) t (C6-C10 aryl), - (CR4R5) t (heterocycle of 4 to 10 members), - (CR4R5) qC (O) (CR4R5) t (ary C6 ~ C10), - (CR4-R5) qC (O) (CR4R5) t (heterocycle of 4 to 10 members), - ( CR4-R5) tO (CR4R5) q (aryl C6-C? 0), - (CR4R5) tO (CR4R5) q (heterocycle of 4 to 10 members), - (CR4R5) qS02 (CR4R5) t (ary C6-C10) and - (CR4R5) q-S02 (CR4R5) t (heterocycle of 4 to 10 members), each of q and t being, independently, an integer of 0 to 5, with 1 or 2 ring carbon atoms of the heterocyclic portions of the above R10 groups optionally substituted with an oxo portion (= 0 =) and, the alkyl, alkenyl, alkynyl, aryl and heterocyclic portions of the R10 groups being previous optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR6, -C (0) R6, -C (0) OR6, -OC (0) R6, -NR6C ( 0) R7, -C (0) NRdR7, -N-R6R7, -NR6OR7, C? -C? Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, - (CR R5) t (C-C-io aryl) and - (CR4R5) t (heterocycle of 4 to 10 members), where t is an integer from 0 to 5; each of R 4 and R 5 is independently selected from H and C 1 -C 2 alkyl; each of R6 and R7 is independently selected from H, C6 alkyl, (CR4R5) t (C6-C10 aryl), and - (CR4R5) t- (4- to 10-membered heterocycle), where t is an integer from 0 to 5, with 1 or 2 ring carbon atoms of the heterocyclic group being optionally substituted with an oxo (= O) portion, and the alkyl, aryl and heterocyclic portions of the above groups R6 and R7 being optionally substituted with 1 to 3 substituents, selected independently of halogen, cyano, nitro, -NR R5, trifluoromethyl, trifluoromethoxy, C2-C6 alkyl, C2-C6 alkenyl, C3-C6 alkynyl, hydroxy and C6-C6 alkoxy; R 8 is H, -C (O) (C-t-Cß alkyl), benzyl, benzyloxycarbonyl or (C 1 -C 6 alkyl) 3 S ylyl; R9 is C? -C6 alkyl; R10 is H or C1-C10 alkyl; and R11 is selected from chlorine, bromine, iodine, fluoro and cyano; with the proviso that when X2 is = O, then R11 is cyano, or from 1 to 3 of the groups R4 or R5 of the portion -CR4-R5) n of the R2 groups mentioned above are Ct-Cß alkyl or are replaced by a halogen substituent. Specific embodiments of the present invention include compounds of formula 2 (which is a specific embodiment within the genus of formula 1) wherein R12, R13, R14 and R15 are each independently selected from H, halogen, methyl and ethyl. More specific embodiments include the compounds of formula 2, wherein R14 and R15 are H and each of R12 and R13 is independently selected from H and methyl. In a preferred embodiment of the compounds of formula 2, each of R12, R13, R14 and R15 are H. Other specific embodiments of the present invention include compounds of formula 3 (which is a specific embodiment within the genus of formula 1 ) wherein R12, R13, R14 and R15 are each independently selected from H, halogen, methyl and ethyl, with the proviso that at least one of R12, R13, R14 and R15 is not H. More specific modalities include the compounds of formula 3, wherein R14 and R15 are both H, R12 is methyl and R13 is selected from H and methyl.

The invention further relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoal infection, or a disorder related to a bacterial or protozoal infection in a mammal, fish or bird, comprising a therapeutically effective amount of a compound of formula 1, or one of the pharmaceutically acceptable salts or solvates. The invention further relates to a method for treating a bacterial infection or a protozoal infection, or a disorder related to a bacterial or protozoal infection in a mammal, fish or bird, which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula 1, or one of the pharmaceutically acceptable salts or solvates thereof. The term "treat", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting progress or preventing the disorder or condition to which that term applies or one or more symptoms. of said disorder or condition. The term "treatment", as used herein, refers to the action of treating, being treated as it has just been defined. Tai and as used herein, unless otherwise indicated, the term "bacterial infection (s)", "protozoan infection (s)" and "disorders related to bacterial infections or infections. protozoa "include the following: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis, related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. cassielavus, S. epidermidis , S. haemolyticus or Peptostreptococcus spp .; pharyngitis, rheumatic fever and glomerulonephritis associated with infection by Streptococcus pyogenes, groups of streptococci C and G, Corynebacterium diptheriae or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycopiasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae or Chamydia pneumoniae; infections in the blood and tissues, including endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E. faecalis, E. faecium, E. durans, including strains resistant to antibacterials known as, although not limited to them , beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; infections and abscesses of the skin and soft tissue without complications and puerperal fever related to infection by Staphylococcus aureus, staphylococcoscoagulase negative (ie, S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, streptococcal groups CF (streptococci from small colonies), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., Or Bartonella henselae; acute urinary tract infections without complications related to infection by Staphylococcus aureus, coagulase-negative Staphylococcus species or Enterococcus spp .; urethritis and cervicitis; 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. aureaus (intoxicated food and toxic shock syndrome) or streptococci of groups A, B and C; ulcers related to Helicobacter pylori infection; systemic febrile syndromes related to Borrelia recurrentis infection; Lyme disease related to Borrelia burgdorferi infection; conjunctivitis, keratitis and dacryocyst related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, 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; infections caused by Mycobacterium tuberculosis, M. leprae, M. paratuberculosis, M. Kansasii or M. Chelonei; gastroenteritis related to Campylobacter jejuni infection; intestinal protozoa related to infection by Cryptosporidium spp., odontogenic infection related to viridans streptococcal infection; persistent cough related to Bordetella pertussis infection; Gas gangrene related to infection by Clostridium perfringens or Bacteroides spp .; and atherosclerosis or cardiovascular disease related to infection by Helicobacter 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. haemolytica, P. multocida, Mycoplasma bovis or Bordetella spp .; enteric disease of cattle related to infection by E. coli or protozoa (ie, coccidia, cryptosporidia, etc.); mastitis of dairy cows related to S. aureus infection, Strep. uberis, Streptococcus agalactiae, Streptococcus dysgalactiae, klebsiella spp., Corynebacterium or Enterococcus spp .; porcine respiratory disease related to infection by A. pleuro, P. multocida or Mycoplasma spp .; enteric swine disease related to infection by E. coli, Lawsonia intracellularis, Salmonella or Serpulina hyodysinteriae; the necrosis 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 red eye of the cows related to the infection by Moraxella bovis; premature bovine abortion related to infection caused by protozoa (ie, neosporium); urinary tract infection in dogs and cats related to E. coli infection; skin and soft tissue infections in dogs and cats related to infection by S. epidermidis, S. inteimedios, Coagulase negative Staphylococcus or P. multocida; and dental or oral infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp .; Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and protozoal infections and disorders related to such infections that can be treated or prevented according to the method of the present invention are cited in JP Sandord et al., "The Sanford Guide To Antimicrobial Therapy", 26th Edition (Antimicrobial Therapy, Inc., 1996). The term "halogen", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halogen groups are fluoro, chloro and bromo. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals with linear portions, cyclical and / or branched. It will be appreciated that to include cyclic portions, the alkyl group should include at least 3 carbon atoms. The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl groups as defined above that have at least one carbon-carbon double bond at some point in the alkyl chain . The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl groups as defined above having at least one carbon-carbon triple bond at some point in the alkyl chain . 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 "4- to 10-membered heterocycle", as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms, each selected from 0, S and N, each of the heterocyclic groups having 4 to 10 carbon atoms in its ring system. The non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but the aromatic heterocyclic groups should have at least 5 atoms in their ring system. Heterocyclic groups include ring systems fused with benzene and ring systems substituted with one or more oxo moieties. An example of a 4-membered heterocyclic group is azetidinyl (azetidine derivative). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, tiepanyl, oxazepinyl, diazeoinyl, thiazepinyl, 1,3. , 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxoianilo, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3 -azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzoimidazolyl, bezofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, bezoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. When possible, the above groups, when they come from the compounds listed above, can be linked by C or linked by N. For example, a group derived from pyrrole can be pyrrol-1-yl (linked by N) or pyrrol-3-yl (joined by C). The term "pharmaceutically acceptable salt (s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of formula 1 The compounds of formula 1 which are basic in nature can 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 formula 1 are those which form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as acetate salts, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dichlorohydrate, edetate, edisilate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycolylaryl, hexylresorcinate , hydrabamine, hydrobromide, hydrochloride, iodide, ostothionate, lactate, lactobionate, laurate, malate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, theoclate, tosiiate, triethioiodide and valerate. The compounds of formula 1 which are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal and alkali earth metal salts and, in particular, the sodium and potassium salts. The present invention further includes all radioisotope-labeled forms of the compounds of formula 1 and pharmaceutically acceptable salts thereof, wherein the radioisotope is selected from 3H, 1C and 14C. Such compounds labeled with radioisotopes are useful as research or diagnostic tools. Certain compounds of formula 1 can have asymmetric centers and, therefore, exist in different enantiomeric forms. This invention relates to the use of all isomers and stereoisomers of the compounds of formula 1 and mixtures thereof. In particular, the invention includes the E and Z isomers of the group -OR1 (when X2 is = NOR1) attached to the nitrogen of the oxime portion at the C-9 position of the macrolide ring of formula 1. The present invention also includes compounds labeled with isotopes and pharmaceutically acceptable salts thereof, which are identical to those shown in formula 1, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, and 36CI , respectively. The compounds of the invention, their prodrugs and the pharmaceutically acceptable salts of said compounds and of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, those incorporating radioactive isotopes such as 3 H and 1 C, are useful in drug assays and / or distribution in substrate tissues. The isotopes with tritium, that is, 3H and with carbon 14, that is, 14C, are particularly preferred for their ease of preparation and detection. In addition, replacement with heavier isotopes such as deuterium, ie, 2H, can provide certain therapeutic advantages derived from increased metabolic stability, for example, a longer half-life in vivo or from the need for lower doses and, therefore, can be preferred in certain circumstances. The isotope-labeled compounds of formula 1 of this invention and their prodrugs can be prepared in a general manner by carrying out the procedures described in the schemes and / or in the following examples and preparations, substituting an unlabelled reagent with isotopes for a reagent labeled with Isotope readily available. This invention further includes pharmaceutical compositions and methods for treating bacterial infections by administering prodrugs of the compounds of formula 1. Compounds of formula 1 having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds in which an amino acid portion, or a polypeptide chain of two or more (eg, two, three or four) amino acid portions is covalently linked via an amide or ester linkage to an amino, hydroxy or carboxylic group free of the compounds of formula 1. The amino acid portions include, but are not limited to, the 20 natural amino acids, commonly designated by three-letter symbols and also include 4-hydroxyproline, hydroxylysine, demosin, sodemosin, 3-methylhistidine. , norvaline, beta-alanine, gamma-aminobutyric acid, citrullinehomocysteine, homoserine, omitin and methionine sulfone. Other types of prodrugs are also contemplated. For example, free carboxyl groups can be derivatized in the form of amides or alkyl esters. Free hydroxy groups can be derivatized using groups including, hemisuccinates, phosphate esters, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, but without being limited thereto, as described in Advanced Drug Delivery Reviews, 1996, 19, 115. The carbamate prodrugs of hydroxy and amino groups are also included, as are the carbonate prodrugs, suifonate esters and sulfate esters of the hydroxy groups such as esters of (acyloxy) methyl and of (acyloxy) ethyl in which the acyl group can be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functional groups , or in which the acyl group is an amino acid ester as described above. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All these prodrug moieties may incorporate groups that include, but are not limited to, ether, amine and carboxylic acid functional groups.

DETAILED DESCRIPTION OF THE INVENTION The preparation of the compounds of the present invention is illustrated in the following schemes: SCHEME 1 fifteen SCHEME 2 a SCHEME 2 (CONTINUED) SCHEME 2 (CONTINUED) 4 ' SCHEME 3 The preparation of the compounds of the present invention is illustrated in the above schemes. The starting materials and / or the final compounds of formula 1 in which R10 is a non-ethyl portion, within the definition of R10 illustrated above, can be prepared as described in published PCT applications WO 98/01571 (Biotica Tech. Ltd. and Pfizer Inc.) and WO 98/01546 (assigned to Biotica Tech. Ltd.). Other specific procedures that relate to the synthesis of the compounds of the present invention are cited in the PCT international patent application with publication number WO 98/38199 (published September 3, 1998), PCT international patent application with number WO 98/56800 (published December 17, 1998), United States Provisional Patent Application No. 60/101, 263 (filed September 22, 1998), United States Provisional Patent Application Number 60 / 111, 728 (filed December 10, 1998), European patent application number EP 487,411 and European patent application number EP 799,833. In the above schemes, all substituents are as defined for formula 1 above, unless otherwise indicated. The starting materials may or may not require appropriate protection of the functional group before various modifications take place and deprotection after the desired modifications are completed. The protecting groups most commonly used for amino portions in the macrolide compounds of this invention are the benzyloxycarbonyl (Cbz) and t-butyloxycarbonyl (Boc) groups. The hydroxyl groups are generally protected in the form of acetates, Cbz carbonates or a trialkylsilyl group. The hydroxyl group at the C-2 'position is a potentially reactive hydroxyl group among the numerous hydroxyl groups present in the macrolide compounds of the type claimed herein. The C-2 'hydroxyl group is selectively protected by treating the compound with one equivalent of acetic anhydride in dichloromethane in the absence of an external base. This process selectively converts the hydroxyl group to C-2 'in the corresponding acetate. The hydroxyl protecting group can be removed by treating the compound with methanol at a temperature ranging from about 0 ° C to 40 ° C to about 65 ° C for 10 to 48 hours. Other methods of protection and selective deprotection will be known to those skilled in the art. Referring to Scheme 1, the compound of formula 5, in which Ri1 is a halogen group and the portion substituents are as defined above, can be prepared by treating the compound of formula 4 with a base such as sodium hydride, potassium, potassium hexamethyldisilazide (KHMDS), pyridine, sodium carbonate or lithium diisopropylamide, preferably KHMDS with, and a halogenating agent such as N-fluorobencensulfonamida, SELECTFLUOR ™ (marketed by Air Products and Chemicals, Inc., Allentown, Pennsylvania, United States of America) for fluorac.ón, pyridinium tribromide or cyanogen bromide for the bromination, or hexachloroethane for chlorination, in a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), N-methylpyrrolidone or CH2Cl2 , or a mixture of the above solvents, preferably DMF. The reaction temperature, which depends greatly on the reagent used, can vary from -78 ° C to 60 ° C. In this step, R8 is preferably a hydroxy protecting group such as an acetyl group, a benzyl group or a trialkylsilyl group. In order to provide the compound of formula 6, the deprotection of the hydroxy at position C-2 'can proceed using methanol, if R8 is an acetyl group, by hydrogenation if R8 is a benzyl group, or with fluoride anion such as tetrabutylammonium fluoride, if R is a trialkylsilyl group. The compound of formula 6 corresponds to the compound of formula 1 wherein R8 is H. Scheme 2 illustrates a process for preparing the compounds of the present invention by introducing the R11 group in one of the first stages in the synthesis of the final compounds. In step 1 of scheme 2, a halogen group R11 can be introduced according to a process substantially the same as that described for scheme 1 above. In step 2 of scheme 2, the compound of formula 9 can be prepared by treating the compound of formula 8 with a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1, 1 '- carbonyldiimidazole (CDI) in methylene chloride. Treatment of the compound of formula 9 with hydrazine in acetonitrile at about 60 ° C provides the cyclic carbazate of formula 10. Treatment of the compound of formula 10 with O-alkylhydroxyamine in ethanol gives the oxime of formula 11. If desired, an amination reductive with an appropriate aldehyde of formula R2-C (O) H and deprotection of the hydroxy group at C-2 ', provides the compound of formula 12 which corresponds to a compound of formula 1 wherein X1 is -NH- and X2 is = NOR1. The compound of formula 10 can also be converted to a compound of formula 14 wherein X 1 is -NH-, as indicated in step 4 'of scheme 2 above, treating the compound of formula 10 with an appropriate heterocycle, such as a substituted imidazole, and a, β-unsaturated aldehyde such as acrolein in acetic acid, followed by reduction with sodium borohydride.

Scheme 3 illustrates the preparation of the compounds of formula 13, which correspond to the compounds of formula 1 in which X2 is = 0. In this procedure, the compound of formula 9 can be prepared as described above. The compound of formula 9 can be converted into the compound of formula 13 wherein X1 is O, CR4R5 or NR4, by treating the compound of formula 9 with NH2-X1-R2, where X1 O, CR4R5 or NR4 are. The compounds of the present invention can have asymmetric carbon atoms. Such mixtures of diastereomers 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 enantiomer mixtures into a mixture of diastereomers by reaction with an appropriate optically active compound (e.g., an alcohol), separating the diastereomers and converting (e.g., by hydrolysis) the individual diastereomers to the pure enantiomers. corresponding. Such isomers, including mixtures of diastereomers and pure enantiomers, are all considered part of the invention. The compounds of formula 1 which are basic in nature can form a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the latter into the compound free base by treatment with an alkaline reagent, and then converting the above free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid, in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated in a solution of the free base in an organic solvent, by adding an appropriate mineral or organic acid to the solution. The compounds of formula 1 which are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the sodium and potassium salts. These salts can be prepared by conventional techniques. The chemical bases which are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula 1. Such non-toxic base salts include those derived from pharmacologically acceptable cations such such as sodium, potassium, calcium, magnesium and the like. These salts can be easily prepared by treating the 8 corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanol solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, stoichiometric amounts of the reagents are preferably employed to ensure that the reaction is completed and that the maximum yields of the desired final product are obtained. The activity of the compounds of the present invention against bacterial and protozoan pathogens is demonstrated by the ability of the compounds to inhibit the development of defined strains of human pathogens (test I) or animals (tests II and III).

Assay I Assay I, described below, employs conventional methodology and interpretation criteria and is designed to provide guidelines for chemical modifications that can lead to compounds that circumvent defined mechanisms of macrolide resistance. In trial I, a group of bacterial strains is assembled, including a diversity of target pathogenic species, including representatives of mechanisms of resistance to macrolides that have been characterized. The use of this group allows to establish the chemical structure / activity relation with respect to the pharmacological potency, spectrum of activity and structural elements or modifications that may be necessary to circumvent the mechanisms of resistance. The bacterial pathogens included in the tracking group are shown in the following table. In many cases, both the macrolide sensitive parental strain and the macrolide resistance strain derived therefrom are available to provide a more accurate assessment of the ability of the compounds to circumvent the resistance mechanism. The strains containing the gene with the name ermAIermB / ermC are resistant to antibiotics macrolides, lincosamides and streptogramin B, due to modifications (methylation) of the 23S rRNA molecules by an Erm methylase, which usually prevents the binding of the three structural classes. Two types of macrolide expulsion have been described; srA encodes a component of an expulsion system in staphylococci that prevents the entry of macrolides and streptogramins, while mefA / E encodes a transmembrane protein that seems to expel only macrolides. Inactivation of macrolide antibiotics can occur and can be induced by 2'-hydroxyl phosphorylation (mph) or by cleavage of macrocyclic lactone (esterase). The strains can be characterized using the conventional technology of chain reaction with polymerase (PCR) and / or by 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 Chemotherapy, 40 (11), 2562-2566 (1996). The assay is performed in microtiter trays and is interpreted in accordance with the standards Preformance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition; Approved Standard, published by The National Committee for Clinical Laboratory Standards (NCCLS); To compare the strains, the minimum inhibitory concentration (MIC) is used. The compounds are initially dissolved in dimethylsulfoxide (DMSO) as stock solutions 40 mg / ml.

Assay II is used to assay activity against Pasteurella multocida and assay III is used to assay activity against Pasteurella haemolytica.

Test II This test is based on the method of dilution with liquids in microliter format. A single colony of P. multocida (strain 59A067) is inoculated into 5 ml of brain-heart infusion broth (BHI). The test compounds are prepared by solubilizing 1 mg of the compound in 125 μl of dimethyl sulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The concentrations of test compound used range from 200 μg / ml to 0.098 μg / ml in serial dilutions in half. The BHI inoculated with P. multocida is diluted with non-inoculated BHI broth to obtain a suspension of 104 cells per 200 μl. The cell suspensions in BHI are mixed with the respective serial dilutions of the test compound and incubated at 37 ° C for 8 hours. The minimum inhibitory concentration (MIC) is equal to the concentration of the compound that exhibits a 100% inhibition of the development 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 in BHI broth are inoculated and incubated overnight at 37 ° C with shaking (200 rpm). The next morning, 300 μl of the fully grown P. haemolytica culture is inoculated into 3 ml of fresh BHI broth and the mixture is incubated at 37 ° C with shaking (200 rpm). The appropriate amounts of the test compounds are dissolved in ethanol and a series of serial dilutions are prepared in half. Two ml of the respective serial dilution are mixed with 18 ml of molten BHI agar and solidified. When the inoculated P. Haemolytica culture reaches a standard McFarland density of 0.5, approximately 5 μl of the P. haemolytica culture is inoculated onto BHI agar plates containing the various concentrations of the test compound using a Steers Replicator and incubated for 18 hours at 37 ° C. The initial concentrations of the test compound vary from 100 to 200 μg / ml. The MIC is equal to the concentration of the test compound which shows a 100% inhibition of the development of P. haemolytica, as determined by comparison with a non-inoculated control. The in vivo activity of the compounds of formula 1 can be determined by conventional animal protection studies well known to those skilled in the art, usually carried out in mice. The mice are divided into cages (10 per cage) after arrival and allowed to acclimate for a minimum of 48 hours before being used. The animals are inoculated with 0.5 ml of a bacterial suspension of 3x103 colony-forming units (CFU / ml) (strain 59A006 of P. multocida) intraperitoneally. Each experiment has at least three non-medicated control groups that include one infected with a 0.1X inoculation dose and two infected with a 1X inoculation dose; a data set of a 10X inoculation was also used. In general, all mice can be inoculated in a given study over a period of 30 to 90 minutes, especially if a repeating syringe (such as a Comwall® syringe) is used to administer the inoculation dose. Thirty minutes after beginning the inoculation, the first treatment with compound is administered. It may be necessary for a second person to start dosing the compound if all the animals have not yet been inoculated at the end of the thirty minute period. The routes of administration are subcutaneous or oral doses. Subcutaneous doses were administered to the flaccid skin of the back of the neck, while oral doses were administered via a feeding needle. In both cases, a volume of 0.2 ml per mouse is used. The compounds are administered 30 minutes, 4 hours and 24 hours after inoculation. A control compound of known efficacy administered by the same route is included in each assay. The animals are observed daily and the number of survivors in each group is noted. The control of the P. multocida model continues for 96 hours (four days) after inoculation.

PD50 is a calculated dose at which the test compound protects 50% of a group of mice from mortality due to bacterial infection, which would be fatal in the absence of drug treatment. The compounds of formula 1, and the pharmaceutically acceptable salts and solvates thereof (hereinafter "the active compounds"), can be administered orally, parenterally, topically or rectally, in the treatment or prevention of bacterial or protozoal infections. In general, these compounds are administered in the most desirable manner in doses ranging from about 0.2 mg per kg of body weight and per day (mg / kg / day) to about 200 mg / kg / day in a single dose or in doses divided (ie, from 1 to 4 doses per day) although variations will necessarily occur depending on the species, weight and condition of the subject to be treated and the particular administration route chosen. However, it is most desirable to employ a dosage level that is in the range of about 4 mg / kg / day to about 50 mg / kg / day. However, variations will occur depending on the species of mammal, fish or bird to be treated and their individual response to said medication, as well as the type of pharmaceutical formulation chosen and the period of time and interval in which said administration is performed. In some cases, lower dosage levels than the lower limit of the range mentioned above may be more than adequate, while, in other cases, even higher doses may be employed without causing any untoward side effects, provided that such larger doses are first divided into several small doses to be administered throughout the day. The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the routes indicated above and such administration can be carried out in a single dose or in multiple doses. More particularly, the active compounds can be administered in a wide variety of different dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, tablets, dragees, hard candies, powders, sprays, creams, ointments , suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be conveniently sweetened and / or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrants such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for forming tablets. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; also including the preferred materials in this respect lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, coloring materials or pigments and, if desired, emulsifying and / or suspending agents, together with diluents such as water. , ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions of an active compound in sesame or peanut oil or in aqueous propylene glycol can be employed. Aqueous solutions should be suitably buffered (preferably with pH greater than 8) if necessary and the liquid diluent should first be made isotonic. 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 accomplished by conventional pharmaceutical techniques well known to those skilled in the art.

In addition, it is also possible to administer the active compounds of the present invention topically and this can be done by means of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with conventional pharmaceutical practice. For administration to animals other than humans, such as cattle or domestic animals, the active compounds can be administered in animal feed or orally in the form of potions. The active compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. The active compounds can also be associated with soluble polymers, such as targetable drug vehicles. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenyl, polyhydroxyethylaspartamide-phenol or poly (ethylene oxide) -silylisine substituted with palmitoyl moieties. In addition, the active compounds can be associated with a class of biodegradable polymers useful for achieving the controlled release of a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. The following examples illustrate specific embodiments of the invention, although the scope of the invention will not be limited to the examples presented in a specific manner. The following example illustrates a specific embodiment of the invention, although the scope of the invention will not be limited to the example presented specifically. In the following example, "Ac" represents an acetyl group, "Me" represents a methyl group and "Et" represents an ethyl group.

EXAMPLE 1 At -78 ° C, 1.74 ml of 0.5 M solution of KHMDS in toluene (0.87 mmol) was added to a solution containing the above compound of formula (in which "Ac" represents an acetyl group) (513). mg, 0.58 mmole) in 5.8 ml of DMF. After 30 minutes of stirring at -78 ° C, SELECTFLUOR ™ (sold by Air Products and Chemicals, Inc., Allentown, Pennyslvania, United States of America) (236 mg, 0.87 mmol) was added to this solution. After stirring for 30 minutes at -78 ° C, the new SELECTFLUOR ™ (27 mg, 0.076 mmol) was added. After a further 30 minutes of stirring at the same temperature, the reaction mixture was diluted with EtOAc (ethyl acetate) and washed with water and brine. It was dried over sodium sulfate and the solvent was removed giving 477 mg (93%) of a compound corresponding to formula 31 above, except that it had the hydroxy group of C-2 'protected with an acetyl group. This material was dissolved in 50 ml of MeOH and heated to 50 ° C overnight. Evaporation of the solvent and chromatography on SiO2 yielded the compound of formula 31 (corresponding to the compound of formula 2 cited above in which R12, R13, R14 and R15 are each H); NMR (CDCl 3, d) 8.93 (1 H, d), 8.42 (1 H, dd), 8.04 (1 H, dd), 7.57 (1 H, s), 7.35 (1 H, d), 7.24 (1 H , dd), 6.13 (1 H, s), 4.89 (1 H, dd), 4.28 (1 H, d), 4.19 (2 H, m), 4.07 (1 H, d), 3.69 (3 H, s), 3.66 (1 H, s), 3.56 (1 H, m), 3.48 (1 H, m), 3.41 (1 H, m), 3.24 (1 H, m), 2.76 (1 H, m), 2.60 ( 2H, m), 2.57 (3H, s), 2.36 (6H, s), 1.93 (2H, m), 1.74 (3H, d), 1.76-1.20 (6H, m), 1. 49 (3H, s), 1 .34 (3H, s), 1 .27 (3H, d), 1.22 (3H, d), 1 .1 1 (3H, d), 0.98 (3H, d), 0.83 (3H, t).

EXAMPLE 2 Following the procedures described in scheme 2 above, a compound corresponding to formula 1 was prepared, wherein X1 is -CH (CH3) (CH2) 2-, X2 is = NOCH3, R8 is H, R9 is CH3, R10 is CH2CH3, R11 is F and R12 is 4- (pyridin-3-yl) -imidazol-1-yl. MS 874 (M + 1). 32 The following examples, each having a structure according to formula 32 above, were prepared following the following procedure, which describes the preparation of the compound of Example 3. Examples 4 to 10 were prepared using the same procedure and using an appropriate heterocyclic compound instead of phenylimidazole.

EXAMPLE 3 12.7 μl of 90% acrolein (0.171 mmol) was added to a solution of compound 10 (100 mg, 0.155 mmol) and phenylimidazole (67.0 mg, 0.465 mmol) in 1.5 ml of acetic acid. The resulting mixture was stirred at room temperature overnight. Sodium cyanoborohydride (46.7 mg, 0.775 mmole) was then added and the solution was stirred at room temperature overnight. The solution was diluted with water and its pH adjusted to 10 with 40% aqueous NaOH solution. The aqueous solution was extracted with methylene chloride. The combined methylene chloride layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by TLC (thin layer chromatography) (89% methylene chloride-10% methanol-1% ammonium hydroxide), affording 6 mg (5% yield) of Example 3.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula or one of the pharmaceutically acceptable salts or solvates thereof, wherein: X1 is O, -CR4R5- or -NR4-; X2 = 0 u = N0R1-; R1 is H or C1-C0 alkyl, with 1 to 3 carbon atoms of said alkyl optionally replaced by a heteroatom selected from 0, S and -N (R4) -. and said alkyl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of -C- (0) O (C1-C10 alkyl), C1-C10 alkoxy, C1-C10 alkanoyl, halogen, nitro, cyano, 4-heterocyclyl to 10 members, C1-C10 alkyl, -NR4R5, C6-C aryl, or -S (0) n (C1-C10 alkyl), where n is an integer ranging from 0 to 2 and -SO2NR4R5; R2 is - (CR4R5) p (4- to 10-membered heterocycle) or - (C-R4R5) n (C6-C6 aryl), where n is an integer from 0 to 6, being from 1 to 3 R4 groups or R5 of the - (CR4R5) n- portion of the above R2 groups optionally substituted with a halogen substituent, and the heterocyclic and aryl portions of the above R groups being optionally substituted with 1 to 4 R3 groups; each R3 is independently selected from halogen, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, alkoxy CI-CT, Ci-C-io alkyl, C2-Ce alkenyl, C -Ce alkynyl, -C (0) R6, - C (0) 0R6, -OC (0) R6, -NR6C (0) R7 -NR6C (0) NR1R7 -NR6C (0) OR7 -C (0) NR6R7, -NR6R7 -NR6OR7, -S02-NR6R7, -S - (0) j (C? -C? Alkyl), where j is an integer from 0 to 2, - (CR1 R2) t (C3-C? O aryl), - (CR4R5) t (4- to 10-membered heterocycle) ), - (CR4R5) qC (0) (CR4R5) t (aryl Ce-Cio), - (CR4R5) qC (0) - (CR4R5) t (heterocycle of 4 to 10 members), - (CR4R5) tO (CR4R5) ) q (aryl Ce-Cio), - (CR4R5) tO (CR4R5) q (heterocycle of 4 to 10 members), (CR4R5) qS02 (CR4R5) t (AriIo Ce-Cio) and - (CR4R5) q-S02 (CR4R5) t (heterocycle of 4 to 10 members), each of q and t being, independently, an integer from 0 to 5 wherein 1 or 2 ring carbon atoms of the heterocyclic portions of the above R 10 groups are optionally substituted with an oxo portion (= O) and the alkyl, alkenyl, alkynyl, aryl and heterocyclic portions of the above R 0 groups being optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR6, -C (0) R6, -C (0) OR6, -0C (0) R6 -NR6C (0) R7 - C (0) NR6R7, -N-RdR7, -NR60R7, C?-Cß alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, - (CR 4 R 5) t (aryl Ce-Cι) and - (CR R 5) t (heterocycle of 4 to 10 members), where t is an integer 0 to 5, each of R 4 and R 5 is independently selected from H and C 1 -C 6 alkyl; each of Rd and R7 is independently selected from H, C -C6 alkyl, - (CR4R5) t (aryI Ce-Cio), and - (CR4R5) t- (heterocyclic from 4 to 10 members), where t is an integer of 0 to 5, with 1 or 2 ring carbon atoms of the heterocyclic group being optionally substituted with an oxo portion (= 0), and the alkyl, aryl and heterocyclic portions of the above Rβ and R7 groups being optionally substituted with 1 to 3 substituents , independently selected from halogen, cyano, nitro, NR4R5, trifluoromethyl, trifluoromethoxy, Ci-Cß alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy and C?-C6 alkoxy; R8 is H, -C (0) (C 1 -C 5 alky), benzyl, benzyloxycarbonyl or (C 1 -C 6 alkyl) 3-Silyl; R9 is C? -C6 alkyl; R10 is H or C1-C10 alkyl; and R11 is selected from chlorine, bromine, iodine, fluoro and cyano; with the proviso that when X2 is = 0, then R11 is cyano, or from 1 to 3 of the groups R4 or R5 of the - (CR4-R5) n- portion of the R2 groups mentioned above are alkyl d-Ce or they are replaced by a halogen substituent.

2 - A compound of formula or one of the pharmaceutically acceptable salts or solvates thereof, wherein each of R12, R13, R14 and R15 is independently selected from H, halogen, methyl and ethyl.

3. A compound according to claim 2, further characterized in that R14 and R15 are both H and each of R12 and R13 is independently selected from H and methyl.

4. A compound according to claim 2, further characterized by each of R12. R13 R14 and R15 is H.

5.- A compound of formula or one of the pharmaceutically acceptable salts or solvates thereof, wherein each of R12, R13, R14 and R15 is independently selected from H, halogen, methyl and ethyl, with the proviso that at least one of R12, R13, R14 and R15 are not H.

6. - A compound according to claim 5, further characterized in that R14 and R15 are both H, R12 is methyl and R13 is selected from H and methyl.

7. A pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, Or a disorder related to 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.

8.- The use of a compound in accordance with the claim 1 for the preparation of a medicament for treating a selected disorder of a bacterial infection, a protozoal infection, or a disorder related to a bacterial infection or a protozoal infection in a mammal, fish or bird.

9. A process for preparing a compound according to claim 1, further characterized in that R11 is a halogen group, which comprises treating a compound of formula wherein R8, R9, R10, X1, X2 and R2 are as defined in claim 1, with a halogenating agent.