MXPA01000114A - Novel antibacterial and prokinetic macrolides - Google Patents

Abstract

This invention relates to novel erythromycin derivatives useful as antibacterial, antiprotozoal and/or prokinetic agents, and to intermediates that are useful in the preparation of said compounds. The active compounds of the present invention 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 active compounds of the present invention and to methods of treating bacterial and protozoal infections by administering said compounds.

Description

NOVEDOSOS MACROLIDOS ANTIBACTERIALES AND PROC1NETICOS BACKGROUND OF THE INVENTION This invention relates to novel macrolide compounds which are useful as antibacterial, antiprotozoal and / or prokinetic agents in mammals, including man, as well as fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and methods for treating bacterial and protozoal infections and gastrointestinal disorders in mammals, birds and fish by administering the new compounds to mammals, fish and birds in need of such treatment. Macrolides are known to be useful in the treatment of a broad spectrum of bacterial and protozoal infections in mammals, birds and fish. Such antibiotics include various derivatives of erythromycin A such as azithromycin which is commercially available and cited in the U.S. Patents. Nos. 4,474,768 and 4,517,359, both incorporated herein by reference in their entirety. Other macrolide antibiotics are disclosed and claimed in the PCT international application No. PCT / IB99 / 00741, filed May 15, 1998, and the patent of E.U.A. No. 5,527,780, granted on June 18, 1996, each of them incorporated herein by reference in its entirety. Like azithromycin and other macrolide antibiotics, the novel macrolide compounds of the present invention possess activity against various bacterial and protozoal infections as described below. Macrolides are also known to be useful as prokinetic agents in the treatment of gastrointestinal disorders. Prokinetic agents (also called motility-enhancing agents) are compounds that induce contractions of gastrointestinal smooth muscles, both in vitro and in vivo. These agents include motilin agonists, a 22 amino acid polypeptide that produces increased motility of several portions of the intestines. For a review of the clinical development of erythromycin derivatives with prokinetic activity, see R. Faghih, Drugs of the future. 23 (8): 861-872 (1998). Defects in the normal gastrointestinal motility model can lead to the development of painful, debilitating and chronic disorders. Examples of these disorders include gastroesophageal reflux disease, delayed gastric evacuation, diabetic gastroparesis, pediatric gastroparesis, anorexia, gall bladder stasis, postoperative paralytic ileus, systemic sclerosis, chronic constipation (colonic inertia), emesis, gastritis, and intestinal pseudo-obstruction, For example, they suffer from constipation, pain that tends to cause cramps and vomiting. Prokinetic agents can additionally be useful in the placement of diagnostic and therapeutic instruments. For example, prokinetic agents can facilitate the insertion of enteric food tubes into the nearby small intestine. In intestinal pseudo-obstruction, these agents can assist in the decompression of the upper gastrointestinal tract by nasogastric tubal aspiration. Accordingly, there is a need for the development of an effective prokinetic agent.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to intermediate compounds of the formula and with salts or solvates thereof, wherein: a is 0 or 1; R1 is hydrogen or a hydroxyl protecting group; R 2 is H, C 1 -C 6 alkyl) C 3 -C 6 cycloalkyl, or C 5 -C 0 cycloalkenyl 0) C 2 -C 6 alkenyl, (CrC 6 alkoxy) CrC 6 alkyl, (C 1 -C 6 alkylthio) C 6 alkyl, - (CR10R1 1) m (C6-C aryl 0), and - (CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer from 0 to 6, and the preceding R groups, except hydrogen, are optionally substituted by one to three substituents of R8; R3 is hydrogen or methyl optionally substituted by one or two groups independently selected from nitro, cyano, R6C (O) and R6OC (O); or R3 is azido, -OR6, -NHR6, or -SR6; R 4 is hydrogen or C 1 -C 10 alkyl optionally substituted by one or two R 8 groups; each R6 is independently selected from hydrogen, Ci-Ce alkyl, C2-C2 alkenyl, C2-C2 alkynyl, (C3-C0 cycloalkyl) d6C6 alkyl, - (CR10R11) m (C6-C10 aryl) and - (CR10R11) m (4- to 10-membered heterocyclic) wherein each m is independently an integer from 0 to 6; and the preceding R6 groups, except hydrogen, are optionally substituted by one to three substituents of R8; R7a is hydrogen or methyl; X1 is = 0 or ÑOR6; each R 8 is independently selected from C 1 -C 10 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR 9, -C (O) R 9 , -C (O) OR9, -NR10C (O) OR12, -OC (O) R9, -NR10SO2R12, -SO2NR9R10, -NR10C (O) R9, -C (0) NR9R10, -NR9R10, -S (O) j (CR 10 R 11) m (C 6 -C 0 aryl), -S (0) j (C C alk), where j is an integer from 0 to 2, - (CR 10 R 11) m (heterocyclic from 4 to 10) members), wherein each m is independently an integer from 0 to 4; said alkyl, alkenyl and alkynyl groups optionally contain from 1 or 2 straight fractions selected from O, -S (0) j- wherein j is an integer from 0 to 2, and -N (R9) - with the proviso that two O atoms, two S atoms, or one O and S atom are not directly linked together, and the condition that an O atom, an S atom or an N atom are not directly bonded to a triple bond or an aromatic double bond; said cycloalkyl, aryl and heterocyclic R2 groups are optionally fused to a Ce-Cio aryl group, a C5-C8 cycloalkyl, or a 4- to 10-membered heterocyclic group; and said alkyl, cycloalkyl, aryl and heterocyclic R2 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, cyano, nitro, trifluoro, difluoromethoxy, trifluoromethoxy, azido-NR10SO2R12, -NR10C (O) R9, -C (O) NR9R10, -NR9R10, -OR9, CrC10 alkyl > - (CR10R11) m (C6-C10 aryl), and - (CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer from 0 to 4; each R9 is independently selected from H, CrCio alkyl, - (CR10R11) m (C6-C10 aryl), and - (CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer from 0 to 4; said alkyl group optionally includes 1 or 2 straight fractions selected from O, -S (O) r wherein j is an integer between 0 to 2, and -N (R10) - with the proviso that two O atoms, two atoms S, or an atom of O and S are not directly linked together; said cycloalkyl, aryl, and heterocyclic R 9 groups are optionally fused to an aryl group C 6 -C 0 0, a C 5 -C 5 cycloalkyl group, or a 4 to 10 membered heterocyclic group; and the preceding R9 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (0) R10, -OC (0) R1 , -NR10C (O) R11, -C (O) NR10R11, NR10R12, hydroxyl, CrC6 alkyl, and CI-CT alkoxy, with the proviso that R9 must be attached through a carbon atom unless R9 must be attached through a carbon atom unless R9 is H; each R 10 and R 11 is independently H or C 1 -C 2 alkyl; each R12 is selected from among the substituents supplied in the definition of R9 except that R12 is not H; and, with the proviso that when a is zero, R4 is hydrogen. The present invention also relates to compounds of the formula and with pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein; a, R1, R2, R4, R7a, and X1 are as defined above for said compound of the formula I; R5 is -C (O) -, -C (= NH) - or (C2-C4 alkylene) wherein the alkylene group is optionally substituted by one to three substituents of R8 wherein R8 is as defined above for said compound of formula 1, X 2 is NH, O, S or CH 2, Y is NH, O or S, R 3 is H or halo The present invention also relates to compounds and intermediates of the formula and with pharmaceutically acceptable salts, prodrugs and solvates, wherein: a, R1, R2, R4, R7a, R5, R6, R13, Y and X1 are as defined above for said compounds of formula 1 and 2. The present invention it is also related to intermediates of the formula and with salts and solvates thereof, wherein: a, R1, R2, R4, R7a, R6, and X1 are as defined above for said compounds of formula 1; W is O or S; Z is -N (R6) -, O, S, or -CH (R14) wherein R14 is H, NO2, CN, -C (O) R9 or C (O) OR9; and R8 and R9 are as defined above for said compound of formula 1. The present invention also relates to compounds and intermediates of the formula and with pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein: a, R1, R2, R4, R7a, R5, R6, R13, Z, W and X1 are as defined above for said compounds of formula 1, 2, and 4 but with the proviso that when Z is O then W is not O. The present invention is also related to intermediates of the formula and with salts and solvates thereof, wherein; a, R1, R2, R4, R7a, and X1 are as defined above for said compound of formula 1. The present invention is also related to intermediates of the formula and with salts and solvates thereof, wherein; a, R1, R2, R4, R7a, and X1 are as defined for said compound of formula 1. The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoal infection, and a disorder related to a bacterial or protozoal infection, in a mammal, fish or bird, which comprises a therapeutically effective amount of a compound of formula 2, 3, or 5, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically carrier acceptable. The invention also relates to a method for treating a bacterial infection or a protozoal infection, or a disorder related to bacterial or protozoal infection, in a mammal, fish or bird which comprises administering to said mammal, fish or bird an amount Therapeutically effective of a compound of the formula 2, 3, or 5, or a pharmaceutically acceptable salt, prodrug or solvate thereof. The invention also relates to a method for treating cancer or atherosclerosis in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula 2, 3, or 5 or a pharmaceutically acceptable salt, prodrug or solvate. of the same. The term "treat", as used herein, unless otherwise indicated, means to reverse, alleviate, inhibit progress or avoid the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. . The term "treatment", as used herein, refers to the act of treating, "treating" as defined immediately above. As used here, unless otherwise indicated. The terms or phrases "bacterial infections", "protozoal infections", and disorders related to bacterial infections or protozoal infections "include the following: pneumonia, otitis media, sinusitis, bronchitis, tonsillitis and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus inlfuenzae, Moraxelle catarrhalis, Stsphylococcus aureus, Enterococcus faccalis, E. Faecium, E. Cassolflavus, S. Epidermidis, S. Hemolylitcus, or Peptostrsptococccus spp.; pharyngitis, rheumatic fever, and glomerulonephritis associated with infection by Streptococcus pyogenes, Streptococcus Group C and G, corinebacterium diphtheria, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; blood and tissue related infections, including endocarditis and ostemielitis, caused by S. aurens haemoliticus, E. feacalis, E. faecium, E. durans, including strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin , aminoglycosides, quinolones, chloramphenicol, tetracyclines, and macrolides; uncomplicated infections of skin and soft tissue and abscesses, and puerperal fever related to infection by Staphylococcus aureus, coagulase-negative staphylococci (ie, S. epidermitis, S. hemoliticus, etc.), Streptociccus pyogenes, Streptococcus agalactiae, Streptococcal CF (streptococcal) groups of minute colonies), viridians streptococci, Corinebacterium MINITISSIMUM, Clostridium spp., or Bartonella henselae; Acute infections without complication of the urinary tract related to infection by Staphylococcus aureus, Staphylococcal coagulase negative species, or Enterococcus spp .; urethritis and cervicitis; sexually transmitted diseases related to infection by Chlamydia trachomatis, Haeilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiseria gonorrheae; toxin diseases related to S. aureus infection (food poisoning and toxic shock syndrome), or streptococcal groups A, B, and C; ulcers related to Helicobacter pylori infection; systemic febrile syndromes related to infection by Borrelia rcurrentis; Lyme disease related to Borrelia burgdoríeri infection; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp .; Disease disseminated by Mycobacterium avuim complex (MAC) related to infection by Mycobacterium avium, or Mycobacterium intracellulare; infections caused by Mycobacterium tuberculosis, M. leprae, Mparatuberculosis, m. Kansallil, or M. Chelonei; gastroenteritis related to Campilobacter jejuni infection; intestinal protozoa related to infection by Cryptospiridum spp .; odontogenic infection related to viridians streptococcal infection; persistent cough related to Bordetella pertussis infection; Gas gangrene related to infection by Clostridium períringens or Bacteroides spp .; and atherosclerosis or cardiovascular disease related to infection by Heliobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoal infections, and disorders related to such infections, which can be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. heamolytica, P. multocida, Mycolplasma bovis, or bordetella spp .; enteric bovine disease related to E. coli infection or protozoa (ie, coccidia, cryptosporidia, etc); Dairy cow mastitis related to infection by S. aurens, Strep. Uberis, Streptococcus agalactiae, Streptococcus dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp., Respiratory disease of pigs related to infection by A. pleuro., P. multocida, or Mycolplasma spp .; Enteric disease of pigs related to infection by E.coli, Lawsonia intracelularis, Salmonella, or Serpulina hyodysinteriae; cow foot rot associated with infection by Fasubacterirum spp .; bovine metritis related to E.coli infection; bovine warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; acute bovine conjunctivitis related to infections by Moraxella bovis; premature abortion of the cow related to infection by protozoa (ie, neosporio); urinary tract infection in dogs and cats caused by infection by E. coli skin and soft tissue infections in dogs and cats related to infection by S. epidermidis, S. intermedius, Staphylococcus coagulase negative or P. multocida; and dental or mouth 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, which can be treated or prevented according to the method of the present invention are cited in J.P. Sandord, "Sandord's Guide to Antimicrobial Therapy." Issue 26, (Antimicrobial Therapy, Inc., 1996). The term "halo", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro. The term "alkyl", as used herein, unless otherwise indicated, includes monovalent hydrocarbon radicals with straight or branched moieties. Said alkyl group may include one or two double or triple bonds it is to be understood that for said alkyl group includes a double or triple carbon-carbon bond, at least 2 carbon atoms are required in said alkyl group. 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 heterocyclic group", as used herein, unless otherwise indicated, includes aromatic and non-aromatic groups containing one or more heteroatoms each selected from O, S, and N, wherein Each heterocyclic group has 4 to 10 atoms in its cyclic system. The non-aromatic heterocyclic groups include groups having only 4 atoms in their cyclic system, but the aromatic heterocyclic groups must have at least five atoms in their cyclic system. Heterocyclic groups include benzo-fused cyclic systems and cyclic systems substituted with one or more oxo-fractions. An example of a five-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinoline. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, piperidino, morpholinyl, thiomorpholinyl, thioxanil, homopiperinidyl, oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl 1, 2,3,6-tetrahydropyridinyl, 2-pyrralinyl, 3-pyrrolinyl, indolinyl, "H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1 .0.] Heptanyl, 3H-indolyl and quinozinyl Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, nolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofuraz anyl, benzothiophenyl, benzotazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, derived from the compounds listed above, can be C-linked or N-linked where possible. For example, a group derived from pyrrole can be pyrrol-1-yl (N-linked) or pyrrole-3-yl (C-linked). The term "protecting group" refers to an appropriate chemical group that can be attached to a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various functional groups are described in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d Ed., John Wiley and Sons (1991) (hereinafter, "Grene and Wuts"); L. Fieser and M. Fieser, Reagents of Fieser and Fieser for Organic Synthesis. John Willey and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). The term "therapeutically effective amount" refers to an amount effective to treat or alleviate disorders involving gastrointestinal motility or an amount effective to increase gastrointestinal motility in a patient, one or the other as monotherapy or in combination with other agents. The term "treating" as used herein refers to the relief of symptoms of a particular disorder involving gastrointestinal motility in a patient, the improvement of an ascertainable measure associated with a particular disorder, or the increase of gastrointestinal motility, eg, to facilitate the placement of diagnostic or therapeutic instruments. As used herein, the term "patient" refers to mammals (including humans), fish or birds suffering from disorders characterized by impaired gastrointestinal motility or in need of increased gastrointestinal motility. The term "pharmaceutically acceptable carrier" refers to a carrier that can be administered to a patient together with a compound of this invention. The carrier does not destroy the pharmacological activity of the prokinetic agent and is not toxic when administered in sufficient doses to deliver a therapeutic amount of the prokinetic agent. The phrase "pharmaceutically acceptable salts", as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the present invention. The compounds of the present invention which are basic in nature are capable of forming a wide variety of salts with various organic and inorganic acids. The acids which can be used to prepare the pharmaceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, ie salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide salts , nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1 '-methylene-bis- (2-hydroxy-3-naphthoate)]. The compounds of the present invention that include a basic moiety, such as an amino group, can form pharmaceutically acceptable salts with various amino acids, in addition to the aforementioned acids. As used herein, unless otherwise indicated, "Ac" indicates an acetyl group. As used herein, unless otherwise indicated, "Me" denotes a methyl group. As used herein, unless otherwise indicated, "Et" denotes an ethyl group. Those compounds of the present invention that are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts, and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention. The present invention also includes isotopically labeled compounds, and pharmaceutically acceptable salts thereof, which are identical to those cited in formulas 1-7, but bearing in mind that one or more atoms are replaced by an atom with an atomic mass. or number of mass different from the atomic mass or number of mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 1 C, 15N, 18O, 35S, 18F, and 35CI, respectively. The compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or 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 in which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated isotopes, ie, 3 H and carbon-14 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 that result in greater metabolic stability, for example increased half-life in vivo or reduced dosage requirements and, therefore, can be preferred in some circumstances. Isotopically labeled compounds of formulas X7 of this invention and prodrugs thereof can generally be preferred by carrying out the procedures disclosed in the schemes and / or in the examples and preparations below, substituting an easily available isotopically labeled reagent for a non-reactive agent. Isotopically labeled. This invention also includes pharmaceutical compositions and methods for treating bacterial infections through administration of prodrugs of compounds of formulas X7. The compounds of the formulas 1 ^ 7 having free amino, amido, hydroxyl or carboxylic groups can be converted into prodrugs. The prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues is covalently linked through an amide or ester linkage with a free amino group, hydroxyl or carboxylic acid of the compounds of the formulas V7. Amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by 3-letter symbols and also include 4-hydroxyproline, hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid , citrulline, homocysteine, homoserin, ornithine and methionine sulfone. Additional types of prodrugs are also included. For example, free carboxyl groups can be derivatives such as amides or phosphate esters, dimethylaminoacetates, and phosphoryloxymethyl oxycarbonyl, as described in D. Fleisher, R. Bong, B.H. Stewart, Advanced Drug Release Reviews (1996) 19, 115. Carbamates of hydroxyl groups and amines are also included, such as carbonate prodrugs, sulfate esters, phosphate esters of hydroxyl groups. The derivatization of hydroxyl groups such as ethers (acyloxy) methyl and (acyloxy) ethyl wherein the acyl group can be an alkyl ester, optionally substituted with groups including but not limited to functionalities of ether, amine and carboxylic acid, or where the acyl group is an amino acid ester as described above, they are also included. Prodrugs of this type are described in R.P. Robinson, J. Med Chem. 1996, 39, 10. The present invention also includes pharmaceutical compositions for increasing the motility of the gastrointestinal tract comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier or diluent. These pharmaceutical compositions may comprise one or more additional reagents having a prokinetic or other therapeutic or prophylactic effect. The present invention also includes a method for increasing gastrointestinal motility in humans, other mammals, fish and birds in need of such treatment. This method can be used to treat disorders characterized by impaired gastrointestinal motility such as gastroesophageal reflux disease, pediatric gastroparesis, postoperative paralytic ileus, intestinal pseudo-obstruction, gallbladder stasis, systemic sclerosis, anorexia, gastritis, emesis and chronic constipation. Alternatively, this method can be used to facilitate the placement of diagnostic and therapeutic instruments, such as the insertion of feeding tubes into the proximal small intestine. The methods of the present invention comprise administering to a human, another mammal, fish or bird in need of such treatment, a therapeutically effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound as It was defined earlier. This invention contemplates methods of treatment in which the compounds of the present invention are administered either as a single agent or in combination with other therapeutic agents.

Unless otherwise indicated, references herein made to gastrointestinal disorders include disorders that occur in mammals, fish and birds, as well as related disorders that can be treated or prevented by the administration of the compounds of the present invention. Certain compounds of formulas X7 may contain one or more asymmetric carbons and therefore may exist in different isomeric forms. This invention includes all the individual pure enantiomers and individual diastereomers of the compounds of the formulas 1 7 and mixtures comprising any combination of these isomers. Each stereogenic carbon may be of the R or S configuration in particular, the invention includes both R and S configurations of the methyl group at C-8 and C-10 of the macrolite ring of the formulas J, and both E and Z isomers of the group -OR6 connected to the nitrogen of the C-9 oxime fraction of the macrolide ring of formulas 17.7 Although specific compounds exemplified in this application can be described in a particular stereochemical configuration, compounds having both the opposite stereochemistry in any chiral center given or mixtures thereof are also contemplated. The compounds of the formulas 1-7 can also additionally exist as tautomers. This invention includes all these pure tautomers and mixtures thereof. The invention includes uses of any of the above compounds or mixtures of the compounds.

DETAILED DESCRIPTION OF THE INVENTION The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated 5 a, R 1, R 2, R 3, R 4, R 5, R 6, R 7 a, R 12, W, X 1, X 2, Y and Z are defined as above.

PREPARATION A fifteen SCHEME 1 SCHEME 2 SCHEME 3 where R3 is azido SCHEME 4 9 NC / Me groups are trans SCHEME 5 In the reaction of preparation A, the compound of formula B wherein R11 is a leaving group, such as alkylsulfonyloxy (CrC6), allylsulfonyloxy (C8-C10), acyloxy (Ci-Cß) or imidizolyl-carbonyloxy, is converted into the corresponding ketene acetal compound of the formula 9 treating 8 with a base, such as 1-8-diazabicyl [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, ethyldiisopropylamine , triethylamine, lithium examethyldisilazide, preferably 1,8-diazabicyclo [5.4.0] unded-7-ene, in the presence of a polar aprotic solvent, such as acetonitrile, dimethylformamide, tetrahydrofuran, preferably acetonitrile. The reaction is stirred at a temperature between about 20 ° C and about 100 ° C, preferably about 80 ° C, for a period of time between about 0.5 and about 6 hours, preferably about 2 hours. The initial compound of formula 8 can be prepared as described in the patent of E.U.A. No. 5,543,400. The starting compounds of formula 8 wherein R4 are several groups can be prepared as described in WO 98/09978. In the reaction of scheme 1, the conversion of 9 to 1 is performed by mixing ketene acetal 9 with a nucleophile at room temperature or elevated temperature (up to 100 ° C) in an inert solvent such as acetonitrile or trifluoroethanol. The process can be catalyzed by the addition of acid such as acetic acid or a base such as triethylamine. When R3 is R6NH-, R60- and R6 is substituted with a terminal amino group, hydroxyl or thiol, or a protected amino group, protected hydroxyl, or protected thiol, the compound 1 can then be converted to 2 by heating this compound in a solvent inert such as acetonitrile or THF. The temperature can be between room temperature and 100 ° C. Some salts such as Yb (OTf) 3 and Sc (OTf) 3 can be used as a catalyst. The process can also be catalyzed by the addition of acid such as acetic acid or SnCl. When X2 is NH, the compound 2 can further be converted to 3 by a reductive amination with R6 -CHO and a reducing agent such as NaBH3CN or NaBH (OAc) 3. This reaction can be carried out between 0 ° and 50 ° C in a solvent such as ethanol, acetic acid, or THF. In scheme 2, compound 1, in which R3 is R6NH, is first converted to 4 by the action of phosgene or carbonyl dimidazole and ammonium or amine in an inert solvent such as THF. Compound 4 can then be converted to 5 by heating between 50 ° and 100 ° C in an inert solvent such as acetonitrile or THF. The process can also be catalyzed by the addition of acid such as acetic acid or SnCl. Alternatively, compound 4 can be converted to 5 by the action of SnCl 4 and NBS in an aprotic solvent such as CH 2 Cl 2 at low temperatures, preferably between -20 ° and 0 °. In scheme 3, compound 9 is converted to 1 and 6 by the action of azidotrimethylsilane and tetrabutylammonium fluoride in an inert solvent such as THF at room temperature wherein R3 of formula 1 is N3.

In scheme 4, compound 9 is converted to 7 by the action of trimethylsilyl cyanide and tetrabutylammonium fluoride in an inert solvent such as THF at room temperature. In scheme 5, when R1 is a protective hydroxyl group, compound 2, 3, or 5 generated in scheme 1 or 2 can be halogenated in C2 and converted to compound 2 ', 3' or 5 '. Compound 2, 3 or 5 is treated with a strong base such as KHMDS (potassium hexamethyldisilazide) at low temperature (-78 ° C) in CH 2 Cl 2 and then treated with a halogenating agent such as SELECTOFLUOR ™. R13a in the compound 2 ', 3' or 5 'can be Fl, Cl, Br or l. The compounds of the present invention may have recently generated asymmetric carbon atoms. Such diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. All these isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention. The C8 epimers are specifically claimed. The compounds of the formulas 1-7 which are basic in nature are capable of forming a wide variety of salts with various organic and inorganic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formulas 1-7 from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter into a compound of free base by treatment with an alkaline reagent and subsequently converting the last free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base 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 ethanol or methanol. Upon careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution. Those compounds of formulas 1-7 which are acidic in nature are capable of forming basic 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 basic salts of this invention are those which form non-toxic basic salts with the acidic compounds of the formulas 1-7. Such non-toxic basic salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be prepared by treating the 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, these may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same way as above. In any case, stoichiomeric amounts of reagents are preferably used in order to ensure the integrity of the reaction and maximum yields of the desired final product. The activity of the compounds of the present invention against bacterial and protozoan pathogens is demonstrated by the ability of the compounds to inhibit the development of defined strains of human (Test 1) or animal (Test II and III) pathogens.

Test I The test I described below employs conventional methodology and criteria of interpretation and is designed to provide direction to chemical modifications that can lead to compounds that encircle defined mechanisms of macrolide resistance. In trial I, the panel of bacterial strains is assembled to include a variety of target pathogenic species, including representatives of macrolide resistance mechanisms that have been characterized. The use of this panel allows the chemical activity / structure relationship to be determined with respect to the power, spectrum of activity, and structural elements or modifications that may be necessary to obviate resistance mechanisms. The bacterial pathogens that comprise the classification panel are shown in the table below. In many cases, both the parenteral strain susceptible to macrolides and the macrolide-resistant strain derived therefrom are available to provide a more accurate assessment of the ability of the compound to circumvent the mechanism of resistance. Strains containing the gene with the designation of ermA / ermB / ermC are resistant to antibiotics macrolides, liconsamides, and streptogramin B due to modifications (methylation) of 23S rRNA molecules by an Erm methylase, whereby the binding of all three structural classes. Two types of macrolide flux have been described: msrA encodes a component of a staphylococcal flow system that prevents the entry of macrolides and streptogramins while mefA / E encodes a transmembrane protein that appears to emanate only macrolides. Inactivation of macrolide antibiotics can occur and can be mediated by either a 2'-hydroxyl phosphorylation (mph) or by decomposition of the macrocyclic lactone (esterase). The layers can be characterized using conventional polymerase chain reaction (PCR) technology and / or sequencing of the resistance determinant. The use of PCR technology in this application is described in J. Sutcliffe, "Detection of Determinants Resistant to Erythromycin by PCR", Antimicrobial Agents and Chemotherapy, 40 (11), 2562-2566 (1996). The test is carried out in microtitre trays and interpreted according to Performance Standards for Antimicrobial Discs Susceptibility Tests - Sixth Edition; Approved Standard, published by guidelines of the National Committee for Clinical Laboratory Standards (NCCLS); The minimum inhibitory concentration (MIC) is used to compare strains. The compounds are initially dissolved in dimethylsulfoxide (DMSO) as concentrated solutions of 40 mg / ml.

Test II is used to test activity against Pasteurella multocida and assay III is used to test activity against Pasteurella haemolylica.

Test II This test is based on the liquid dilution method in microtitre format. A simple 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 dimethylsulfoxide (DMSO). Dilutions of the test compound are prepared using uninoculated BHI broth. The concentrations of the test compound used a range from 200 μg / ml to 0.098 μg / ml by serial double dilutions. The inoculated BHI of P. multocida is diluted with uninoculated BHI broth to make a suspension of 104 cells per 200 μl. BHI cell suspensions are mixed with respective serial dilutions of the test compound, and incubated at 37 ° C for 18 hours. The minimum inhibitory concentration (MIC) is equal to the concentration of the compound exhibiting 100% inhibition of P. multocida development as determined by comparison with a non-inoculated control.

Test lll This test is based on the agar dilution method using a Steers Replicator. Two to five colonies isolated from an agar plate are inoculated in BHI broth and incubated overnight at 37 ° C with shaking (200 rpm). The next morning, 300 μl of fully developed P. haemolytica preculture is inoculated in 3 ml of fresh BHI broth and incubated at 37 ° C with shaking (200 rpm). The appropriate amounts of the test compounds are dissolved in ethanol and a series of serial double dilutions are prepared. Two ml of respective serial dilution is mixed with 18 ml of BHI agar and solidified. When the inoculated culture of P. haemolytica reaches the standard density of 0.5 McFarland, approximately 5 μl of the p culture. haemolytica is inoculated on BHI agar plates containing the different concentrations of the test compound using a Steers Replicator and incubated for eighteen hours at 37 ° C. The initial concentrations of the test compound range from 100-200 μl. The MIC is equal to the concentration of the test compound exhibiting inhibition of 100% growth of P. haemolytica as determined by comparison with a non-inoculated control. The in vivo activity of the compounds of formulas 1-7 can be determined by conventional animal protection studies well known to those skilled in the art, usually performed in mice. Mice are assigned to cages (10 per cage) at the time of 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 3 x 103 CFU / ml intraperitoneally (P. multocida strain 59A006). Each experiment has at least 3 non-medicated control groups including one infected with challenge dose of 0.1X and two infected with challenge dose 1X; A group of 10X challenge data can also be used. Generally, all mice in a given study can be challenged within 30-90 minutes, especially if a repeating syringe (such as a Comwall® syringe) is used to administer the challenge. Thirty minutes after starting the challenge, the first compound treatment is provided. It may be necessary for a second person to start dosing compounds if all animals have not been challenged at the end of 30 minutes. Administration routes are in subcutaneous or oral doses. Subcutaneous doses are administered to the loose skin on the back of the neck while oral doses are given by means of a feeding needle. In both cases, a volume of 0.2 ml is used per mouse. The compounds are administered 30 minutes, 4 hours, and 24 hours after the challenge. A control compound of known efficacy administered by the same route is included in each test. The animals are observed daily, and the number of survivors in each group is recorded. Monitoring the P. multocida model continues for 96 hours (4 days) after the challenge. The PD50 is a calculated dose in which the tested compound protects in a 50% a group of mice the mortality due to bacterial infection which would be lethal in the absence of drug treatment.

The compounds of formulas 2, 3, and 5 and the pharmaceutically acceptable salts, prodrugs and solvates thereof (hereinafter "the active compounds"), can be administered via oral, parenteral, topical, or rectal routes. in the treatment or prevention of bacterial or protozoal infections. In general, these compounds are most desirably administered in doses in the range between 0.2 mg per kg of body weight per day and 200 mg per kg of body weight per day in approximately single or divided doses (ie, from 1 to 4 doses per day), although variations would necessarily occur depending on the species, the weight and condition of the subject treated and the particular route of administration chosen. However, a dosage level that is in the range between 4 mg / kg / day and 50 mg / kg / day approximately is preferably employed. However, variations may occur depending on the species of mammal, fish or bird treated and their individual response to said medicament, as well as depending on the type of pharmaceutical formulation chosen and the period of time and interval in which such administration is carried out. . In some instances, dosage levels below the lower limit of the aforementioned range may be more adequate, while in other cases even higher doses may be employed without producing any harmful side effects, as long as such higher doses are first divided into several doses small for administration during the day.

The active compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the previously indicated routes, and such administration can be carried out in single or 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 several inert pharmaceutically acceptable carriers in the form of tablets, capsules, lozenges, troches, candies, powders, sprays, creams , ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, the oral pharmaceutical compositions may be appropriately sweetened and / or flavored. In general, the active compounds are present in such dosage forms at concentration levels in a range between about 5.0% and 70% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used together with various disintegrants such as starch (preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium Iauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this connection also include lactose or lactin as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if desired, also emulsifying and / or suspending agents, together with such diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions of an active compound in any sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be appropriately buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular injection purposes, intramuscular and subcutaneous. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques known to those skilled in the art. Additionally, it is also possible to administer the active compounds of the present invention topically and this can be done by means of creams, jellies, gels, pastes, patches, ointments and the like, according to standard pharmaceutical practice. For administration to animals other than humans, such as domestic animals or livestock, the active compounds may be administered in the animal feed or orally as a purge composition. The active compounds can also be administered in the form of liposome delivery systems, such as small unilaminal vesicles, large unilaminal 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 coupled with soluble polymers as carriers of objective drugs. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenyl, polyhydroxyethylaspartamide-phenyl, or polyethylene-polylysine oxide substituted with palmitoyl residues. In addition, the active compounds can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polypepsilon caprolactone, polyhydroxyl butyric acid, polyorthoesters, polyacetals, polyhydropyrans, polyanoacrylates and cross-linked or antipathetic block copolymers of hydrogels.

The compounds of this invention can be co-administered with other compounds of this invention or with other prokinetic compounds to increase the effect of the therapy. The combination therapies according to the invention can exert an additive or synergistic prokinetic effect, for example, since each agent component of the combination can act on a different site or through a different mechanism. The use of such combination therapies can also advantageously reduce the dosage of a given conventional procinetic agent, which would be required for a desired therapeutic effect, in comparison when such an agent is administered as a monotherapy. Such combinations may reduce or eliminate the side effects of conventional prokinetic therapies as long as they do not interfere with the prokinetic activity of those agents. These combinations reduce the potential for resistance to single agent therapies, while minimizing any associated toxicity. Alternatively, the pharmaceutical compositions according to this invention may be comprised of a combination of a compound of this invention and another agent with a different therapeutic or prophylactic effect. The examples given below illustrate specific embodiments of the invention, but the scope of the invention is not limited to the examples specifically presented.

EXAMPLE 1 To a ketene acetal solution (9.6 mg, 0.01 mmol) in 5 mL of ethanol was added 2-aminoetone thiol (1 mg, 0.01 mmol). After stirring 1 hour at room temperature, the ethanol was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 0.1 M sodium hydroxide solution and brine. This was dried Na2SO4 and evaporated. The residue was chromatographed on SiO2 (TLC plate, 6% MeOH, 0.5% NH4OH CH2 Cl2) to give 2 mg of the purified product: MS m / e 671 (M + 1).

EXAMPLE 2 Cetene acetal (9, 100 mg, 0.17 mmol) was dissolved in 1 mL of 2-mercaptoethanol and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with 0.005 M sodium hydroxide solution. The organic layer was further washed with water and brine, and dried over Na2SO. The ethyl acetate was removed under reduced pressure and the residue was chromatographed on SiO2 (preparative TLC, acetone: hexane = 1: 1) to yield 30 mg of the desired product: MS m / z 672 (M + 1).

EXAMPLE 3 Cetena acetal (9, 28 mg, 0.03 mmol) was suspended in 2 mL of ethylene glycol. A small amount of acetonitrile was added to make a homogeneous solution. The solution was heated at 50 ° C for 4 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The ethyl acetate was washed with water and dried over Na2SO4. Evaporation of the solvent produced 28 mg of the crude product: MS m / e 614 (M + 1).

EXAMPLE 4 Cetena acetal (9, 28 mg, 0.05 mmol) was dissolved in 3 mL of ethylenediamine and heated at 60 ° C for 1 hour. The reaction mixture was poured into 20 mL of water. The reaction mixture was poured into 20 mL of water. The resulting aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. Drying over Na2SO and evaporating the solvent gave 26 mg of the crude product: MS m / e (M + 1).

EXAMPLE 5 To a solution of azidotrimethylsilane (26ul, 0.20 mmoles) and tetrabutylammonium fluoride (190 μL of 1 M solution in THF) in 3 mL of THF was added ketene acetal (9, 100 mg, 0.17 mmole). The solution was stirred at room temperature for 3 days. The solvent was evaporated and the residue was chromatographed on SiO2 (prep TLC, acetone: hexane = 1: 1) to yield 27 mg of V. MS m / e 637 (M + 1); and 7 mg of 6: MS m / e 637 (M + l).

EXAMPLE 6 To a solution of trimethylsilyl cyanide (27 μL, 0.20 mmol) and tetrabutylammonium fluoride (253 μL of 1 M solution in THF, 0.26 mmol) in 3 mL of THF was added ketene acetal (9 150 mg, 0.17 mmol). The solution was stirred at room temperature for 1 hour, then diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated. The residue was chromatographed over S¡02 (acetone: hexane = 3.7) to yield 75 mg of 7: MS m / e 621 (M + 1).

Claims (8)

1. NOVELTY OF THE INVENTION CLAIMS 1.- A compound of the formula fifteen or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein: a is 0 or 1; X1 is = O or = NOR6; X2 is NH, O, S, or CH2; R1 is hydrogen a hydroxyl protecting group; R2 is H, C1-C6 alkyl, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, C2-C5 alkenyl, C2-C6 alkynyl, (C1-C6 alkoxy) C1-C6 alkyl, (C1-C6 alkylthio) C1-C6 alkyl , - (CR10R11) m (C6-C10 aryl), and - (CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer from 0 to 6, and the preceding R2 groups, except hydrogen, they are optionally substituted by one or three substituents of R8; R 4 is hydrogen or C 1 -C 10 alkyl optionally substituted by one or two R 8 groups; R5 is -C (O) -, cyano, -C (NH2) N-, or (C2-4) alkylene wherein the alkylene group is optionally substituted by one to three substituents R8; each R6 is independently selected from hydrogen, C1-C6 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, (C3-C10 cycloalkyl) C1-C6 alkyl, - (CR10R1) m (C6-C10 aryl), and - ( CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer from 0 to 6; and the preceding R6 groups, except hydrogen, are optionally substituted by one or three substituents of R8; R7a is hydrogen or methyl; each R8 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, and trifluoromethoxy, azido, -OR9, -C (0) R9, -C (O) OR9, -NR10C (O) OR12, -OC (O) R9, -NR10SO2R12, -SO2NR9R10, -NR10C (O) R9, -C (O) NR9R10, -NR9R10, -S (O) j (CR10R11) m (C6 aryl) -C10), -S (O) j (C1-C6 alkyl), wherein j in an integer from 0 to 2, - (CR10R11) m (4 to 10 membered heterocyclic), wherein m is independently an integer of 0 to 4; said alkyl, alkenyl and alkynyl groups optionally contain 1 or 2 hetero selected fractions of O, -S (O) j- wherein j is an integer from 0 to 2, and -N (R9) - with the proviso that two atoms of Or, two S atoms, or one O and S atom are not directly linked together, and the condition that an S atom or an N atom is not directly linked to a triple bond or an aromatic double bond; said cycloalkyl, aryl and heterocyclic R2 groups are optionally fused to a C6-C10 aryl group, a C5-C8 cycloalkyl, or a 4- to 10-membered heterocyclic group; and said alkyl, cycloalkyl, aryl and heterocyclic R2 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro trifluoromethyl, difluoromethyl, trifluoromethoxy, azido, -NR10SO2R12, -NR10C (O) R9, -C ( O) NR9R10, -NR9R10, -OR9, C1-C10 alkyl, - (CR10R11) m (C6-C10 aryl), and - (CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer from 0 to 4; each R9 is independently selected from H, C1-C10 alkyl, - (CR10R11) m (C6-C10 aryl), and - (CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer of 0 to 4; said alkyl group optionally includes 1 or 2 hetero fractions selected from O, -S (O) j- wherein j is an integer 0 to 2, and -N (R10) - with the proviso that two O atoms, two atoms S, or an atom of O and S are not directly linked together; said cycloalkyl, aryl, and heterocyclic R9 groups are optionally fused to a C6-C10 aryl group, a C5-C8 cycloalkyl group, or a 4- to 10-membered heterocyclic group; and the foregoing R9 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difiuoromethoxy, trifluoromethoxy, azido, -C (O) R107 -OC (0) R1 °, -NR10C (O) R11, -C (O) NR10R11, NR10R11, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy, and with the proviso that R9 must be attached through a carbon atom unless R9 is H; each R 10 and R 1 is independently H or C 1 -C 6 alkyl; each R12 is selected from among the substituents supplied in the definition of R9 except that R12 is not H; and with the proviso that when a is zero, R4 is hydrogen Y is NH, O, or S; W is O or S; Z is -N (R6) -, O, S, or -CH (R14), wherein R14 is H, N02, CN, -C (0) R9, or C (0) OR9; R13 is H or halo.
2. 2. A pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, and a disorder related to a bacterial or protozoal infection, in a mammal, fish or bird, which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
3. 3. The use of a compound as claimed in claim 1 for the manufacture of a medicament for a method for treating a disorder selected from a bacterial infection, a protozoal infection, and a disorder related to a bacterial or protozoal infection , in a mammal, fish or bird.
4. 4. The use of a compound as claimed in claim 1, for the manufacture of a medicament for treating cancer or atherosclerosis in a mammal. 5.- A compound of the formula or a salt or solvate thereof, wherein: a is 0 or 1; X1 is = 0 or = NOR6; R1 is hydrogen a hydroxyl protecting group; R2 is H, C1-C6 alkyl, C3-C10 cycloalkyl; C5-C10 cycloalkenyl, C2-C5 alkenyl, C2-C6 alkynyl, (C1-C6 alkoxy) C1-C6 alkyl, (C1-C6 alkylthio) C1-C6 alkyl, - (CR10R11) m (C6-C10 aryl), and - (CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer from 0 to 6, and the preceding R2 groups, except hydrogen, are optionally substituted by one or three substituents of R8; R3 is hydrogen or methyl optionally substituted by one or two groups independently selected from nitro, cyano, R6C (0) and R6OC (0); or R3 is azido, -OR6, - (CR10R11) mNR10R6 or -SR6; R 4 is hydrogen or C 1 -C 10 alkyl optionally substituted by one or two R 8 groups; each R6 is independently selected from hydrogen, C1-C6 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, (C3-C10 cycloalkyl) C1-C6 alkyl, -CR10R11) m (C6-C10 aryl), and - (CR10R11) m (4 to 10 membered heterocyclic), wherein each m is independently an integer from 0 to 6; and the preceding R6 groups, except hydrogen, are optionally substituted by one or three substituents of R8; R7a is hydrogen or methyl; each R8 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR9, -C (0) R9, -C ( 0) OR9, -NR10C (O) OR12, -OC (0) R9, -NR10SO2R12, -S02NR9R1 °, -NR10C (O) R9, -C (0) NR9R10, -NR9R10, -S (O) j (CR10R11 ) m (C6-C10 aryl), -S (O) j (C1-C6 alkyl), wherein j is an integer from 0 to 2, - (CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer from 0 to 4; said alkyl, alkenyl and alkynyl groups optionally contain 1 or 2 hetero fractions selected from O, -S (O) G wherein j is an integer from 0 to 2, and -N (R9) - with the proviso that two O atoms , two atoms of S, or an atom of O and S are directly linked together, and the condition that an atom of O, an atom of S or an atom of N are not directly linked to a triple bond or an aromatic double bond; said cycloalkyl, aryl and heterocyclic R2 groups are optionally fused to a C6-C10 aryl group, a C5-C8 cycloalkyl, or a 4- to 10-membered heterocyclic group; and said alkyl, cycloalkyl, aryl and heterocyclic R2 groups are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR10SO2R12, -NR10C (O) R9, -NR9R10 , -OR9, C1-C10 alkyl, - (CR10R11) m (C6-C10 aryl), and - (CR10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer from 0 to 4; each R9 is independently selected from H, C1-C10 alkyl, - (CR10R11) m (C6-C10 aryl), and - (R10R11) m (4- to 10-membered heterocyclic), wherein each m is independently an integer of 0 to 4; said alkyl group optionally includes 1 or 2 hetero fractions selected from O, -S (O) j- wherein j is an integer between 0 to 2, and -N (R10) - with the proviso that two O atoms, two atoms of S, or an atom of O and S are directly linked together; said cycloalkyl, aryl, and heterocyclic R9 groups are optionally fused to a C6-C10 aryl group, a C5-C8 cycloalkyl group, or a 4- to 10-membered heterocyclic group; and the foregoing R9 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R10, -OC (O) R10, -NR10C (O) R11, -C (O) NR10R11, NR10R11, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy, and with the proviso that R9 must be attached through a carbon atom unless R9 is H; > 10) 11 12 each R and R is independently H or C 1 -C 6 alkyl; each R is selected from among the substituents supplied in the definition of R9 .12 14. except that R1 is not H; W is O or S; Z is -N (R &) -, O, S, or -CH (R 'where R14 is H, NO2, CN, -C (O) R9 or C (O) OR9, and with the proviso that when a is zero, R4 is hydrogen 6. A compound according to claim 5 wherein said compound is a compound of formula 1 and is 1, X1 is O, R is H, R2 is CH2CH3 and R4 is hydrogen. A compound according to claim 6 wherein R3 is S (CH2) 2NH2, S (CH2) 2OH, 0 (CH2) 2OH, or NH (CH2) 2OH 8. A compound according to claim 5 wherein said compound is a compound of the formula 7 is already 1, X1 is O, R1 is H, R2 is CH2CH3 and R4 is CH3.