MXPA01000120A - 4-oxo-2-ureido-1,4,5,6-tetrahydro-pyrimidine derivatives useful as antibacterial and antiprotozoal agents - Google Patents

Abstract

The present invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein Z, R<1>, R<9>, and R<10>are as defined herein. The invention also relates to pharmaceutical compositions containing the above compounds and to methods of treating bacterial and protozoal infections in mammals by administering the above compounds.

Description

DERIVATIVES OF 4-OXO-2-URE1DO-1, 4,5,6-TETRAHIDRO-PIRIMlPlNA FIELD OF THE INVENTION This invention relates to novel compounds which are useful as antibacterial agents and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and methods for treating bacterial and protozoal infections in mammals, fish and birds by administering the novel compounds in mammals, fish and birds that require such treatment.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of the formula: and with pharmaceutically acceptable salts, prodrugs and solvates of the mimes, wherein: Z is a group having the following structure wherein X is - (CH2) n- and n is 0 or 1; R1 is selected from the different α-carbon side chain substituents on naturally occurring amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine; or R1 is selected from the different α-carbon side chain substituents on the amino acids selected from hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone; or R1 is selected from H, alkyl CIC-IO, C2-C10 alkenyl, C2-C10 alkynyl, - (CR4R5) t (C3-C10 cycloalkyl), (CR4R5) t (C6-C10 aryio), - (CR4R5) t (heterocyclic of 4 to 10 members), and C (0) R3, wherein each t is independently an integer between 0 and 5, said alkyl, alkenyl and alkynyl groups optionally containing one or two hetero fractions selected from O, -S (O) j- where j is an integer between 0 and 2, and -N (R4) -as long as two atoms of O, two atoms of S, or one atom of O and S are not directly linked together, and provided that an atom of O, an atom of S or an atom of N are not directly bound to a triple bond or a non-aromatic double bond; said cycloalkyl, aryl and heterocyclic R 1 groups are optionally fused with a benzene ring, a Cs-Cs cycloalkyl group, or a 4- to 10-membered heterocyclic group; the fractions of (CR4R5) - of the above groups R1 optionally include a double or triple carbon-carbon bond where t is an integer between 2 and 5; and the above R1 groups, except H but including any optional fused ring mentioned above, are optionally substituted by 1 to 5 R2 groups, and with the proviso that R1 must be linked through a carbon atom unless R1 is H; and as long as that if Z is then R1 can not be H; each R2 is independently selected from C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR3, -C (O) R3, C (O) OR3, -NR4C (O) OR6, -OC (O) R3, -NR4SO2R6, -SO2NR3R4, -NR4C (O) R3, -C (O) NR3R4, -NR3R4, -S (O) j ( CR4R5) m (C6-C10 aryl), -S (O) j (d6C6 alkyl), where j is an integer between 0 and 2, - (CR4R5) m (C6-C aryl 0), -O (CR4R5) m (C6-C10 aryl), -NR4 (CR4R5) m (C6-C10 aryl), and - (CR4R5) m (4- to 10-membered heterocyclic group), wherein each m is independently an integer between 0 and 4; said alkyl, alkenyl and alkynyl groups optionally contain one or two hetero fractions selected from O, -S (O) j- wherein j is an integer between 0 and 2, and -N (R3) - with the proviso that two atoms of Or, two atoms of S, or an atom of O and S or are directly linked together, and provided that an atom of O, an atom of S or an atom of N are not directly linked to a triple bond or a non-aromatic double bond; said cycloalkyl, aryl and heterocyclic R2 groups are optionally fused to an aryl group Cedo, a C5-C8 cycloalkyl group, 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, trifiuoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C (O) R3 , -C (O) OR3, -OC (O) R3, NR4C (O) OR6, NR4C (O) R3, -C (O) NR3R4. -NR3R4, -OR3, d-C10 alkyl, - (CR4R5) m (aryl Cedo), and (CR4R5) m (heterocyclic group of 4 to 10 members), wherein each m is independently an integer between 0 and 4; each R3 is independently selected from H, d-C10 alkyl, - (CR4R5) m (C6-C? 0 aryl), and - (CR4R5) m (4- to 10-membered heterocyclic group), wherein each m is independently a whole between 0 and 4; said alkyl group optionally includes one or two hetero fractions selected from O, -S (O) j- wherein j is an integer between 0 and 2, and -N (R4) - with the proviso that two O atoms, two atoms of S, or an atom of O and S are not directly linked together; said cycloalkyl, aryl and heterocyclic R3 groups are optionally fused with a Ce-Cio aryl group, a C5-C8 cycloalkyl group, or a 4- to 10-membered heterocyclic group; and the foregoing substituents R3, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R4, -C (O) OR4, -OC (O) R4, NR4C (O) R5, -C (O) NR4R5, NR4R5, hydroxyl, d-C6 alkyl, and C-Cβ alkoxy, with the proviso that R3 must be attached through a carbon atom to less than R3 is H; each R 4 and R 5 is independently H or d-C 6 alkyl; each R6 is selected from the substituents provided by the definition of R3 except that R6 is not H; R7 is selected from the a-carbon substituents on naturally occurring amino acids, as defined in R1, as well as the a-carbon substituents on the amino acids between hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, citrulline, homocysteine , homoserin, ornithine and methionine sulfone; R8 is H, C? -C6, - (CR4R5) t (C3-C10 cycloalkyl), - (CR4R5) t (aryl Ce-Cio), or - (CR4R5) t (heterocyclic group of 4 to 10 members), where t is integer between 1 and 5; R9 is independently H or C1-C5 alkyl, and, R10 is H, C6 alkyl, - (CR4R5) t (C3-C10 cycloalkyl), - (CR4R5) t (C6-C aryl 0), or - (CR4R5) t (heterocyclic group of 4 to 10 members), where t is an integer between 0 and 5.

As an example of R1 or R7 as an α-carbon side hip substituent on naturally occurring amino acids, R1 or R7 can be methyl or - (CH2) 3NHC (NH) NH2 of alanine or arginine, respectively.

In the first preferred embodiment of the compound of formula 1: Z is and R1 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CR4R5) t (C3-C10 cycloalkyl), - (CR4R5) t (C6-C6 o aryl), or - (CR4R5) t (heterocyclic group of 4 to 10 members), wherein each t is independently an integer 0 and 5, said alkyl, alkenyl and alkynyl groups optionally containing one or two hetero fractions selected from O, -S (O) j- wherein j is integer between 0 and 2, and -N (R4) - with the proviso that two O atoms, two S atoms, or one O and S atom are not directly bonded together, and with the proviso that one atom of Or, an S atom or an N atom are not directly linked to a triple bond or a non-aromatic double bond; said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused with a benzene ring, a C5-C8 cycloalkyl group, or a 4- to 10-membered heterocyclic group; the fractions - (CR4R5) - of the above groups R1 optionally include a double or triple carbon-carbon bond where t is an integer between 2 and 5; and the preceding R1 groups, including any optional fused ring mentioned above, are optionally substituted by 1 to 5 R2 groups, and with the proviso that R1 must be linked through a carbon atom; and R9 and R10 are as defined above. In the second preferred embodiment of the compound of formula 1 the preferred groups are as indicated in the first preferred embodiment, except that R9 and R10 are H. Specific embodiments of the present invention include the following compounds as well as salts, prodrugs and pharmaceutically acceptable solvates of the following compounds: 3S-amino-6-methyl-5S-amino-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -amide -guanidino-hexane; 3S-amino-6-guanidino-hexanoic acid methyl- (5R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -amide; 3S-amino-6-guanidino-hexanoic 5S-ethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -methyl-amide; (3S-amino-6-guanidinohexanoic acid 5R-ethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidon-5-yl) -methyl-amide; (3S-amino-6-guanido-hexanoic acid 5S-hydroxymethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -methyl-amide; 3S-amino-6-guanidino-hexanoic acid 5S-hydroxymethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -methyl-amide; (3S-amino-6-guanidino-hexanoic acid 5R-fluoromethyl-4-oxo-2-uretho-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -methyl-amide; (3S-amino-6-guanidino-hexanoic acid 5S-fIuoromethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -methyl-amide; [5S- (4-amino-butyl) -4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl] -amide of 3S-amino-6-guanidino-hexanoic acid; 3S-amino-6-guanidino-hexanoic acid [5R- (4-amino-butyl) -4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl] -amide; [5S- (3 H-imidazol-4-ylmethyl) -4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl-amide of 3S-amino-6-guanidino-hexanoic acid; [5R- (1 H-imidazol-4-ylmethyl) -4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl] -amide of 3S-amino acid 6-guanidino-hexanoic; (3S-amino-6-guanidino-hexanoic acid 5S-carbamoylmethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -amide; (3S-amino-6-guanidino-hexanoic acid 5R-carbamoylmethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -amide; (3S, 7-diamino-heptanoic acid 5S-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydiO-pyrimidin-5-yl) amide; (3S, 7-diaminoheptanoic acid 5R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) amide; 3S-amino-4- (1 H-imidazol-4-yl) -N- (5R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -butyramide; 3R-amino-4- (1 H-imidazol-4-yl) -N- (5R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -butyramide; 3R-amino-6-guanidino-haxanoic acid methyl- (5S-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -amide; Methyl- (3R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -amide of 3R-amino-6-guanidino-hexanoic acid; 3S-Amino-4- (1 H -indol-3-yl) -N- (5R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) - Butyramide; 3S-Amino-4- (1 H -indole-3-yl) -N- (5 S -methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -butyramide; (2S-amino-5-guanidino-pentanoic acid 5R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide; (5S-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide of 2S-amino-5-guanidino-pentanoic acid; 2R-Methylene-4-oxo-2-uretho-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide of 2R-amino-5-guanidino-pentanoic acid; 2R-amino-5-guanidino-pentanoic acid 5S-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide; 3R-amino-6-guanidino hexanoic acid (5S-hydroxymethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -methyl-amide: ( 3R-amino-6-guanidino-hexanoic acid 5R-hydroxymethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -methyl-amide; (3R-amino-6-guanidino-hexanoic acid 5R-fluoromethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -methyl-amide; and, 3R-amino-6-guanidino-hexanoic acid (5S-fluoromethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl) -methyl-amide. The invention also relates to a pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula 1, a prodrug thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention also relates to a pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula 1, a prodrug thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam antibiotic, quinolone, tetracycline, streptrogramin, aminoglycoside, glycopeptide, macrolide or oxazolidinone; a combination with a compound which inhibits the bacterial or protozoan expulsion flow or degradation of a compound according to formula 1. The invention also relates to a method for treating a disorder selected from a bacterial infection, a protozoal infection, and related disorders. with bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises the administration to said mammal, fish or bird of a therapeutically effective amount of a compound of formula 1, a prodrug thereof, a solvate thereof or a pharmaceutically acceptable salt thereof. The invention also relates to a method for treating a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises administration to said mammal, fish , or bird of a therapeutically effective amount of a compound of formula 1, a prodrug thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, in combination or co-administered with a beta-lactam antibiotic, quinolone, tetracycline , streptogramin, aminoglycoside, glycopeptide, macrolide or oxazolidinone; or in combination with a compound which inhibits the bacterial or protozoan expulsion flow or degradation of a compound according to formula 1. The term "treat" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting progress, or avoiding the disorder or condition to which that 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 herein, unless otherwise indicated, the terms or phrases "bacterial infections," "protozoan infections," and "disorders related to bacterial infections or protozoal infections" include but are not limited to the following: pneumonia, otitis , sinusitis, bronchitis, tonsillitis and mastoiditis, related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Morzolla catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. cassolflavus, S. epidermidis, S. hemolylictus, or Peptosireptococcus ssp.; pharyngitis, rheumatic fever, and glomerulonephritis associated with infection by Streptococcus pyogenes, Group C and G streptococcus, Corinebacterium diphtheriae, 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 osteomyelitis, caused by S. aurens, S. haemoliticus, E. faecalis, E. faecium, E. durans, including known anti-bacterial resistant strains such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines, oxazolidinones, and macrolides; uncomplicated infections of skin and soft tissue and abscesses, puerperal fever related to infection by Staphylococcus aureus, coagulase negative staphylococcus (ie, S. epidermitis, S. hemoliticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal CF groups (streptococci of minute colonies), viridans streptococci, Corinebacterium minutissimum, Clostridium spp., or Bartonella henselae; acute infections without complication of the urinary tract related to infection by Straphylococcus aureus, coagulase negative staphylococcal 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; 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 recurrentis, Lyme disease related to Borrelia burgdorferi infection; conjunctivitis, keratitis, and dacrosistitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp .; Disease disseminated by Mycobacterium avium complex (MAC) related to infection by Mycobacterium avium, or Mycobacterium intracellulare; infections caused by Mycobacterium tuberculosis, M. leprae, M. paratuberculosis, M. kansallil, 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 períringens 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, which can be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. multocida, Mycoplasma bovis, or bordetella spp .; bovine enteric disease related to infection by protozoa (ie, coccidia, cryptosporidia, etc); Dairy cow mastitis related to infection by S. aureus, Strep. uberis, Streptococcus agalectiae, Streptococcus dysgalactiae, Corynebacterium, or Enterococcus spp .; respiratory disease of pigs related to A pleuro infection, P. multicida, or Mycoplasma spp .; Enteric disease of pigs related to infection by Lawsonia intracellularis, Salmonella, or Serpulina hyodysinteriae; savanna related to infection by Fusobacterium spp .; bovine warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; acute bovine conjunctivitis related to infection by Moraxella bovis; premature abortion of the cow related to infection by protozoa (ie, neosporio); skin and soft tissue infections in dogs and cats related to infection by S. epidermidis, S. intermedius, Coagulase negative Staphylococcus 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". Edition 26, (Antimicrobial Therapy, Inc., 1996). The compounds of the present invention can be active against the bacteria and protozoa, and associated conditions, known above, or specific strains of the bacteria and protozoa mentioned above. 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 indicated to the contrary, includes saturated monovalent hydrocarbon radicals having linear, cyclic or branched moieties. It is understood that for said alkyl group to include cyclic fractions it must contain at least three carbon atoms. The term "alkenyl" as used herein, unless otherwise indicated, includes alkyl groups, as defined above, having at least one carbon-carbon double bond.

The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl groups, as defined above, having at least one carbon-carbon triple bond. 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 "different α-carbon side chain substituents on naturally occurring amino acids", as used herein, unless otherwise indicated, is -CH 3 for alanine, - (CH 2) 3 NHC (NH) NH 2 for arginine , -CH2C (O) NH2 for asparagine, -CH2C (O) OH for aspartic acid, -CH2SH for cysteine, -CH2CH2C (O) NH2 for glutamine, -CH2CH2C (O) OH for glutamic acid, -H for glycine , -CH2- imidazole for histidine, -CH (CH3) CH2CH3 for solucin, -CH2CH (CH3) 2 for leucine, - (CH2) 4NH2 for lysine, -CH2CH2SCH3 for methionine, -CH2-phenyl for phenylalanine, -CH OH for serine, -CH (OH) CH3 for threonine, -CH2-indole for tryptophan, -CH2- (4-'enol) for tyrosine and CH (CH3) 2 for valine. Other substituents are familiar or easily determined by those skilled in the art. The term "heterocyclic group of 4 to 10 members", as used herein, unless otherwise indicated, includes aromatic heterocyclic groups and nonaromatic 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 four atoms in their cyclic system, but the aromatic heterocyclic groups must have at least five atoms in their cyclic system. Heterocyclic groups include benz-fused cyclic systems and cyclic systems substituted with one or more or fractions. An example of a four-membered heterocyclic group is azetidinyl (azetidine derivative). An example of a five-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, homopiperinidyl, oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2, 3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanil, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, triazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pterinidilo, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The above groups, as derived from the compounds listed above, can be C-linked or N-linked where possible. For example, a pyrrole derivative group can be pyrrol-1-yl (N-linked) or pyrrole-3-yl (C-linked). The terms "heterocyclic group of 5 to 12 members", "heterocyclic group of 5 to 6 members", and other uses of "heterocyclic" correspond to the above definition with the appropriate number of cyclic members. The term "Me" means methyl, "Et" means ethyl, and "Ac" means acetyl. The phrase "pharmaceutically acceptable salts", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention which are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids which can be used to prepare salts of pharmaceutically acceptable acid addition of such basic compounds are those that form salts not toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate , sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, 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. 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 salts of alkali metals or alkaline earth metals and, particularly, calcium, magnesium, sodium and potassium salts of the compounds of the present invention. The compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment which may employ or contain these. The compounds of formula 1 can also exist as tautomers. This invention relates to the use of all these tautomers and mixtures thereof. The invention also includes isotopically labeled compounds, and pharmaceutically acceptable salts thereof, which are identical to those cited in formula 1, but bearing in mind that one or more atoms are replaced by an atom having an atomic mass or number of mass different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 35S, 18F, and 36CI, 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. Triatiated isotopes, ie, 3H and carbon-14 are particularly preferred for their ease of preparation and detection. In addition, replacement with heavier isotopes such as deuterium, i.e., 2H, can provide certain therapeutic advantages that result in greater metabolic stability, for example an increased average vMa in vivo or reduced dosage requirements and, therefore, can be preferred in some circumstances. Isotopically labeled compounds of formula 1 of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples and preparations below, by replacing an isotopically labeled reagent readily available with a reagent not isotopically labeled.

This invention also includes pharmaceutical compositions and methods for treating bacterial infections through the administration of prodrugs of the compounds of formula 1. Compounds of formula 1 having free carboxylic, hydroxyl, amido, or aminic groups can be converted to prodrugs . Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more amino acid residues (eg, two, three or four) is covalently linked through an amide or ester linkage with a carboxylic acid group, hydroxyl or free amino of the compounds of formula 1. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three-letter symbols and also include 4-hydroxyproline, demosin, isodemosin, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also included. For example, free carboxyl groups can be derivatives such as alkyl amides or esters. Free hydroxyl groups can be derived using groups including, but not limited to, hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as described in Advance Drug Delivery Reviews, 1995, 19, 115. Prodrugs of carbamates of hydroxyl groups and amines are also included, such as carbonate prodrugs, sulfonate esters and sulfate esters of hydroxyl groups. The derivatization of hydroxyl groups such as esters (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 ester, 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 J. Med Chem. 1996, 39, 10. Free amines can also be derived as amides, suifonamides or phosphonamides. All these prodrug fractions can incorporate groups including but not limited to functional groups of ether, amine and carboxylic acid.

DETAILED DESCRIPTION OF THE INVENTION The preparation of the compounds of the present invention is described and illustrated below. The preparation of the compounds of formula 1 can be carried out more flexibly through the assembly of fragments A and B as described below.

SCHEME 1 Fragment A Fragment B Coupling of fragment A and fragment B Following the precedent of J. Am. Chem Soc, 1997, 119, 11777 and Eur. J. Org. Chem., 1998, 777 the two fragments can be coupled using an amide coupling agent such as bis (-2-oxo-3-oxazoiidinyl) phosphinic chloride (BOP-CI), 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), 1,1 '-carbonyl-diimidazole (CDI), or a carbodiimide such as dicyclohexylcarbodiimide (DCC).

Preparation of fragment A The compounds represented by fragment A, when n = 0 and R5 and R8 are H and R7 is as defined above, are commercially available. It may be advantageous to protect amines or other functional groups of nitrogen such as their 9-florenylmethoxycarbonyl (FMOC), benzyloxycarbonyl (CBZ) or tert-butoxycarbonyl (BOB) carbamates (see Protective Groups in Organic Synthesis, T. Kociennski, Ed., Thieme Medical Publisher, New York, 1994) and subsequently check out at an appropriate time. Fragment A, when n = 0 and R5 is H, R8 is lower alkyl and R7 is as defined above, can be prepared by reductive alkylation of the appropriate commercially available amino acid. The combination of the amine and the appropriate aldehyde in a solvent such as methanol or ethanol and treatment with a reducing agent such as sodium borohydrate (NaBH4), sodium triacetoxyborohydrate (NaBH (OAc) 3) or sodium cyanoborohydride (NaCNBH3) a a temperature on the scale between 0 ° C and 50 ° C supplies the product. The resulting secondary amine can be protected, as described above, or it can be reacted in a second reductive alkylation reaction to give the compound where n = 0 and R5 and R8 are independently lower alkyl and R7 is as defined. Fragment A, when n = 1, R5 and R8 are H and R7 is as defined, can be prepared by homologizing the corresponding commercially available amino acid (where n = 0) according to the precedent in J. Am. Chem Soc, 1997, 119 , 11777 and Eur. J. Org. Chem., 1998, 777. It may be advantageous to protect the amine before coupling with fragment B. Fragment A, when n = 1, at least one between R5 or R8 is not H and R7 is as defined, it can be prepared by homologation followed by reductive alkylation, as before.

Preparation of fragment B Fragment B, where R1 is H and R4 is as defined, can be prepared using the chemistries described in Eur. J. Org. Chem., 1998, 777. If R4 is different from H or methyl then R4 can be introduced as its aldehyde, replacing the formaldehyde in the chemistry presented in the previous reference. The preparation of fragment B, where R1 is as defined but not H and R4 is as defined, can be carried out more flexibly through the assembly of the C and guanilurea fragments as described below based on the preceding from J. Am. Chem Soc, 1987, 52, 4007. L is a leaving group such as -O-tosyl (-OTs), -O-mesyl (-OMs) or halide.

Fragment C Fragment D Fragment B The B fragment can also be assembled based on the chemistries in J. Am. Chem Soc., 1997, 1 19, 1777 where the fragment C, as shown below with L = NH2, is coupled with the E fragment. , prepared as in said reference. The fragment C can be prepared using the chemistry in the above reference and modified apriopiadamente, using methods known to the person skilled in the art.

Fragment C Fragment E Fragment B Preparation of fragment C Fragment C, where L = OTs, R4 is as defined and R1 is selected from the substituents of a-carbon on naturally occurring amino acids, can be prepared first by forming compound 2 according to the preceding in Arch. Biochem . Biophys., 1960, 90, 254 from the appropriate amino acid (D or L).

Compound 2 can then be processed into fragment C based on the preceding one in Eur. J. Org. Chem., 1998, 777. Fragment C, where L = OTs, R4 is as defined and R1 is as defined but not selected among a-carbon substituents on naturally occurring amino acids can be prepared from D - or L-serine. The formation of compound 3 (see Eur. J. Org. Chem., 1998, 777) followed by the displacement of tosyl with the appropriate nucleophile, for example, a Grignard, organolithium or organocerium reagent. { Tetrahedron Lett., 1984, 25, 4233), in a solvent such as tetrahydrofuran (THF), dioxane or diethyl ether (Et 2 O) at a temperature in the range between -78 ° C and 25 ° C can provide compound 4. These reagents can be prepared from the corresponding halide using standard procedures (see Organometallics In Synthesis, A Manual, M. Schlosser, Ed., John Wiley &Sons Ltd., New York, 1994). Compound 4 can then be made into fragment C using the foregoing chemistries in Arch. Biochem.

Biophys., 1960, 90, 254 followed by tosylation of the resulting primary alcohol, for example, by reaction with tosyl chloride in an aprotic solvent, such as methylene chloride or dimethylformamide, and in the presence of an amine base such as pyridine. or triethylamine. The fragment C, where R1 is -CH2-NR3R4 can be prepared by reductive amination, as before, with the appropriate amine (HNR3R4) to the aldehyde 5, generated from an oxidation of 6 under Swern conditions (J. Org. ., 1976, 41, 3329) or Dess-Martin. { J. Org. Chem., 1983, 48, 4155). Compound 6 is an intermediate in the preparation of compound 3. The resulting amine can then be made into fragment C using the foregoing chemistries in Arch. Biochem. Biophys., 1960, 90, 254 followed by a tosylation of the resulting primary alcohol, for example, by reaction with tosyl chloride in an aprotic solvent, such as methylene chloride or dimethylformamide, and in the presence of an amine base such as pyridine or triethylamine.

The fragment C, where R1 = -COR3, can be prepared by the addition of the appropriate nucleophile R3 to 5 followed by an oxidation (see above references). The resulting ketone can then be made into fragment C using the foregoing chemistries in Arch. Biochem. Biophys., 1960, 90, 254 followed by tosylation of the resulting primary alcohol, for example, by reaction with tosyl chloride in an aprotic solvent, such as methylene chloride or dimethylformamide, and in the presence of an amine base such as pyridine. or triethylamine. The fragment C, where R1 = -COOR3 or -CONR3R4, can be prepared by an oxidation of the 5 to the acid, for example through the action of potassium permanganate. { Tetrahedron Lett., 1986, 27, 4537 and J. Am. Chem. Soc, 1987, 109 7575) or sodium chlorite (J. Org. Chem. 1989. 54, 4100), followed by esterification with HOR3 or amidation with HNR3R4. , for example in the presence of a coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiomide hydrochloride (EDC), diethyl pyrocarbonate (DEPC), DCC, CDI or f. EDQ in a solvent such as dichloromethane, DMF chloroform at a temperature on the scale between 0 ° C and 25 ° C. The resulting ester or amide can then be worked into fragment C as before. The fragment C, where R1 is = aryl, heteroaryl, allyl or vinyl, can be prepared by reacting the di-BOC-glycine a-bromide with the appropriate Grignard reagent, R1-MgBr, based on the preceding Syn., 1987, 3, 223. This coupled product can be deprotected with trifluoroacetic acid and then worked up as before in fragment C.

In the above chemistries, it may be advantageous to protect the nitrogen functionalities such as their tert-butoxycarbonyl carbamates before coupling with guanilurea and deprotecting, for example with trifluoroacetic acid, before coupling with fragment A. If in any of the foregoing chemistries the Methyl ester in fragment C is not compatible, then the carboxylic acid can be masked as a different and more stable ester. For example, a tert-butyl ester can be introduced in exchange for a methyl ester using standard chemistry (see Protective Groups in Organic Synthesis, T. Greene and P. Wuts, Ed., John Wiley &; Sons Ltd., New York, 1991 or Protective Groups, P. Kocienski, Ed., Thieme Medical Publishers, New York, 1994) and deprotected and the methyl ester introduced again before coupling with guanil urea. The ester can also be maintained as its carboxylic acid until before the coupling where the methyl ester could be introduced.

Preparation of fragment D Fragment D, where R9 and R10 are H is commercially available. Fragment D, where R9 is H and R10 is as defined, can be prepared using the methods described in Can. J. Chem., 1954, 32, 242, J. Amer. Chem. Soc, 1959, 81 2220 and Bull, Acad. Pol. Sci. Ser. Sci. Chim, 1953, 74. Fragment D, where R9 is as defined and R10 is as defined can be prepared using the methods described in Arzneim.

Forsch., 1978, 28, 1435 or by modification by one skilled in the art, of the above references to fragment D, when R9 is H and R10 is as defined. In the foregoing description, the compounds may contain R1 groups which can not be compatible with the chemistries described. The functional groups within R1 that are not compatible with the chemistry used can be protected. For example, an alcohol can be protected as an ether (benzyl, allyl or silyl) or ester (benzoate, pivaloate or acetate) and subsequently deprotected at the appropriate time. If R1 contains a ketone, it may be necessary to protect it, for example as a dimethyl ketal through the use of methanol and catalytic acid such as camphorsulfonic acid or p-toluenesulfonic acid (p-TsOH). The deprotection of the ketal using aqueous acid can be carried out at a later time. Alternatively, a ketone can be masked as its protected alcohol, which can then be regenerated by deprotection and oxidation, for example under P em conditions (J. Org. Chem., 1976, 41, 3329). An amine can be protected as its 9-fluorenylmethoxycarbonyl- (FMOC), benzyloxycarbonyl- (CBZ) or terbutoxycarbonyl (BOC) carbamates (see Protective Groups in Organic Synthesis, T. Greene and P. Wuts, Ed., John Wiley & Sons Ltd., New York, 1991 or Protective Groups, P. Kociensky, Ed., Thieme Medical Publishers, New York, 1994) and subsequently be unprotected at an appropriate time. It may also be advantageous to introduce said groups in a subsequent step using an intermediate compound which can, at an appropriate time, be worked up to the desired R1. Acids, carbonyl-bonded amides and esters can be generated from a protected primary alcohol, which is unmasked by deprotection and made by double oxidation, for example under Swem conditions followed by the action of potassium permanganate. { Tetrahedron Lett., 1986, 27, 4537 and J. Am. Chem. Soc, 1987, 109, 7575), or sodium chlorite. { J. Org. Chem., 1986, 51, 567 and J. Am. Chem. Soc, 1997, 119, 7974) in the carboxylic acid. This can then be coupled with the appropriate alcohol or amine, for example by the addition of DCC, to produce the desired amide or ester. An N-linked amine or sulfonamide can be carried as an amine, protected as before, which is then deprotected and acylated or sulfonylated. The N-linked amides and sulfonamides and amines can alternatively be introduced by displacement of a leaving group. For example, a protected alcohol can be deprotected and the resulting alcohol transformed into the mesylate, for example through the action of methanesulfonyl chloride and triethylamine (NrZt3). { J. Org. Chem., 1970, 35, 3195). The mesylate is then displaced by the azide, for example using sodium azide in N, N-dimethylformamide (DMF) and the azide is reduced to the primary amine used for example triphenylphosphine followed by aqueous hydrolysis. The acylation can then supply the corresponding amine. Fractions containing sulfur can also be introduced in this way, for example, by displacing the aforementioned mesylate with the appropriate thiolate or protected thiolate, followed if necessary by oxidation of the sulfide to the sulfoxide or sulphone. The compounds of the present invention have asymmetric carbon atoms. Compounds that have a mixture of isomers in one or more centers will exist as diastereomeric mixtures, which 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 mixtures of diastereomers, are considered as part of the invention. The compounds of the present invention which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration in animals, it is often desirable in practice to initially isolate the compound of the present invention, from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter again to the free base compound 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 basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen organic acid or mineral in an aqueous solvent medium or in an appropriate organic solvent, such as methanol or ethanol. 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 the present invention which are acidic in nature, are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical salts which are used as reagents for preparing the pharmaceutically acceptable basic salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic basic salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium, etc. These salts can be easily prepared? treating the corresponding acidic compounds with an aqueous solution containing the desired alkali metal alkoxide or metal hydroxide, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alconol solutions of the acidic compounds and the desired alkali metal alkoxide or metal hydroxide, and then evaporating the resulting solution to dryness in the same previous manner. In either case, stoichiometric amounts of reagents are preferably employed in order to ensure the integrity of the reaction and maximum yields of the desired final product. The antibacterial activity of the compounds of the present invention against bacterial pathogens is demonstrated by the ability of the compounds to inhibit the development of defined pathogen strains.

Assay The assay, described below, employs conventional methodology and interpretation criteria and is designed to provide direction for chemical modifications that can lead to compounds with antibacterial activity against susceptible and drug-resistant organisms including, but not limited to beta-resistance. lactam, macrolide and vancomycin. In the assay, a panel of bacterial strains is assembled to include a variety of target pathogenic species, including representative species of antibiotic-resistant bacteria. The use of this panel allows to determine the activity / chemical structure relation with respect to the power and spectrum of activity. 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 of Clinical Laboratory Standards (NCCLS); the minimum inhibitory concentration (MIC) is used to compare strains. The compounds are initially dissolved in dimethylsulfoxide (DMSO) as standard solutions. The activity of the compounds of the present invention can also be evaluated according to the Steers replicator technique which is a standard in vitro bacterial test method described by Steers, Antibiotics and Chemotherapy 1959, 9, 307. The in vivo activity of the compounds of the present invention can be determined by conventional animal protection studies well known to those skilled in the art, usually carried out in rodents. According to an in vivo model, the compounds are evaluated for efficacy in rodent models with acute bacterial infection. An example of such an in vivo system is provided as follows. Mice (mixed sex mice CF1; 18-20 g) are assigned to boxes at the time of arrival, and allowed to acclimate 1-2 days before being placed in the study. Acute infection is produced by inoculation of the bacteria's intraperitoneum. { Staphylococcus aurens strain 01A1095) suspended in 5% sterile porcine gastric mucin. The inoculum is prepared by developing the culture overnight at 37 ° C on blood agar, harvesting the resulting surface growth with sterile brain and heart infusion broth, and adjusting this suspension to turbidity that when diluted 1: 10 in gastric mucin swine at 5% would produce 100% mortality.

Mice (10 per group) are treated subcutaneously, at 0.5 and 4 hours after stimulation. Appropriate controls that are not treated (infected but not treated) and positive (vancomycin or minocycline, etc.) are included in each study. The percentage of survival is recorded after a period of observation of 4 days; The PD5o (mg / kg / dose calculated to protect 50% of the infected animals) is determined by the probit method. The compounds of the present invention, and the pharmaceutically acceptable salts thereof (hereinafter "the active compounds"), can be administered via oral, parenteral, topical, rectal, or inhalation routes in the treatment of infections. bacterial and protozoa In general, these compounds are preferably administered in doses ranging from 0.2 mg / kg / day to approximately 200 mg / kg / day in single or divided doses (ie, between 1 and 4 doses per day), although variations will necessarily occur depending on of the species, weight and condition of the subject treated and the particular route of administration chosen. However, a dosage level that is on the scale between 3 mg / kg / day and 60 mg / kg / day is preferably used. However, variations may occur depending on the species of mammal, fish or bird being 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 performed. . In some instances, dosage levels below the lower limit of the aforementioned scale may be more suitable, while in other cases even higher levels can be employed without producing any harmful side effects, as long as such higher doses are first divided into several more 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 dosage forms, that is, they can be combined with several inert pharmaceutically acceptable carriers in the form of tablets, capsules, lozenges, lozenges, powders, sprays, creams, ointments , suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such vehicles include solid fillers or diluents, sterile aqueous media and various non-toxic organic solvents, etc. 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 ranging from 5% to 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 lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type can also be used as fillings in gelatin capsules; Preferred materials with respect to this 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 material or dyes, and, if desired, emulsifying and / or suspending agents as well, together with such diluents. such as water, ethanol, propylene glycol, glycerin and various combinations thereof. For parenteral administration, solutions of a compound of the present invention may be employed in sesame oil or peanut or aqueous propylene glycol. The use of a cyclodextrin derivative such as beta-cyclodextrin sulfobutyl ether, sodium salt, may also be advantageous. The aqueous solutions should be appropriately buffered (preferably pH> 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, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the active compounds of the present invention and this can be done by creams, jellies, gels, pastes, patches, ointments and the like, according to standard pharmaceutical practice. For administration to animals, such as livestock or pets, the active compounds can be administered in the food - of the animals or orally as a purge composition. 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 coupled with soluble polymers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide, phenyl, polyhydroxyethylaspartamide-phenol, 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 acid and polyglycolic acid copolymers, poly-epsilon caprolactone, polyhydroxyl butyric acid, polyorthoesters , polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or unfriendly block copolymers of hydrogels.

Claims (1)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula: 0 and with pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein: Z is a group having the following structure wherein X is - (CH2) n- and n is 0 or 1; R1 is selected from the different α-carbon side chain substituents on naturally occurring amino acids selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine; or R1 is selected from the different α-carbon side chain substituents on the amino acids selected from hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, gamma-aminobutyric acid, citrulline, homocysteine, homoserin, ornithine and methionine sulfone; or R1 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C2 alkynyl, - (CR4R5) t (C3-C10 cycloalkyl), - (CR4R5) t (aryl Ce-Cio), - ( CR4R5) t (4 to 10 membered heterocyclic), and C (O) R3, wherein each t is independently an integer between 0 and 5, said alkyl, alkenyl and alkynyl groups optionally containing one or two hetero fractions selected from O , -S (O) r where j is an integer between 0 and 2, and -N (R4) - provided that two O atoms, two S atoms, or one O and S atom are not directly bonded between yes, and as long as an atom of O, an atom of S or an atom of N are not directly linked to a triple bond or a non-aromatic double bond; said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused with a benzene ring, a C5-C8 cycloalkyl group, or a 4- to 10-membered heterocyclic group; the fractions of - (CR4R5) -of the above groups R1 optionally include a carbon or carbon double or triple bond where t is an integer between 2 and 5; and the above R1 groups, except H but including any optionally mentioned fused ring above, are optionally substituted by 1 to 5 R2 groups, and with the proviso that R1 must be linked through a carbon atom unless R1 is H; and as long as if Z is then R1 can not be H; each R 2 is independently selected from C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, C 3 -C 10 cycloalkyl, oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR 3, - C (O) R3, -C (O) OR3, -NR4C (O) OR6, -OC (O) R3, -NR4SO2R6, -SO2NR3R4, -NR4C (O) R3, -C (O) NR3R4, -NR3R4, -S (O) j (CR4R5) m (C6-C10 aryl), -SYO ^ C6-C6 alkyl), where j is an integer between 0 and 2, - (CR4R5) m (Ce-Cι aryl), -0 (CR4R5) m (C6-C? 0 aryl), -NR4 (CR4R5) m (C6-C? O aryl), and - (CR4R5) m (4- to 10-membered heterocyclic group), wherein each m is independently an integer between 0 and 4; said alkyl, alkenyl and alkynyl groups optionally contain one or two hetero fractions selected from O, -S (O) j- wherein j is an integer between 0 and 2, and -N (R3) - with the proviso that two atoms of Or, two atoms of S, or one atom of O and S are not directly linked together, and with the proviso that an atom of 0 an atom of S or an atom of N are not directly linked to a triple bond or a bond double non-aromatic; said cycloalkyl, aryl and heterocyclic R2 groups are optionally fused to a Ce-Cio aryl group, a C5-C8 cycloalkyl group, 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, -NR4SO2R6, - S02NR3R4, -C (0) R3 , -C (0) OR3, -OC (O) R3, -NR4C (O) OR6, NR4C (O) R3, - C (O) NR3R4, -NR3R4, -OR3, C1-C10 alkyl, - (CR4R5) m (aryl C6-C? o), and - (CR4R5) m (heterocyclic group of 4 to 10 members), wherein each m is independently an integer between 0 and 4; each R3 is independently selected from H, C1-C10 alkyl, - (CR4R5) m (aryl C6-C? 0), and - (CR R5) m (heterocyclic group from 4 to 10 members), wherein each m is independently an integer between 0 and 4; said alkyl group optionally includes one or two hetero fractions selected from O, -S (O) j- wherein j • is an integer between 0 and 2, and -N (R4) - with the proviso that two O atoms, two S atoms, or an atom of O and S are not directly linked together; said cycloalkyl, aryl and heterocyclic R3 groups are optionally fused with a Ce-Cio aryl group, a C5-C8 cycloalkyl group, or a 4- to 10-membered heterocyclic group; and the foregoing substituents R3, except H, are optionally substituted by 1 to 5 substituents independently selected from oxo, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C (O) R4, -C (O) OR4, -OC (O) R 4, NP "C (O) R 5, - C (O) NR 4 R 5, NR 4 R 5, hydroxyl, d-C 6 alkyl, and d-C 6 alkoxy, with the proviso that R 3 must be attached through an atom of carbon unless R3 is H, each R4 and R5 is independently H or C6-C6 alkyl, each R6 is selected from the substituents provided by the definition of R3 except that R6 is not H, R7 is selected from the substituents of a-carbon on naturally occurring amino acids, as defined in R1, as well as the a-carbon substituents on the amino acids selected from hydroxylysine, demosin, isodemosin, 3-methylhistidine, norvaline, citrulline, homocysteine, homoserine, ornithine and methionine sulfone; R8 is H, alkyl d-Ce, - (CR4R5) t (C3-C10 cycloalkyl), - (CR4R5 ) t (C6-C10 aryl), or - (CR4R5) t (4- to 10-membered heterocyclic group), where t is an integer between 1 and 5; R9 is independently H or C? -C5 alkyl; and, R10 is H, C? -C6 alkyl, - (CR4R5) t (C3-C10 cycloalkyl), - (CR4R5) t (C6-C? 0 aryl), or - (CR4R5) t (4 to 6 heterocyclic group) 10 members), where t is an integer between 0 and 5. 2 - The compound according to claim 1 wherein Z is and R1 is C1-C10 alkyl, C2-C2 alkenyl, C2-C10 alkynyl, ~ (CR4R5) t (C3-C10 cycloalkyl), - (CR4R5) t (C6-C6aryl aryl), or - (CR4R5) ) t (4- to 10-membered heterocyclic), wherein each t is independently an integer from 0 to 5, said alkyl, alkenyl and alkynyl groups optionally containing a hetero atom selected from O, -S (O) j - where j is an integer between 0 and 2, and -N (R4) - provided that two O atoms, two S atoms, or an O and S atom are not directly linked together, and with the condition that an O atom, an S atom or an N atom are not directly linked to a triple bond or a non-aromatic double bond; said cycloalkyl, aryl and heterocyclic R groups are optionally fused with a benzene ring, a Cs-Cs cycloalkyl group, or a 4- to 10-membered heterocyclic group; the fractions of - (CR4R5) - of the above R groups optionally include a double or triple carbon-carbon bond where t is an integer between 2 and 5; and the preceding R1 groups, including any optional fused ring mentioned above, are optionally substituted by 1 to 5 R2 groups, and with the proviso that R1 is attached through a carbon atom. 3. The compound according to claim 2 wherein R9 and R10 are both H. 4. The compound according to claim 1 wherein said compound is selected from the following compounds as well as pharmaceutically acceptable salts, prodrugs and solvates of the following compounds: 3S-amino-6-guanidino-hexanoic acid methyl- (5S-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyridimidin-5-yl) -amide; 3S-amino-6-guanidino-hexanoic acid methylo- (5R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyridimidn-5-yl) -amide; 5S-ethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-ii) -methyl-amide of 3S-amino-6-guanidinohexanoic acid; (3S-amino-6-guanidino-hexanoic acid 5R-ethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -methyl-amide; (3S-amino-6-guanidino-hexanoic acid 5S-hydroxymethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -methyl-amide; (3S-amino-6-guanidinohexanoic acid 5R-hydroxymethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -methyl-amide; (3S-amino-6-guanidino-hexanoic acid 5R-fluoromethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -methyl-amide; (3S-amino-6-guanidino-hexanoic acid 5S-fluoromethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -methyl-amide; 3S-amino-6-guanidino-hexanoic acid [5S- (4-amino-butyl) -4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl] -amide; 3S-amino-6-guanidino-hexanoic acid [5R- (4-amino-butyl) -4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyrimidin-5-yl] -amide; 3S-amino-6-guanidino-hexanoic acid [5S- (1 H-imidazol-4-ylmethyl) -4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl] -amide; [5R- (1 H-imidazol-4-ylmethyl) -4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl] -amide of 3S-amino-6-guanidino-hexanoic acid; (3S-amino-6-guanidino-hexanoic acid 5S-carbamoylmethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide; (3S-amino-6-guanidino-hexanoic acid 5S-carbamoylmethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyridin-5-yl) -amide; 3S, 7-diamino-heptanoic acid 5S-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide; (5R-Methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide of 3S, 7-diamino-heptanoic acid; 3S-amino-4- (1 H-imidazol-4-yl) -N- (5R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydro-pyridimin-5-yl) -butyramide; 3R-amino-4- (1H-imidazole-4-γ-N-dR-methyl-oxo-4-oxido-1-dd-d-tetrahydropyridimin-Si-butyramide; methyl- (5S-methyl-4-oxo-2 3R-amino-6-guanidinohexanoic acid-1-amide-4,5,6-tetrahydropyridimidin-5-yl) -amide: methyl- (5R-methyl-4-oxo-2-ureido-1,4) 3R-amino-6-guanidino-hexanoic acid 5,6-tetrahydropyridimidin-5-yl) -amide; 3S-amino-4- (1 H -indol-3-yl) -N- (5R-methyl-4-) oxo-2-ureido-1, 4,5,6-tetrahydro-pyridimin-5-yl) -butyramide; 3S-amino-4- (1 H -indol-3-yl) -N- (5S-methyl) -4-oxo-2-ureido-1, 4,5,6-tetrahydropyridimin-5-yl) -butyramide; (2S-amino-5-guanidino-pentanoic acid 5R-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide; (2S-amino-5-guanidino-pentanoic acid 5S-methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide; 2R-Methyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide of 2R-amino-5-guanidino-pentanoic acid; 2R-amino-5-guanidino-pentanoic acid 5S-methyI-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide; 3R-amino-6-guanidino-hexanoic acid (5S-hydroxymethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -amide; 3R-amino-6-guanidino-hexanoic acid 5R-hydroxymethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -methyl-amide; (3R-amino-6-guanidino-hexanoic acid 5R-fluoromethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyridin-5-yl) -methyl-amide; and 3R-amino-6-guanidino-hexanoic acid (5S-fluoromethyl-4-oxo-2-ureido-1, 4,5,6-tetrahydropyrimidin-5-yl) -methyl-amide. 5. A pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 6. The pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, an infection and protozoa, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound according to claim 1 in combination with a beta-lactam antibiotic, quinolone, tetracycline, streptogramin, aminoglycoside, glycopeptide, macrolide or oxazolidinone; or in combination with a compound which inhibits the bacterial or protozoan expulsion flow or degradation of a compound according to claim 1. 7. A method for treating a disorder selected from a bacterial infection, a protozoal infection, and disorders related to infections bacterial or protozoal infections, in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of claim 1. 8. The method for treating a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises administration to said mammal, fish or bird of a therapeutically effective amount of a compound of claim 1, in combination or co-administered with a beta-lactam antibiotic, quinolone, tetracycline ina, streptogramin, aminoglycoside, glycopeptide, macrolide or oxazolidinone; or in combination with a compound which inhibits the bacterial or protozoan expulsion flow or degradation of a compound according to claim 1.