MXPA06003317A - Polybiotin compounds for magnetic resonance imagining and drug delivery - Google Patents

Abstract

The invention relates generally to biotin-containing compounds that are useful as imaging agents and drug-delivery agents. Another aspect of the invention relates to the aforementioned compounds chelated to a metal atom. In a preferred embodiment, the metal atom is a gadolinium. Another aspect of the invention relates to a compound comprising three biotin moieties and a pharmaceutical agent covalently bound to a heterocyclic core. In certain embodiments, the pharmaceutical agent is an antibiotic, antiviral, or radionuclide. Another aspect of the present invention relates to a method of treating disease involving administering the compounds of the invention to a mammal. Another aspect of the present invention relates to a method of acquiring a magnetic resonance image using the compounds of the invention.

Description

POLYGIOTINE COMPOUNDS FOR FORMING MAGNETIC RESONANCE IMAGES AND DRUG SUPPLY FIELD AND BACKGROUND OF THE INVENTION Magnetic resonance imaging (MRI) is an imaging technique used mainly in clinical settings to produce detailed, very clear photographs of internal organs and tissues. These photographs are much more detailed than those of other exploration techniques. MRI began as a tomographic imaging method which produces an image of only a thin slice of the human body; however, MRI has advanced beyond this to become a volume imaging technique. The quality of images obtained using MRI can be increased by the intravenous (i.v.) administration of a contrast agent before the MRI examination. The contrast agents allow particular organs or tissues to be visualized more clearly by increasing the signal level of the particular organ or tissue in relation to that of its surroundings. An important application of magnetic resonance imaging is the visualization of tumors. A methodology for obtaining images of high quality tumors involves the use of antibodies that bind to the tumor cell. In a variant of this technique, a non-radiolabelled antibody to localize and clear the circulation is administered followed by a radiolabel low molecular weight agent with high affinity for the targeted antibody (Paganelli, G. et al. ., J. Nucí, Med Comm. 12: 211-234 (1991), Green,? M Bíochem. J. 89: 585-91 (1963), Hnatowich DJ et al., J.? Ucl, Med. 28: 1294-1302 (1987)). Avidin, a cationic glycoprotein found in egg whites, has been used in the imaging of tumors in conjunction with biotin, a vitamin of natural origin. Avidin has a very high affinity for biotin and is capable of binding four biotin molecules that form a complex of avidito-biotin (d = 10. sup.-15 M). Two basic methodologies have been used to target tumors with the avidin-biotin system in patients and animals. In the first method, conjugated antibodies of avidin (or streptavidin) are injected and days later when the antibody-tumor binding is maximized, a radioactive biotin derivative is injected to localize the tumor. Unfortunately, incomplete removal of the unlinked antibody from the blood can obscure the visualization of the target site. In the second method, the blood pool is reduced by injecting biotinylated antibodies followed three days later by cold avidin. The resulting circulating biotinylated antibody-avidin complexes are separated from the blood through the liver. Radioactive biotin is then injected which binds to the antibody-biotin-avidin complexes already located in the tumor. However, using "pre-directed" steps, both methodologies for locating tumors require that a subject undergo multiple procedures over the course of a few days. A study by Morrel et al. , reported the absorption of IgG labeled with In-111 and human serum albumin (HSA) in a rat model infected with E. coli. It was found that the accumulation of both protein tags is sufficient to produce clear images of the site of infection (Morrel, EM et al., J. Nucí, Med 30: 1538-1545 (1989).) In addition, the current biotin system Avidin suffers from a slow concentration of target and suboptimal relations of objective to non-objective linkage which prevent the acquisition of high quality images due to poor contrast and resolution, therefore, there is a need for robust agents for the formation of images that are linked with high specificity to the tumor tissue to produce high quality images, in addition to obtaining high quality images in order to better treat cancer and other conditions, the successful recovery of a disease usually requires treating the patient with a therapeutic drug. A particularly troublesome aspect of the administration of a pharmaceutical compound is the delivery of the compound to the desired tissue in the patient. This may be especially true in the treatment of cancerous tissue by the administration of a radionuclide. The radisnuclide works by releasing radiation which causes the cells to die, hence, the radionuclide needs to be delivered quickly and specifically to the cancerous tissue to avoid damaging the healthy tissue. In response to this need, many strategies and materials have been developed to safely deliver a drug to diseased tissue. However, there is still a need to provide pharmaceutical agents to the diseased tissue with high selectivity. BRIEF DESCRIPTION OF THE INVENTION The invention relates in general to biotin-containing compounds that are useful as agents for imaging and agents for the delivery of drugs. In certain embodiments, the compounds of the invention comprise a heterocyclic core to which three or four portions of biotin are attached. In a preferred embodiment, four portions of biotin are attached to a heterocyclic core comprising a 12-membered ring. In certain embodiments, the biotin portion is attached to the core by a linkage comprising an amide bond. Another aspect of the invention relates to the aforementioned compound that is chelated to a metal atom. In a preferred embodiment, the metal atom is a gadolinium. Another aspect of the invention relates to a compound comprising three portions of biotin and a pharmaceutical agent covalently linked to a heterocyclic nucleus. In certain embodiments, the pharmaceutical agent is an antibiotic, antiviral, or radionuclide. Another aspect of the present invention relates to a method for treating a condition that involves administering the compounds of the invention to a mammal. Another aspect of the present invention relates to a method for acquiring a magnetic resonance image using the compounds of the invention. BRIEF DESCRIPTION OF THE FIGURES Figure 1 represents the synthesis of DOTA. Figure 2 represents the synthesis of Biotin-DOTA. Figure 3 shows the normal inflammation-countermultiple relationship obtained one hour after the injection of the radiolabelled polybicylin with Tc-99m to 5 rats (average) with inflammation in the thigh. DETAILED DESCRIPTION OF THE INVENTION The invention generally relates to biotin-containing compounds that are useful as agents for imaging and agents for the delivery of drugs. The compounds of the invention comprise a core base structure to which at least one group of biotin is attached. In preferred embodiments, three or four groups are attached to the core scaffold. The biotin groups serve to direct the agent for imaging or drug delivery agent to a desired site with high specificity. In certain embodiments, the biotin groups are attached to the core scaffold by a linkage comprising at least one amide linkage. In a preferred embodiment, the linkage is an alkyl group that contains two amide linkers. In certain embodiments, the core scaffold is a monocyclic heteroalkyl group that forms a ring with 8, 10, 12, 14 or 16 members. In a preferred embodiment, the core scaffold comprises a chelation group. In a preferred embodiment, the core scaffold is a 12-membered heteroalkyl ring containing four nitrogen atoms. In certain embodiments, the compound of the invention refers to the compound described above which is converted to a complex with a metal atom. In certain embodiments, said metal atom is selected to give the superior properties of the complex as an MRI contrast agent. In certain modalitiessaid metal atom is In-111, Tc-99m, 1-123, 1-125 F-18, Ga-67, or Ga-68. In certain embodiments, the metal atom is selected to give the superior properties of the complex as a drug for the treatment of cancer. In a preferred embodiment, the metal atom is 90Y, 99mTc, 188Re, 32P, 166Ho, 109Pd, 140La, 153Sm, 165Dy, or 169Er. In a more preferred embodiment, the metal atom is Gd3 +, Mn2 +, Fe3 +, Cr3 +, dysprosium, holmium, or erbium. In certain embodiments, a group for imaging is covalently linked to the core scaffold. The term "group for image formation" refers to a composition capable of generating a detectable image when linked to a target. In certain embodiments, the imaging group contains a radionuclide such as In-111, Tc-99m, 1-123, 1-125 F-18, Ga-67, or Ga-68. The group for the formation of images can be visualized using Positron Emission Tomography (PET) orSingle Photon Emission Tomography (SPECT). In other embodiments, the imaging agent is an atom with uneven rotation or free radical (eg, Fe or Gd) or contrast agent (eg (DTPA) chelated manganese) for Magnetic Resonance Imaging ( MRI). Additional contrast agents are described for Magnetic Resonance Imaging in the subsequent discussion of MRI Contrast Agents. In certain embodiments, a therapeutic group is covalently linked to the core scaffold. The term "therapeutic group" refers to an agent that is capable of treating a condition. In certain modalities, the therapeutic group is able to prevent the establishment or growth (systemic or local) of a tumor or infection. Examples include drugs (e.g., antibiotics, anti-virals, antifungals), toxins (e.g., castor), radionuclides (e.g., 1-131, Re-186, Re-188, Y-90, Bi-212, At -211, Sr-89, Ho-166, Sm-153, Cu-67 and Cu-64), hormonal antagonists (e.g., tamoxifen), heavy metal complexes (e.g., cisplatin), oligonucleotides (e.g., anti-sense nucleotides). Preferred therapeutic agents are drugs (eg, antibiotics, anti-virals, antifungals), toxins (eg, castor), radionuclides (for example, 1-131, Re-186, Re-188, Y-90, Bi-212, At-211, Sr-89, Ho-166, Sm-153, Cu-67 and Cu-64), antagonists hormonal (e.g., tamoxifen), heavy metal complexes (e.g., cisplatin), oligonucleotides (e.g., anti-sense oligonucleotides that bind to a target nucleic acid sequence (e.g., mRNA sequence)), chemotherapeutic nucleotides, peptides, non-specific proteins (non-antibody) (e.g., sugar oligomers), boron-containing compound (e.g., carborane), photodynamic agents (e.g., rhodamine 123), enediins (e.g., calicheamicins, esperamycins, dinemicin, neocarzinostatin chromophore, and kedarcidin chromophore) and transcription-based drugs. In a preferred embodiment for treating or preventing the establishment or growth of a tumor, the therapeutic agent is a radionuclide, toxin, hormonal antagonist, heavy metal complex, oligonucleotide, chemotherapeutic nucleotide, peptide, non-specific protein (non-antibody), a boron compound or an enediin. In a preferred embodiment for treating or preventing the establishment or growth of a bacterial infection, the therapeutic agent is an antibiotic, radionuclide or oligonucleotide. In a preferred embodiment for treating or preventing the establishment or growth of a viral infection, the therapeutic agent is an antiviral compound, radionuclide or oligonucleotide. In a preferred embodiment for treating or preventing the establishment or growth of a fungal infection, the therapeutic agent is an antifungal compound, radionuclide or oligonucleotide. Another aspect of the present invention relates in general to a method for generating a magnetic resonance image of a human or animal body, comprising the steps of administering to the body of a subject in need of magnetic resonance imaging the compound of the invention, and generate a magnetic resonance image. In certain embodiments, said compound comprises at least three biotin groups. In certain embodiments, said compound comprises gadolinium, technetium, or iodine. In a preferred embodiment, said compound comprises at least three groups of biotin and gadolinium. Another aspect of the present invention relates generally to a method for treating a patient in need of a pharmaceutically effective amount of the compound of the invention for the purpose of treating a condition. In certain modalities, the condition is a bacterial, viral or fungal infection. In certain modalities, the condition is cancer.

In certain embodiments, said compound comprises at least three biotin groups. In certain modalities, said compound comprises a therapeutic group. In a preferred embodiment, the therapeutic group comprises a radionuclide, antibiotic, antiviral, or antifungal compound. In a preferred embodiment, the therapeutic group comprises a radionuclide. In a preferred embodiment, said compound comprises at least three groups of biotin and gadolinium. MRI Contrast Agents Clinical imaging technology plays an important role in the diagnosis of damage and disease processes. Many parts of the human body can now be examined using a variety of diagnostic imaging techniques. Radiography has long been used to image body parts through which externally generated x-rays are transmitted. Computed tomography (CAT) provides x-ray images in cross sections of a body plane. Tissues or specific organs can be targeted in positron emission tomography (PET), single photon emission computed tomography (SPECT), and gamma scintigraphy. In PET, SPECT, and gamma scintigraphy, radiopharmaceutical agents capable of being separated (concentrated) to a degree in the patient's tissue or organ are internally administered, and images are generated by detecting the radioactive emissions of the concentrated radiopharmaceutical agent. Some of the radiopharmaceutical agents currently used for imaging include nuclides such as 201T1, 99mTc, 133Xe, and the like; nuclide chelates; radiolabelled metabolic agents such as 1: LC-deoxy-D-glucose, 18F-2-fluorodeoxy-D-glucose, fatty acid [1-1: LC] - and [123I] -β-methyl analogues, 13N-ammonia, and similar agents for infarction avid such as 99mtc-tetracycline, 99Tc ~ pyrophosphate, 203Hg-mercurials, S7Ga-citrate, and the like and radiolabelled ligands, peptides, and monoclonal antibodies. Complete cells such as erythrocytes, platelets, leukocytes, and other cells can also be labeled with a radionuclide and function as radiopharmaceutical agents. D. R. Elmaleh, et al. [(1984) Proc. Nati Acad. Sci. USA 81, 918-921] describes the agent, labeled 99mTc-Ap4 A (9rnTc-Ap4 A), used to image tumors implanted in rats. The chelation of 99p? Tc to Ap4 A in this study gave a mixture, in which 99mTc was annexed to dinucleotide Ap4 A and which also could have contained 99mtc without forming chelates. This study was based on the premise that some human tumor cells are permeable to exogenous ATP and ADP, and that these cells incorporate the intact nucleotides in intracellular accumulations unlike normal cells. Ap4 A was found to impregnate in hepato cells but not in a number of untransformed mammalian cell lines. In addition to accumulating in implanted tumors, 99mTc-Ap4 A in the 1984 study also accumulated in the kidney, liver, bones, muscles, and lungs. The amount and type of clinical information that can be derived from PET, SPECT, and gamma scintigraphy images is related in part to the ability to concentrate the radiopharmaceutical agent in the targeted tissue or organ. Although many radiopharmaceutical agents are available for clinical use, the resolution of the generated image may be limited depending on several factors. The resolution of a particular agent for imaging to form diseased or damaged tissue depends in part on the affinity of the radiopharmaceutical agent with the site of the damage or condition compared to its affinity with the surrounding healthy tissue. In MRI the contrast in the generated images can be improved by introducing in the area to be represented in images an agent generally mentioned as a contrast agent, which affects the characteristics of the revolving revolving nuclei (the "imaging nuclei" which are generally protons and more especially water protons) which are responsible for the resonance signals from which the images are generated. The improvement obtained with the use of contrast agents allows particular organs or tissues to be visualized more clearly by increasing or decreasing the signal level of the particular organ or tissue in relation to that of its surroundings. The contrast agents that increase the signal level of the target site in relation to that of its surroundings are called contrast agents "positive" while those that decrease the level of signal in relation to their surroundings are called "negative" contrast agents. Most materials that are now proposed as MRI contrast media achieve a contrast effect because they contain paramagnetic, super-paramagnetic, or ferromagnetic species. For ferromagnetic and super-paramagnetic contrast agents, which are negative MRI contrast agents, the improved image contrast is derived mainly from the reduction in the revolving coefficient of rotation known as T2 or as the spin-turn relaxation time, a reduction resulting from the effect in the image-forming nuclei of the fields generated by the ferromagnetic and super-paramagnetic particles. The paramagnetic contrast agents on the other hand can be either positive or negative MRI contrast agents. The effect of paramagnetic substances on the intensities of the magnetic resonance signal depends on many factors, the most important of which are the concentration of the paramagnetic substance in the site represented in images, the nature of the paramagnetic substance itself, and the strength of the pulse sequence and the magnetic field used in the imaging routine. However, generally, paramagnetic contrast agents are positive MRI contrast agents at low concentrations where their Ti-lowering effect dominates and MRI negative contrast agents at higher concentrations where their T2-lowering effect is dominant. In any case, the reduction in the relaxation time results in the effect in the image-forming nuclei of the magnetic fields generated by the paramagnetic centers. The use of paramagnetic, ferromagnetic, and super-paramagnetic materials as MRI contrast agents has been widely recommended and wide ranges of suitable materials have been suggested in the literature. For example, Lauterbur and others have suggested the use of manganese salts and other salts and inorganic, paramagnetic complexes (see Lauterbur et al., In "Frontiers of Biological Energetics", volume 1, pages 752-759, Academic Press (1978), Lauterbur in Phil, Trans.R. Soc. Lond. B289: 483-487 (1980) and Doyle et al., in J. Comput.Assist.Tomogr.5 (2): 295-296 (1981)). Runge et al. has suggested the use of particulate gadolinium oxalate (see, for example, US Patent No. 4,615,879 and Radiology 147 (3): 789-791 (1983)), Schering AG has suggested the use of paramagnetic metal chelates, for example of aminopolycarboxylic acids such as nitrilotrietic acid (? TA), acid?,?,? ,? ' -ethylenediamintetraacetic acid (EDTA), acid ? -hydroxyethyl -?,? ' ,? ' -Inteacetic ethylendia (HEDTA), acid ?,?, NX -N ", N" -diethylenetriaminpentaacetic acid (DTPA), and acid 1,4,7,10-tetraazacyclododecanetraacetic (DOTA) (see for example EP-A-71564, EP-A-130934, DE-A-3401052 and US Patent No. 4,639,365), and Nycomed AS has suggested the use of paramagnetic metal chelates of iminodiacetic acids (See EP-A-165728). In addition to paramagnetic metals, stable, paramagnetic free radicals have also been suggested for use as positive MRI contrast agents (see for example EP-A-133674). Other paramagnetic MRI contrast agents have been suggested or reviewed in, for example, EP-A-136812, EP-A-185899, EP-A-186947, EP-A-292689, EP-A-230893, EP-A -232751, EP-A-255471, WO85 / 05554, WO86 / 01112, O87 / 01594, O87 / 02893, U.S. Patent No. 4,639,365, U.S. Patent No. 4,687,659, U.S. Patent No. 4,687,658, AJR 141: 1209-1215 (1983), Sem. Nucí Med. 13: 364 (1983), Radiology 147: 781 (1983), J. Nucí. Med. 25: 506 (1984), WO89 / 00557 and International Patent Application No. PCT / EP89 / 00078. Ferromagnetic MRI contrast agents (a term used herein to cover both ferrimagnetic and ferromagnetic materials) and super-paramagnetic materials, for example magnetic iron oxide particles, of sub-domain size, either free or enclosed within or attached, are described. to a particle of a non-magnetic matrix material such as a polysaccharide, by Schroder and Salford in O85 / 02772, by Nycomed AS in WO85 / 04330, by Idder in the American Patent? 4675173, by Schering AG in DE-A-3443252 and by Advanced Magnetics Inc in O88 / 00060. The intravenous administration, in separated periods of time, of the positive contrast agent Gd DTPA-dimeglumine (which after such administration is rapidly distributed extracellularly) and of super-paramagnetic ferrite particles, was proposed by Weissleder et al. in AJR 150: 561-566 (1988) for imaging of liver cancers and by Carvlin et al. Society for Magnetic Resonance Imaging, 5th Annual Meeting, San Antonio, 1987, to study blood flow, kidney. The work of Carvlin and Weissleder on this subject is also reported in Proc. SPIE-Int. Soc. Opt. Eng. (1988) 914 Medical Imaging II, Pages 10-19 and AJR 150 115-120 (1988), respectively. Formation of Images by Fluorescence Fluorescence is emitted when a fluorophore interacts with an incident photon (excitation). The absorption of the photon causes an electron in the fluorophore to rise from its basic state to a higher energy level.

Then, the electron reverts to its original level, releasing a photon (fluorescence emission) whose wavelength depends on the amount of energy that is released during the reversion. A given fluorophore can be emitted at wavelengths, single or multiple (creating an emission spectrum), such as a drop of electrons from several orbitals to their basic states. The emission spectrum is constant for each species of fluorophore. Imaging finds many uses in fluorescence. As examples, the following are considered: (1) an imaging system adapted to a specific emission spectrum can be used to locate a fluorophore. For example, cells that express a green fluorescent protein can be imaged and quantified. (2) Changes in the fluorophore molecule (such as the binding of fura-2 to Ca ++) will lead to alterations in the emission spectrum. An imaging system can be used to measure these spectral changes, as an indication of changes in the fluorophore environment. (3) By measuring the intensity of the fluorescence, an imaging system can estimate the concentration of a fluorescently labeled molecule. A common example of this is in the use of fluorescent microarrays for gene expression analysis.

Location: monochromatic and mul-specttral fluorescence imaging In the simplest case (monochromatic fluorescence imaging), a single fluorophore is used to label a single molecular species. For example, a fluorescein isothiocyanate (FITC) labeled glyphofibrillar acid (GFAP) protein can be used to visualize repair regions after trauma to the CNS. Similarly, a specific location of the chromosomal DNA can be shown by in situ hybridization of the fluorescence. Imaging by multispectral fluorescence demonstrates multiple molecular species in the same image. Each fluorescent mark, discrete, is displayed as a different color. For example, Cy3 could be displayed (green) and Cy5 (red), with the overlapping regions shown as color mixtures (for example, an overlay of the red and green color is shown as yellow). MCID® and AIS handle multispectral fluorescence in two ways. For better quality, each fluorophore is visualized independently, under optimal conditions. For example, discrete FITC and rhodamine fluorescence images are created. The Image Fusion function then combines the two images into a single color image that shows inter-relationships between the components of the marked or labeled tissue (Figure). This method produces the best image quality, for three reasons. First, very sensitive, high-resolution cooled cameras can be used. Second, the fluorescence optics (for example, excitation and emission filters) can be optimally adapted for each wavelength. Third, it has flexible control over the contribution of each discrete image to the final merged image. For the most convenient operation, multiple fluorophores are simultaneously visualized. In this case, the optimum provides simultaneous wavelengths of multispectral excitation and discrete emission for each fluorophore. A color camera is used to represent images of the specimen of various colors. When the standard color cameras are not sensitive enough to visualize the fluorescence emission, an integration color camera is used. Quantification: changes in the fluorophore environment Changes in pH, binding of the fluorophore to specific ions, and many other environmental factors, can lead to an alteration in the emission spectrum of a fluorophore. Traditionally measurements of such changes are made in laboratory instruments. However, several methods have been developed that allow imaging systems to perform similar measurements at cellular and subcellular levels. The MCID includes functions dedicated to the quantification of changes in the fluorophore environment. Aspects in fluorescence imaging systems Typical fluorescence measurements include an area and proportional area, number of fluorescent targets, and fluorescence intensity. Spatial measurements are very simple, and are performed more or less well by most image analyzers. In contrast, intensity measurements can be rather complicated due to fading in fluorescence, and good calibration standards are difficult to create. The proven competence of the MCID in the measurement of the quantitative intensity makes it possible to concentrate on the specimens, not on the deficiency of the measuring instrument. What is very important, standard video cameras are not very suitable for fluorescence applications, and usually a specialized low-light camera is necessary. However, a wide variety of integration cameras are available for use with the MCID and AIS. Components of fluorescence imaging Enhanced CCDs (ICCDs) consist of a video camera coupled to an image intensifier. The intensifier amplifies the incident illumination by means of an adjustable factor. The ICCDs are fast, in that they take a short-term picture of relatively dark specimens. Its main disadvantages are granular images in higher amplifications, poor contrast reproduction in small details, and a severely limited intrascene dynamic range. That is, the ICCDs can not be seen in glossy or dark materials within an image (typical dynamic range of approximately 40: 1).

ICCDs are best suited for dynamic fluorescence imaging, where their ability to provide images quickly is a critical advantage. For most purposes, the GEN IV intensifier is recommended, which exhibits much better image quality tother variants. Several ICCD cameras are available, although the Roper Instruments video ICCD is recommended with the GEN IV intensifier, the integration CCD camera, and the control unit. This is almost as sensitive as a single-phase ICCD, and has the added benefit of being very flexible. For extremely dark specimens, multiphase intensifiers are available, and are most often used in photon counting applications. In our opinion, the work tests with a multiphase ICCD are significant, and it is preferable to use the Black Ice cryogenic integration chambers when a definitive sensitivity is required. The integration cameras are like film. They accumulate incident lighting with the passage of time. In general, integration cameras provide better image quality and a wider dynamic range tintensified cameras. The MCID and AIS support a variety of integration cameras. The integration video cameras are inexpensive and are suitable for moderately bright specimens such as many immuno-labeled cells. For bright specimens, the camera does not need to be cooled. For darker specimens, integration video cameras, cooled (above 0 degrees C) or frozen (below 0 degrees C), are still economical. However, any video camera is not expected to work with difficult specimens. Video integration technology sacrifices sensitivity and dynamic range (limited to 8-10 bits) in exce for low cost. f The next stage of the video cited above is a family of moderate price integration cameras (for example the Roper Sensys or Hamamatsu 4742), which use High resolution CCDs that can be operated in integration mode. Typically, these chambers are cooled to temperatures above zero, and make fine images with fluorescent specimens. For more difficult specimens, cooled chambers of scientific quality can be used. The exact definition of a camera of "scientific quality" varies although, generally, these devices use CCDs of total coverage, digitizers of high precision (> 12 bits), and deep cooling. The most advanced of these cameras uses special CCDs, high sensitivity, and cryogenic cooling (cooling below -100 C). The Black Ice camera incorporates every technical advantage that is known, to give a performance that is absolutely high technology. Unfortunately Black Ice technology is expensive, although there are many scientific quality cameras that are reasonably priced and that give excellent performance. The imaging system A simple video frame (made in 1/30 sec.) Of an intensified camera will be very grainy. The quality of the low luminosity image is improved by averaging it in real time. Therefore, ICCD cameras can be interconnected to any imaging system capable of averaging a fast frame. He himself is useful if the imaging system can also build proportions and perform a fluorescence background subtraction in real time. Integration cameras can present more tone challenge to the imaging system. The efficient use of an integration camera presents the following requirements: (1) Integrated camera and computer program: Although the MCID / AIS can use images from any camera (importing TIFF files), it is convenient if the program if computer program for image analysis also controls the various parameters of exposure and transfer of data from the camera. Making an image acquisition within the computer program of the dedicated camera and analyzing the image in a separate package is very tedious. (2) Accepting high precision data: The imaging system must accept and calibrate data at high bit densities (supply data of integration cameras at 8 - 16 bits). (3) Fast interface: The imaging system should include a fast interface for the integration camera. The best cameras come with a dedicated connection (for example RS422) for the interface board of the imaging system, or with its own interface card. Acquiring images through a SCSI or other slow connection is economical and easy to implement for the manufacturer, although it actually degrades the performance of imaging. The MCID includes a fast and efficient control of the integration cameras, and can be calibrated at high bit densities. The AIS is more limited in the variety of cameras it supports, although it maintains the ability to use high bit densities and the direct control of the supported integration cameras. Imaging by dynamic fluorescence The MCID includes a computer program dedicated to dynamic fluorescence as part of the standard package of image analysis. This has two main benefits, a) The system that performs quantitative autoradiography, morphometry, and fluorescence densitometry can also perform radiometric measurements without any additional cost for the computer program. B) Imaging by dynamic fluorescence does not have to be learned as a discrete program. Rather, the analysis, archiving, annotation, enhancement, and other operations are performed in an entirely easy manner in sequences of fluorescence images, using the familiar functions of the MCID. The MCID will acquire a very large number of closely spaced images directly on the computer. This dynamic online imaging is available with all cameras supported by the MCID, including ICCDs and integration cameras. Radiometric imaging The radiometric imaging has the advantage of the spectral changes shown when the fluorescent dyes bind to their target ions. The MCID supports several types of radiometric imaging, including calcium fura-2 imaging and pH BCECF imaging. The calcium chelator, fura-2, is used to measure cytosolic concentrations of free Ca ++. The saturating calcium form of fura-2 has a maximum absorbance at about 335 NM. The calcium-free form is absorbed to the maximum at approximately 362 NM. The proportion (usually 340: 380) of the fluorescence intensities changes by approximately one order of magnitude between the saturated and calcium-free solutions. Accordingly, a relative brightness of the image 340 reflects an increase in the ratio of Fura-2 bound to Ca ++. Discrete images of 340 and 380 nm are formed of cells incubated or injected with fura-2. The 340 and 380 nm images are corrected by the appropriate background, and a proportion image is formed. The ratio of 340 nm to 380 nm is passed through a simple equation (see below) to arrive at an estimate of the Ca ++ concentration. R in is the ratio (340: 380) of the fluorescence intensity, formed at a minimum concentration of Ca ++. Rmax is the ratio (340: 380) formed at saturating concentration of Ca ++. FO / Fs is the ratio (380 nm) of the fluorescence intensity at a maximum and saturated Ca ++ concentration. KD is the equilibrium dissociation constant for Ca ++ and fura-2, usually established at approximately 225 (Grynkiewicz, Poenie and Tsien, 1985; Williams and Fay, 1990). Each laboratory must calibrate the technique of fura-2 under its own conditions. The proportion image can be displayed using a spectral color to represent the calcium concentration. The ratio can also be displayed by modulating the color and intensity independently. In this case, the intensity reflects the intensity of the images of the original component (essentially equivalent to the confidence of the proportion at that point in the image), and the color reflects the concentration of calcium. A popular indicator dye for intracellular pH BCECF (Rink, Tsien and Pozzan, 1982; Bright et al., 1987). The BCECF is strongly fluorescent at visible wavelengths, with an excitation peak at 503 nm and an emission peak at 525 nm. Both peaks depend on pH, being turned off by acidification and intensified by more alkaline environments. However, at 436-439 nm, the fluorescence depends on the pH. Therefore, a ratio between pH-dependent and pH-independent BCECF images can be constructed. In theory, this ratio will reflect the pH regardless of irrelevant influences such as dye concentration, illumination intensity, etc. A set of filters for pH measurement with the BCECF includes excitation filters at 440 and 495 nm, a dichroic spectrum at 515 nm and a emission filter at 535 nm. Funds are acquired at 440 and 495 nm. All the procedures are for the formation of images with Ca ++. The proportions are passed through the following equation: pH = pK + log (R - Rmax) (Rmax - R) R is the normalized fluorescence ratio of 495/440 nm, obtained as a proportion of the mean intensity value over any portion of the image, at each wavelength, at a pH of 7.0. One starts with a value of 7.17 for pK, and suggests that you calculate the appropriate values for your conditions. The BCECF is most commonly calibrated using the K + / H + ionophore, negericin, to expose the cells to known internal pHs (Thomas, et al., 1979). To correct the background fluorescence, a proportion image is created from two excitation images (340 and 380 nm will be used as examples). MCID offers three ways of correcting the excitation images before the formation of the ratio: a) Subtractive: elimination of background fluorescence and camera intensifier or displacement. The background values are entered for each of the 340 and 380 nm images. These background values are automatically subtracted from the 340 and 380 images before the proportions are calculated. This is a simple, one-step correction, in that the same background error is applied to the entire field of view, b) Proportional: correction of hue error. Two independent nuance corrections are applied, pixel by pixel; one for each excitation image. A white field (the hue field) is acquired in each excitation. In both hue fields, each pixel error is expressed as a ratio. The subsequent excitation images are corrected by the appropriate proportions before the calculation of any proportion, c) Subtractive + proportional: You can use the correction of nuance both substantive and proportional. Flexible excitation conditions A proportion image is calculated from images taken at two excitation wavelengths. In the simplest case, a single image is taken at each excitation wavelength and then a ratio is constructed. However, any sequence of images can be acquired and processed before the construction of a proportion. For example, someone could build a final image from a sequence of 340/380 alterations. This can prevent differential bleaching at a wavelength. One could also specify the deficiency of the discrete excitation conditions. For example, a sequence of 20 timed proportions is taken, using 380 nm images taken every second. However, 340 nm images are taken only every three seconds. Reading data and graphical representation of multiple tip ratio images The data of any number of timed proportions can be read simultaneously. Placing a sample tool in a phase or DIC image, on any excitation image, or on any proportion image, MCID will report data through a complete experiment. The report will include part or all of the: gray level value at an excitation of 1 and 2 Ca ++ concentration ratio or other instrument. Photometer mode In some cases no images are needed. But rather someone wants to generate a single image, define regions of interest in that image and then have the proportions of reading the system of those regions over time. It is as if someone is using the imaging system as a photometer with multiple viewing windows. The MCID allows you to place any number of "photometric windows" in the image, and then reads the density values of these windows to build the ratio. The photometer mode generates a set of Ca ++ ratio and concentration values over time. Any period of time can be used, and any number of regions can be read, when there are no memory storage requirements for the photometer data. The numerical values can be plotted, either during or after the acquisition process. Adjustment of the two excitation wavelengths Ideal radiometric imaging requires that all images be acquired at near-equal intensities, suitably within the linear range of camera operation. Integration cameras offer an elegant solution to the problem of image balancing. Someone can simply adjust the integration time differentially for each excitation. This is easy and quick to do, using the radiometric functions of the MCID. There is more than one problem with ICCDs. The brightness of ICCD could be balanced by changing the intensifier amplification (under computer control) for each wavelength. This is convenient, but dangerous, unless the response of the intensifier has been shown to be linear across a range of amplification factors. Another option is to decrease the intensity of the fluorescence at the brightest wavelength using an ND filter mounted before the excitation filter. Various attenuation filters (eg 25%, 50%, 75%) can be mounted in different positions on the filter wheel, or on a second wheel. This option requires some manipulation with the filter wheel, although it allows the amplification of the intensifier to be maintained at a constant level. Simple excitation, simple emission Simple excitation and simple emission procedures are much simpler than proportioning. All that is necessary is to acquire images at timed intervals, and then measure the intensity values of the fluorescence of those images. Changes in the intensity of the fluorine localization or fluorine localization intensity can be traced (for example the internalization of a GFP-labeled receptor). Changes in intensity are usually qualitative. That is, someone can establish that a change in fluorescence emission occurs, but can not quantify the change in terms of ionic concentrations. An example of a single emission procedure is the use of the Ca ++ indicator, fluo-3. It is excited at 503-506 nm, in the visible portion of the spectrum. Fluo-3 has a weaker affinity with Ca ++ (KD of approximately 400 nm) than with fura-2 or indo-1, allowing the measurement of lower concentrations of Ca ++. He himself also exhibits very marked changes in the intensity of fluorescence (approximately 4 decades) with the Ca ++ bond. This is compared to the tenfold change in fluorescence intensity exhibited by fura-2. The MCID single emission option is similar in use to fura-2 imaging, although there is only one excitation wavelength. When changes are not required in the filter wheel, quite short intervals between images are possible. Definitions For convenience, certain terms used in the specification, examples, and appended claims are gathered here. The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. The preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. The term "alkyl" refers to the radical of saturated aliphatic groups, which include straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and alkyl groups substituted with cycloalkyl. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its structure (for example Q1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or less. Also, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure. When a straight chain or branched chain alkyl is referred to as optionally substituted it is meant that in one or more positions the alkyl group is substituted with such substituents as described below, such as, for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl , amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyles, ethers, thioethers, sulfonyl, seleno-ethers, ketones, aldehydes, esters, fluorinated alkyls, and nitriles. Unless the carbon number is otherwise specified, when used herein "lower alkyl" means an alkyl group, as defined above, but having one to ten carbons, more preferably one to six carbon atoms in its base structure. Also, the "lower alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl groups are lower alkyl. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl. The term "aralkyl," as used herein, refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group). The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double or triple bond respectively. The term "aryl" as used herein includes 5-, 6- and 7-membered single ring aromatic groups which can include from zero to four heteroatoms, for example, benzene, anthracene, naphthalene, pyrene, pyrrole, furan, thiophene , imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyrididazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure can also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring can be substituted at one or more positions on the ring with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, or aromatic or heteroaromatic portions, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two attached rings (the rings are "fused rings") wherein at least one of the rings is aromatic , for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and / or heterocyclyls. The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1, 2-dimethylbenzene and ortho-dimethylbenzene are synonymous. The terms "heterocyclyl" or "heterocyclic group" refer to ring structures with 3 to 10 members, more preferably rings with 3 to 7 members, whose ring structures include one to four heteroatoms. The heterocycles can also be polycycles. Heterocyclyl groups include, for example, thiophene, thiantrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxytine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, fenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultans, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, such as, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate , carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic portion, -CF3, -CN, or the like. The terms "polycyclyl" or "polycyclic group" refer to two or more rings (for example, cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and / or heterocyclyls) in which two or more carbons are common to two attached rings, for example, the rings are "fused rings".

The rings that are attached through non-adjacent atoms are called "connected" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, such as, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl , carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic portion, -CF3, -CN, or the like. When, it is used in the present, the term "nitro" means -N02; the term "halogen" designates -F, -Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -S02-. The terms "amine" and "amino" are recognized in the art and refer to both substituted and unsubstituted amines, for example, a portion that may be represented by the general formula: where R9, R10 and R-IQ each independently represent a group allowed by the valence rules.

The term "acylamine" is recognized in the art and refers to a portion that can be represented by the general formula: wherein R9 is as defined above, and R'n represents a hydrogen, an alkyl, an alkenyl or - (CH2) m -R8, where and R8 are as defined above. The term "amido" is recognized in the art as a carbonyl substituted with amino and includes a portion that can be represented by the general formula: where R9 Rio are as defined above. Preferred embodiments of the amide will not include amides which may be unstable. The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S- (CH2) m -R8, wherein m and R8 are as defined above. Representative alkylthio groups include methylthio, ethylthio, and the like.

The term "carbonyl" is recognized in the art and includes such portions as may be represented by the general formula: O L, XR11, or _xJLRI ?? wherein X is a bond or represents an oxygen or a sulfur, and Rii represents a hydrogen, an alkyl, an alkenyl, ~ (CH2) m-R8 or a pharmaceutically acceptable salt, R'n represents a hydrogen, an alkyl, a alkenyl or - (CH 2) m -R 8, where m and R 8 are as defined above. Where X is an oxygen and Rn or R'u is not hydrogen, the formula represents an "ester". Where X is an oxygen, and Rn is as defined above, the portion is referred to herein as a carboxyl group, and particularly when Ru is a hydrogen, the formula represents a "carboxylic acid". Where X is an oxygen, and R'u is hydrogen, the formula represents a "formate". In general, when the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. When X is a sulfur and Rxl and R 'a is not hydrogen, the formula represents a "thioester". When X is sulfur and RX1 is hydrogen, the formula represents a "thiocarboxylic acid." When X is sulfur and Ru 'is hydrogen, the formula represents a "thiolformiate." On the other hand, when X is a bond, Ral is not hydrogen , the above formula represents a group of "ketone." When X is a bond, and Ru, is hydrogen, the above formula represents a group "aldehyde". The terms "alkoxy" or "alkoxy" as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that converts that alkyl to ether is or looks like an alkoxy, as may be represented by any of -O-alkyl, -0-alkenyl, -O-alkynyl, -0- (CH2 ) m-R8, where my R8 are as described above. The term "sulfonate" is recognized in the art and includes a portion that may be represented by the general formula: in which R4? it is a pair of electrons, hydrogen, alkyl, cycloalkyl, or aryl. The terms triflyl, tosyl, mesyl, and nonaflyl are recognized in the art and refer to the trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutansulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are recognized in the art and refer to the functional groups trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester and to the molecules containing said groups, respectively. The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutansulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A broader list of abbreviations used by organic pharmacists of ordinary skill in the art appears in the first edition of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations used by organic pharmacists of ordinary skill in the art are incorporated herein by reference. The term "sulfate" is recognized in the art and includes a portion that may be represented by the general formula: in which R41 is as defined above. The term "sulfonylamino" is recognized in the art and includes a portion that may be represented by the general formula: R The term "sulfamoyl" is recognized in the art and includes a portion that may be represented by the general formula: * The term "sulfonyl" as used herein, refers to a portion that may be represented by the general formula: ## STR2 ## wherein R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. The term "sulfoxide" as used herein, refers to a portion that may be represented by the general formula: O wherein R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl. A "selenoalkyl" refers to an alkyl group having a substituted seleno group appended thereto. The Exemplary "selenoethers" which can be substituted on the alkyl, are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and -Se- (CH2) m-? Om and R7 are as defined previously . Analogous substitutions can be made to the alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, anadoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, alkenyls or alkynyls substituted with carbonyl. When used in the present, the definition of each expression, for example alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. It will be understood that "substitution" or "substituted with" includes the implicit condition that such substitution is in accordance with the permitted valency of the substituted atom and the substituent, and that the substitution results in a stable compound, for example, which does not spontaneously suffers a transformation such as by means of rearrangement, cyclization, elimination, etc. When used herein, it is contemplated that the term "substituted" includes all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for the organic compounds, appropriate. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is not intended that this invention be limited in any way by the permissible substituents of organic compounds. The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The chemistry field of protective groups has been revised. (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).

Certain compounds of the present invention can exist in particular geometric or stereoisomeric forms. The present invention contemplates all compounds of this type, including cis- and trans-isomers, iγ- and S ~-enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic mixtures thereof, and other mixtures thereof, when they fall within the scope of the invention.

Additional, asymmetric carbon atoms may be present in a substituents such as an alkyl group. It is intended that all isomers of this type, as well as mixtures thereof, be included in this invention. If, for example, a particular enantiomer of a compound of the present invention is desired, it can be prepared by an asymmetric synthesis, or by "derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired, pure enantiomers Alternatively, when the molecule contains a basic functional group, such as amino, or an acid functional group, such as carboxyl, diastereomeric salts are formed with an appropriately active, appropriate acid or base, followed by the resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and the subsequent recovery of the pure enantiomers.

Contemplated equivalents of the compounds described above include compounds the limes otherwise correspond to them, and which have the same general properties thereof (eg, that they function as analgesics), wherein one or more simple variations are made of substituents which do not adversely affect the efficacy of the compound by binding to the sigma receptors. In general, the compounds of the present invention can be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and methods. of conventional synthesis. In these reactions, it is also possible to make use of variants which are themselves known, although they are not mentioned here. For the purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inner cover.

COMPOUNDS OF THE INVENTION One aspect of the present invention relates to a compound represented by the formula I: wherein R independently represents for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; n represents independently for each case 1, 2, 3, or 4; X independently represents for each case heteroalkyl, alkenyl, or - [(alkyl-NR1C (O)) m-alkyl] -, wherein m is 1, 2, 3, or 4; and R1 is H or alkyl. In certain embodiments, the present invention relates to compound I, wherein Y represents independently for each case -C (0) -. In certain embodiments, the present invention relates to compound I, wherein n represents independently for each case 2. In certain embodiments, the present invention relates to compound I, wherein n independently represents for each case 2 and R independently represents each case hydrogen. In certain embodiments, the present invention relates to compound I, wherein n represents independently for each case 2, R independently represents hydrogen for each case, and Y is -C (0) -. In certain embodiments, the present invention relates to compound I, wherein X represents independently for each case - [(alkyl-NR ^ -C (0)) m-alkyl] -. In certain embodiments, the present invention relates to compound I, wherein X independently represents for each case - [((C? -C5) alkyl-NRXC (0)) m-alkyl (C? -C5)] -. In certain modalities, the present invention relates to compound I, wherein X represents independently for each case - [(alkyl-NR1C (0)) m-alkyl] -, m is 2, and R1 is H. In certain embodiments, the present invention refers to compound I, wherein X represents independently for each case:, wherein s is 1, 2, 3, or 4. In certain embodiments, the present invention relates to compound I, wherein X represents independently for each case : ? wherein s is 3 or 4. In certain embodiments, the present invention relates to compound I, wherein X independently represents for each case: In certain embodiments, the present invention relates to compound I, wherein n represents independently for each case 2, R independently represents hydrogen for each case, Y is -C (O) -, and X represents independently for each case: Another aspect of the present invention relates to a compound represented by formula II: t t wherein R represents independently for each case H or alkyl; And independently represents for each case -C (0) - or -S (0) -; n represents independently for each case 1, 2, 3, or 4; M is a metal atom; and X independently represents for each case alkyl, heteroalkyl, alkenyl, or - [(alkyl-NR1C (O)) m-alkyl] -, where m is 1, 2, 3, or 4; and R1 is H or alkyl. In certain embodiments, the present invention relates to compound II, wherein M is a transition metal. In certain embodiments, the present invention relates to compound II, wherein M is selected from the group consisting of In-111, Tc-99m, 1-123, 1-125 F-18, Ga-67, Ga-68, 1-131, Re-186, Re-188, Y-90, Bi-212, At-211, Sr-89, Ho-166, Sm-153, Cu-67, and Cu-64. In certain embodiments, the present invention relates to compound II, wherein M is selected from the group consisting of Tc-99m, Ga-67, and Ga-68. In certain embodiments, the present invention relates to compound II, wherein M is selected from the group consisting of Gd3 +, Mn2 +, Fe3 +, Cr3 +, dysprosium, holmium, and erbium. In certain embodiments, the present invention relates to compound II, wherein M is selected from the group consisting of Gd3 +, Mn2 +, Fe3 +, and Cr3 +. In certain embodiments, the present invention relates to compound II, wherein Y represents independently for each case -C (0) -. In certain embodiments, the present invention relates to compound II, wherein n represents independently for each case 2. In certain embodiments, the present invention relates to compound II, wherein n represents independently for each case 2 and R independently represents each case hydrogen. In certain embodiments, the present invention relates to compound II, wherein n represents independently for each case 2, R independently represents hydrogen for each case, and Y is -C (O) -. In certain embodiments, the present invention relates to compound II, wherein X represents independently for each case - [(alkyl-NR ^ (0)) m-alkyl] -. In certain embodiments, the present invention relates to compound II, wherein X represents independently for each case - [((C? -C5) alkyl-^ -C (O)) m-alkyl (C? -C5)] - . In certain embodiments, the present invention relates to compound II, wherein X represents independently for each case - [(alkyl-NRxC (O)) m-alkyl] -, m is 2, and R1 is H. In certain embodiments, the present invention relates to compound I, wherein X represents independently for each case: wherein s is 1, 2, 3 or 4. In certain embodiments, the present invention relates to compound I, wherein X represents independently for each case : ? wherein s is 3 or 4. In certain embodiments, the present invention relates to compound I, wherein X independently represents for each case: In certain embodiments, the present invention relates to compound I, wherein n independently represents for each case 2, R independently represents hydrogen for each case, Y is -C (O) -, and X represents independently for each case: In certain embodiments, the present invention relates to compound II, wherein X independently represents for each case: coordinated with M. In certain embodiments, the present invention relates to compound II, wherein n represents independently for each case 2, R independently represents hydrogen for each case, Y is -C (O) -, M is Gd3 +, and X represents independently for each case: Another aspect of the present invention relates to a compound represented by the formula III: m wherein R represents independently for each case H or alkyl; And independently represents for each case -C (0) - or -S (0) -; n represents independently for each case 1, 2, 3, or 4; A is selected from the group consisting of a covalent bond, alkyl, heteroalkyl, alkenyl, - [(alkyl -NR ^ IO)) m-alkyl] -, where m is 1, 2, 3, or 4; and R1 is H or alkyl; X independently represents for each case an alkyl, heteroalkyl, alkenyl, or - [(alkyl-? R -'- C (O)) m-alkyl] -, where m is 1, 2, 3, or 4; and R1 is H or alkyl; and Z is - (CH) 2C02H, an antibiotic, anti-viral, anti-tumor, anti-inflammatory, anti-infectious, antifungal, radionuclide, hormonal antagonist, heavy metal complexes, oligonucleotide, antisense, chemotherapeutic nucleotide, peptide, protein, polysaccharide , aminoglycoside, antibody and fragments, lipid construct, non-specific protein (non-antibody), compound containing boron, photodynamic agent, enedin, or a transcription-based drug. In certain embodiments, the present invention relates to compound III, wherein Y represents independently for each case -C (O) -. In certain embodiments, the present invention relates to compound III, wherein n represents independently for each case 2. In certain embodiments, the present invention relates to compound III, wherein n represents independently for each case 2 and R independently represents each case hydrogen. In certain embodiments, the present invention relates to compound III, wherein n represents independently for each case 2, R independently represents hydrogen for each case, and A is a covalent bond. In certain embodiments, the present invention relates to compound III, wherein n represents independently for each case 2, R independently represents hydrogen for each case, and Y is -C (0) -. In certain embodiments, the present invention relates to compound III, wherein X represents independently for each case - [(alkyl-NR1C (O)) m-alkyl] -. In certain embodiments, the present invention relates to compound III, wherein X independently represents for each case - [((C? -C5) alkyl-NRXC (O)) m-alkyl (C? -C5)] -. In certain embodiments, the present invention relates to compound III, wherein X represents independently for each case - [(alkyl-NR1C (O)) m-alkyl] -, m is 2, and R1 is H.

In certain embodiments, the present invention relates to compound III, wherein X independently represents for each case - [((C? -C5) alkyl-NRXC (0)) m-alkyl (C? ~ C5)] -, m is 2, and R1 is H. In certain embodiments, the present invention relates to compound III, wherein X independently represents for each case: in donds s is 1, 2, 3 or 4. In certain embodiments, the present invention relates to compound III, wherein X represents independently for each case: wherein s is 3 or 4. In certain embodiments, the present invention relates to compound III, wherein X independently represents for each case: In certain embodiments, the present invention relates to compound III, wherein n independently represents for each case 2, R independently represents hydrogen for each case, Y is -C (0) -, and X represents independently for each case: In certain embodiments, the present invention relates to compound III, wherein n independently represents for each case 2, R independently represents hydrogen for each case, Y is -C (0) -, A is a covalent bond, and X independently represents for each case: In certain embodiments, the present invention relates to compound III, wherein n independently represents for each case 2, R independently represents hydrogen for each case, Y is -C (O) -, Z is an anti-infective, and X represents independently for each case: In certain embodiments, the present invention relates to compound III, wherein n independently represents for each case 2, R independently represents hydrogen for each case, Y is -C (0) -, Z is an anti-tumor, and X represents independently for each case: In certain embodiments, the present invention relates to compound III, wherein n independently represents for each case 2, R independently represents hydrogen for each case, Y is -C (0) -, Z is an anti-inflammatory, and X represents independently for each case: In certain embodiments, the present invention relates to compound III, wherein Z is an anti-infective, anti-inflammatory, or anti-tumor agent. In certain embodiments, the present invention relates to compound III, wherein Z is selected from the group consisting of abacavir sulfate, abarelix, acarbose, acetaminophen, acetylsalicylic acid, acitretin, activated protein C, acyclovir, adefovir dipivoxil, adenosine, hormone adrenocorticotrophic, albuterol, alendronate sodium, allopuric, alpha 1 proteinase inhibitor, alprazalom, alprostadil, altinicline, amifostine, amiodarone, amitriptyline HCL, amlodipine besylate, amoxicillin, amprenavir, anagrelide hydrochloride, anaritide, anastrozole, antisense oligonucleotide, aripiprazole , astemizole, atenolol, bupropion hydrochloride, buspirone, butorphanol tartrate, cabergoline, caffiene, calcitriol, candesartan, cilexetil, candoxatril, capecitabine, captopril, carbamazepine, carbidopa / levodopa, carboplatin, carisoprodol, carvedilol, caspofungin, cefaclor, cefadroxil, ciclosporin , sodium dalteparin, dapitant, desmopressin acetate, diazepam, ABT 594, diclofenac sodium, LCH dicyclomine, didanosine, digoxin, diltiazem hydrochloride, fentanyl, fexofenadine hydrochloride, filgrastim SD01, finasteride, flecainide acetate, fluconazole, fludrocortisone acetate, flumazenil, fluoxetine, flutamide, fluvastatin, fluvoxamine maleate , follitropin alfa / beta, formoterol, fosinopril, sodium fosphenytoin, furosemide, gabapentin, gadodiamide, gadopentetate dimeglumine, gadoteridol, ganaxolone, ganciclovir, gantofiban, gastrin immunoglobulin CW17, gemcitabine hydrochloride, gemfibrozil, gentamicin isotone, gepirone hydrochloride , pioglitazone hydrochloride, sodium piperacillin, pleconaril, poloxalene CW188, posaconazole, NN 304, pranzipexole dihydrochloride, pravastatin sodium, prednisone, pregabalin, primidone, prinomastat, prochlorperazine maleate, valdecoxib, valproic acid, valsartan hydrochlorothiazide, valspodar, Vancomycin HCL, Vecuronium bromide, Venlafaxine hydrochloride, Vera HCL pamilo, vinorelbine tartrate, vitamin B12, vitamin C, voriconazole, sodium warfarin, xaliprodene, and zafirlukast. In certain embodiments, the present invention relates to compound III, wherein A is: In certain embodiments, the present invention relates to compound III, wherein Z is selected from the group consisting of an anti-infective, anti-inflammatory agent , and anti-tumor; and A is: Another aspect of the present invention relates to a compound represented by formula IV: Where R represents independently for each case H or alkyl; And independently represents for each case -C (0) - or -S (0) -; n represents independently for each case 1, 2, 3, or 4; M is a metal atom; A is selected from the group consisting of a covalent bond, alkyl, heteroalkyl, alquenils, or - [(alkyl- R Om-alquilJ -, wherein m is 1, 2, 3, or 4; and R1 is H or alkyl X represents independently for each case an alkyl, heteroalkyl, alkenyl, or - [(alkyl-NR ^ -C (O)) m-alkyl] -, where m is 1, 2, 3, or 4, and R1 is H or alkyl; a functional group X is or is not coordinated with M; and Z is -CH2C02H, an antibiotic, anti-viral, anti-tumor, anti-inflammatory, anti-infective, antifungal, radionuclide, hormone antagonist, heavy metal complexes, oligonucleotide, antisense, chemotherapeutic nucleotide, peptide, protein, polysaccharide, aminoglycoside, antibody and fragments, lipid construct, non-specific protein (non-antibody), boron-containing compound, photodynamic agent, enediin, or a drug based on transcription. In certain embodiments, the present invention relates to compound IV, wherein Y represents independently for each case -C (O) -. In certain embodiments, the present invention relates to compound IV, wherein n represents independently for each case 2. In certain embodiments, the present invention relates to compound IV, wherein n independently represents for each case 2 and R independently represents each case hydrogen. In certain embodiments, the present invention relates to compound IV, wherein n represents independently for each case 2, R independently represents hydrogen for each case, and A is a covalent bond. In certain embodiments, the present invention relates to compound IV, wherein n represents independently for each case 2, R independently represents hydrogen for each case, and Y is -C (0) -. In certain embodiments, the present invention relates to compound IV, wherein X represents independently for each case - [(alkyl-NR1C (0)) m-alkyl] -. In certain embodiments, the present invention relates to compound IV, wherein X represents independently for each case - [(alkyl (Ca-C3) -NRXC (0)) m-alkyl (C? -C5)] -. In certain embodiments, the present invention relates to compound IV, wherein X represents independently for each case - [(alkyl-NRxC (0)) m-alkyl] -, m is 2, and R1 is H. In certain embodiments, the present invention relates to compound IV, wherein X independently represents for each case - [(alkyl (d-C5) -NR ^ 'C (0)) m-alkyl (Cx-C5)] -, m is 2, and R? is H. In certain embodiments, the present invention relates to compound IV, wherein X represents independently for each case - [(C 1 -C 5 alkyl) -NR ^ -C (0)) m-C 1 -C 5 alkyl ] -, m is 2, and R1 is H, and A is a covalent bond. In certain embodiments, the present invention relates to compound IV, wherein X independently represents for each case: , wherein s is 1, 2, 3 or 4. In certain embodiments, the present invention relates to compound IV, wherein X independently represents for each case: In certain embodiments, the present invention relates to compound IV, wherein X independently represents for each case: In certain embodiments, the present invention relates to compound IV, wherein n independently represents for each case 2, R independently represents hydrogen for each case, Y is -C (O) -, and X independently represents for each case: In certain embodiments, the present invention relates to compound IV, wherein n independently represents for each case 2, R independently represents hydrogen for each case, Y is -C (O) -, A is a covalent bond, and X independently represents for each case: In certain embodiments, the present invention relates to compound IV, wherein n independently represents for each case 2, R independently represents hydrogen for each case, Y is -C (0) -, Z is an anti-infective, and X represents independently for each case: In certain embodiments, the present invention relates to compound IV, wherein n represents independently for each case 2, R independently represents hydrogen for each case, Y is -C (0) -, Z is an anti-tumor, and X represents independently for each case: In certain embodiments, the present invention relates to compound IV, wherein n represents independently for each case 2, R independently represents hydrogen for each case, Y is -C (0) -, Z is an anti-inflammatory, and X represents independently for each case: In certain embodiments, the present invention relates to compound IV, wherein Z is an anti-infective, anti-inflammatory, or anti-tumor agent. In certain embodiments, the present invention relates to compound IV, wherein Z is selected from the group consisting of abacavir sulfate, abarelix, acarbose, acetaminophen, acetylsalicylic acid, acitretin, activated protein C, acyclovir, adefovir dipivoxil, adenosine, hormone adrenocorticotrophic, albuterol, alendronate sodium, allopuric, alpha 1 proteinase inhibitor, alprazalom, alprostadil, altinicline, amifostine, amiodarone, amitriptyline HCL, amlodipine besylate, amoxicillin, amprenavir, anagrelide hydrochloride, anaritide, anastrozole, antisense oligonucleotide, aripiprazole , astemizole, atenolol, bupropion hydrochloride, buspirone, butorphanol tartrate, cabergoline, caffiene, calcitriol, candesartan, cilexetil, candoxatril, capecitabine, captopril, carbamazepine, carbidopa / levodopa, carboplatin, carisoprodol, carvedilol, caspofungin, cefaclor, cefadroxil, ciclosporin , sodium dalteparin, dapitant, desmopressin acetate, diazepam, ABT 594, diclofenac sodium, diclofomin HCL, didanosine, digoxin, diltiazem hydrochloride, fentanyl, fexofenadine hydrochloride, filgrastim SD01, finasteride, flecainide acetate, fluconazole, fludrocortisone acetate, flumazenil, fluoxetine, flutamide, fluvastatin, fluvoxamine maleate, follitropin alpha / beta, formoterol, fosinopril, sodium fosphenytoin, furosemide, gabapentin, gadodiamide, gadopentetate dimeglumine, gadoteridol, ganaxolone, ganciclovir, gantofiban, gastrin immunogen CW17, gemcitabine hydrochloride, gemfibrozil, gentamicin isotone, gepirone hydrochloride, hydrochloride of pioglitazone, sodium piperacillin, pleconaril, poloxalene CW188, posaconazole, NN 304, pranzipexole dihydrochloride, pravastatin sodium, prednisone, pregabalin, primidone, prinomastat, prochlorperazine maleate, valdecoxib, valproic acid, valsartan hydrochlorothiazide, valspodar, Vancomycin HCL, Vecuronium bromide, venlafaxine hydrochloride, Verapamil HCL, vinorelbine tartrate, vitamin B12, vitamin C, voriconazole, sodium warfarin, xaliprodene, and zafirlukast. In certain embodiments, the present invention relates to compound IV, wherein A is: In certain embodiments, the present invention relates to compound IV, wherein Z is selected from the group consisting of an anti-infective, anti-inflammatory, and anti-tumor agent; and A is: Methods of the Invention One aspect of the present invention relates to a method for treating a condition in a mammal, comprising the steps of: administering to said mammal a therapeutically effective amount of a compound of formula I, II, III, or IV. In certain embodiments, the present invention relates to the aforementioned methods, wherein said condition is a bacterial infection, viral infection, cancer or is characterized by inflammation. In certain embodiments, the present invention relates to the aforementioned methods, wherein said condition is cancer. In certain embodiments, the present invention relates to the aforementioned methods, wherein said mammal is a human. In certain embodiments, the present invention relates to a formulation, which comprises a compound of the formula I, II, III, or IV and a pharmaceutically acceptable excipient. A method for generating a magnetic resonance image of a human or non-human animal body, comprising the steps of administering into the body of a subject in need of magnetic resonance imaging, a compound of formula II or IV , and generate a magnetic resonance image.

In certain embodiments, the present invention relates to the aforementioned methods, wherein said subject is a human. In certain embodiments, the present invention relates to the aforementioned methods, wherein said compound of formula II wherein M is selected from the group consisting of Gd3 +, Mn2 +, Be3 +, or Cr3 +. In certain embodiments, the present invention relates to the aforementioned methods, wherein said compound of formula II wherein M is Gd3 +. In certain embodiments, the present invention relates to the aforementioned methods, wherein said compound of formula II wherein M is selected from the group consisting of In-111, Tc-99m, 1-123, 1-125 F- 18, Ga-67, Ga-68, 1-131, Re-186, Re-188, Y-90, Bi-212, At-211, Sr-89, Ho-166, Sm-153, Cu-67, and Cu-64. In certain embodiments, the present invention relates to the aforementioned methods, wherein said compound of formula II wherein M is Tc-99m. Bacterial Infection Treatment The antibacterial properties of the compounds of formula I, II, III and IV can be determined from a bacterial lysis assay, as well as by other methods, including, but not limited to, growth inhibition assays (eg. example, as described by Blondelie et al (1992) Biochemistry 31: 12688), fluorescence-based bacterial viability assays (e.g., Molecular Probes BacLight), analysis by flow cytometry (Arroyo et al (1995) J. Virol. 69: 4095-4102), and other assays known to those skilled in the art. Assays for growth inhibition of a microbial target can be used to obtain an ED50 value for the compound, that is, the concentration of a compound required to kill 50% of the microbial sample being analyzed. Alternatively, inhibition of growth by an antimicrobial compound of the invention may also be characterized in terms of the minimum inhibitory concentration (MIC), which is the concentration of the compound required to achieve inhibition of microbial cell growth. Such values are well known to those in the art as representative of the effectiveness of a particular antimicrobial agent (e.g., an antibiotic) against a particular organism or group of organisms. For example, the cytolysis of a bacterial population by an antimicrobial compound can also be characterized, as described above by the minimum inhibitory concentration, which is the concentration required to reduce the viable bacterial population to 99.9%. The MIC5o value can also be used, defined as the concentration of a compound required to reduce the viable bacterial population to 50%. In preferred embodiments, the compounds of the present invention are selected for use based, inter alia, on having MIC values of less than 25 μg / mL, more preferably less than 7 μg / mL, and even more preferably less than 1 μg. / mL against a bacterial target, for example, a Gram-positive bacterium such as methicillin-resistant Staphylococcus aureus or Streptococcus pneumoniae. Another useful parameter for identifying and measuring the effectiveness of the antimicrobial compounds of the invention is the determination of the kinetics of the antimicrobial activity of a compound. Such determination can be made by determining the antimicrobial activity as a function of time. In a preferred embodiment, the compounds exhibit a kinetics which results in efficient lysis of a microorganism. In a preferred embodiment, the compounds are bactericidal. In addition, the preferred antimicrobial compounds of the invention exhibit selective toxicity to the target microorganisms and minimal toxicity to mammalian cells. The determination of the toxic dose (or "LD50") can be made using protocols well known in the field of pharmacology. The determination of the effect of a compound of the invention on mammalian cells, preferably is performed using tissue culture assays, for example, the present compounds can be evaluated according to standard methods known to those skilled in the art (see example Gootz, TD (1990) Clin. Microbiol. Rev. 3: 13-31). For mammalian cells, such assay methods include, among others, trypan blue exclusion and MTT assays (Moore et al. (1994) Compound Research 7: 265-269). When a specific type of cell can release a specific metabolite during changes in membrane permeability, that specific metabolite can be analyzed, for example, the release of hemoglobin in the lysis of red cell cells (Srinivas et al (1992) J. Biol. Chem. 267: 7121-7127). The compounds of the invention are preferably tested against the primary cells, for example, using human skin fibroblasts (HSF) or fetal equine kidney cell cultures (FEK), or other primary cell cultures used by those skilled in the art. Permanent cell lines can also be used, for example, Jurkat cells. In preferred embodiments, the target compounds are selected for use in animals, or animal cell / tissue culture based at least in part on having LD50s of at least one order of magnitude greater than MIC or ED50 as may be the case , and even more preferably at least two, three and even four orders of magnitude greater. That is, in the preferred embodiments where the target compounds are to be administered to an animal, a suitable therapeutic index preferably is greater than 10, and even more preferably more than 10, 1000 or even 10,000. Antibacterial assays for the compounds of the invention can be performed to determine bacterial activity towards both Gram-positive and micro-organisms.

Gram-negative. Typical Gram-negative pathogens which may be sensitive to the antibacterial agents of the present invention may include, for example, species of the genus Escherichia, genus Enterobacter, genus Klebsiella, genus Serratia, genus Proteus and genus Pseudomonas. For example, the objective compositions and methods can be used as part of the treatment and prevention regimens for infections by some of the most frequently found Gram-negative and Gram-positive organisms, including those involving Escherichia coli (E. Coli), Klebsiella peumoniae (K. peu oniae), Serratia marcescens, Enterobacter aerogenes and Enterobacter cloacae (E. aerogenes and E. cloacae), Pseudomonas aeruginosa (P. aeruginosa), Neisseria meningitidis (N. meningitidis), Streptococcus aureus of the Group B and Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyrogenes, Corynebacter diphtheriae, Gardnierella vaginalis, Actinetobacter spp., Bordella pertussis, Haemophilus aegyptius, Haemophilus influenza, Haemophilus ducreyi, Shigella spp, Serratia spp., And Propionibacterium acnes. The above list of pathogens is merely illustrative and in no way be construed as restrictive. Examples of conditions which may be treated include respiratory tract diseases of the pharyngeal cavity; otitis, pharyngitis, pneumonia, peritonitis, pyelonephritis, cystitis, endocarditis, systemic infections, bronchitis, arthritis, local inflammations, skin infections, conjunctivitis, and infections of any vascular access, created surgically for the purpose of hemodialysis. In preferred embodiments, the antibacterial agents of the present invention are selected based on their ability to inhibit the growth of Gram-positive bacteria. Such Gram-positive bacteria include bacteria of the following species: Staphylococcus, Streptococcus, Micrococcus, Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium, Lactobacillus, Listeria, Erysipelothrix, Prspionibacterium, Eubacterium, and Corynebacterium. A variety of Gram-positive organisms are capable of causing sepsis. The most common organisms involved in sepsis are Staphylococcus aureus, Streptoccocus pneumoniae, coagulase-negative staphylococcus, beta-hemolytic streptococci, and enterococci, although any Gram-positive organisms may be involved (see, for example, Bone, (1993) J. Critical Care 8: 51-59). Accordingly, it is specifically contemplated that the subject compositions and methods may be used as part of a therapeutic treatment or prevention program for sepsis involving Gram-positive bacteria. Accordingly, in one embodiment, S. aureus is used as a model of a Gram-positive microorganism in the analysis / selection of the compounds of the present invention. This bacterium is also a significant clinical objective as well as because it is refractive for most systemic antibiotic treatments. Staphylococcus aureus is the most frequent cause of infections in the skin, wounds, and blood and the second most frequent cause of infections in the lower respiratory tract, and the microorganism tends to attack patients with compromised immunity and interned in hospitals. Accordingly, the target compounds can be used to treat such infections caused by Staphylococcus, as well as in the treatment of conjunctivitis, outer ear infections and the like. One of the key contributors to the increase in mortality and morbidity due to bacterial infections is the increasing prevalence of drug-resistant bacteria. Examples of the severity of antibiotic resistance are methicillin-resistant staphylococcus (MRSA), and the emergence of vancomycin-resistant S. aureus, which has become resistant to virtually all currently used antibiotics. Therefore, methicillin-resistant S. aureus can also be used as a model organism resistant to antibiotics to select target compounds. In a preferred embodiment, the antibacterial agents of the present invention can be used in the treatment and / or prevention of endocarditis, for example, which can be caused by MRSA. The frequent use of vancomycin to treat MRSA infections in turn has contributed to the emergence of new strains of enterococcus, the third most prevalent cause of bacterial infection in the United States, which are resistant to vancomycin. Enterococcus causes nothing more and nothing less than 15 per. one hundred cases of bacterial endocarditis; It is also the cause of meningitis, and infections in the urinary tract, stomach and intestines. The infections caused by these vancomycin-resistant enterococci (VRE) frequently do not respond to any of the current therapies, and in many cases prove to be fatal. Accordingly, the target compounds can be selected using an assay based on sensitivity to E. faecalis, and in particular, the vancomycin-resistant isolates are found in clinical settings such as a hospital. The objective compositions can also be selected for the treatment of a Streptococcus infection. Streptococcus species are associated in a wide variety of pathological conditions, including gangrene, puerperal infections, bacterial endocarditis, subacute, septic angina, rheumatic fever, and pneumonia. Therefore, agents that are active against Streptococcus species are very necessary. To further illustrate, E. coli and P. aeruginosa are examples of Gram-negative organisms which may be sensitive to the target antibacterial agents. P. aeruginosa is a particularly problematic source of conditions in conditions such as pulmonary infections in patients with cystic fibrosis, burn infections, eye and urinary tract infections, and infection with P. aeruginosa can result in serious septicemia. In addition, P. aeruginosa resistant to imipenem is increasing in the clinical field. The enteropathogenic E. coli is responsible for attacks of diarrhea in infants and newborns, and diarrhea, including "traveler's diarrhea", in adults. E. coli can be invasive and toxin-producing, sometimes causing fatal infections, such as cystitis, pyelitis, pyelonephritis, appendicitis, peritonitis, gallbladder infection, septicemia, meningitis and endocarditis. In still other embodiments, the target compounds can be used in the treatment of infections caused by Serratia spp. For example, S. marcescens is a source of ophthalmic infections and other topical infections, and can be readily provided in proposed tests to identify those compounds of the present invention which are bactericidal in suitable concentrations against that bacterium. The target compounds can also be used in the treatment of external ear infections (otitis externa), or in the treatment of sexually transmitted diseases such as Nieseria gonorrhea and trichomonas infections. Certain compounds according to the invention can also be selected based on their activity against typical and atypical Mycobacteria and Helicobacter pylori, and also against bacteria-like microorganisms, such as, for example, Mycoplasma and Rickettsia. They are therefore particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens. YcoJbacteri m boris, such as M. tuberculosis, M. africanum, M. ulcerans, and M. leprae, is a severe pathogen. The . Bovis is a significant pathogen throughout the world, causing tuberculosis, mainly in cattle. In other embodiments, the objective compositions can be used in the treatment / prevention of Salmonella infection. Salmonella spp. causes food poisoning, which results in nausea, vomiting, diarrhea and sometimes lethal septicemia. For example, S. typhi is the etiologic agent of typhoid fever. The compositions and methods of the present invention may also be useful in the treatment of Shigella infection. The Shigella spp. including S. dysenteriae, are common aquatic pathogens that cause bacillary dysentery as well as bacteremia and pneumonia. In the United States and Canada, S. sonnei and S. flexneri have become the most common cytological agents in bacillary dysentery. The bacteria of the Yersinia genus are also pathogenic which can be treated by the objective compositions. Y. Enterocholia, for example, is an enteric pathogen. Infection with this microorganism causes severe diarrhea, gastroenteritis and other types of infections such as bacteremia, peritonitis, cholecistis, visceral abscesses, and mesenteric lymphadenitis. Septicemia has been reported with 50% mortality. Y. pestis is the etiological agent of the bubonic, pneumonic, and septicemic plague in humans.

Cancer Treatment The present invention further provides methods for modulating the survival and / or proliferation of trarmed tumor cells with the compounds of formula I, II, III or IV. Such tumors include, but are not limited to, tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, lower jaw, larynx, hypopharynx, salivary glands, paragangliomas, pancreas, stomach, skin, esophagus, and liver. biliary tree, bones, intestine, 'colon, rectum, ovaries, prostate, lung, chest, central nervous system, or brain. Treatment of Inflammatory Diseases The compounds, compositions and methods of the invention are useful for treating inflammatory reactions or conditions, in particular those with overproduction of inflammatory mediators, including, but not limited to, IL-2, IL-5, IL- 8, IFN-gamma, and T? F-alpha. The influx of calcium-activated storage activates several signaling pathways in inflammatory cells, resulting in the production of cytokines and chemokines, release of other inflammatory mediators, soluble, such as autocoids, proteolytic enzymes, and toxic proteins, and over-regulation of cell surface molecules, which include adhesion molecules and receptors, which play key roles in inflammatory and autoimmune diseases. Significant calcium-regulated signaling molecules include the NFAT and NF- transcription factors. appa.B, and the voltage kinases JNK and p38. JNK plays an important role in the up-regulation of transcription factor-activating protein-1 (AP-1), and is involved in the production of TNF-alpha. (Minden A and Karin M, Biochim, Biophys, Acta 1333: F85-104, 1997, Lee J C and Young P R, J. Leukoc, Biol. 59: 152-7, 1996). In activated T cells, NFAT refers to the transcriptional regulation of IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, TNF alpha, and GM-CSF (Crabtree GR and Clipstone NA, Annu, Rev. Biochem. 63: 1045-83, 1994). NF-kappa B is essential for the transcriptional regulation of proinflammatory cytokines, which include IL-1, IL-6, IL-8, IFN.gamma, and TNF-.alpha., As well as the adhesion molecules VCAM-1 and ICAM-1, the alpha chain of the IL-2 receptor, and the cellular growth regulator c-Myc (Baldwin A S, J. Clin Invest. 107: 3-6, 2001; Barnes P J and Karin M, N. Engl. J. Med. 336: 1066-71, 1997). AP-1 transcriptionally regulates IL-2 and matrix metalloproteinase production (Palanki M S, Curr. Med. Chem. 9: 219-27, 2002). Mast cells and basophils express the high affinity IgE receptor (Fc epsilon.Rl) and synthesize histamine. The cross-linking of Fc.epsilon.R1 by an antigen results in calcium influx, degranulation, and the production of proinflammatory icosanoids. In addition to histamine, the secretory granules of human mast cells also contain the triptase, chymase and carboxypeptidase of neutral proteases. Tryptase has been implicated as a fibrinogen factor. The mast cells and basophils participate not only in an allergic disease, but also in chronic and fibrotic diseases that affect various organs, including the lungs (Marone G, Int. Arch. Allergy Immunol. 114: 207-17, 1997). Compounds that can effectively block calcium influx and activation of NFAT, NF-. Kappa.B, AP-1, and degranulation of mast cells / basophils therefore provide potential medical treatments for various inflammatory and autoimmune conditions. Transcription factors such as NF-.kappa.B are activated by extracellular signals or cell-to-cell interactions that become signals of intracellular activation through receptor molecules located in the cell membrane. It has been proposed that a bacterial toxin such as endotoxin induces calcium fluxes in monocytes and the nuclear translocation of NF-.kappa.B, a key step in the generation of the inflammatory response. Under an acute condition, the inflammatory process induced by endotoxins could lead to a serious medical condition such as sepsis. The number of known genes that are transcribed after activation of NF-.kappa.B is constantly increasing. These genes include cytokines (such as IL-1, TNF-alpha, etc.), chemokines (IL-8 for example), growth factors, cellular ligands, and adhesion molecules; Many of these genes are involved in the pathogenesis of rheumatoid arthritis (RA). To date, it is believed that many other inflammatory conditions are related to the action of NF-.kappa.B (for recent reviews, see Yamamoto Y and Gaynor RB, Curr. Mol. Med. L (3): 287-96, 2001, Baldwin AS, J. Clin Invest. 107: 3-6, 2001). For example, pneumococcus causes ear damage in otitis and in association with bacterial meningitis. The pathogenesis of the lesion involves the responses of the host to the cell wall and pneumolysin. The release of cell wall components, particularly during bacterial lysis induced by antibiotics, leads to an influx of leukocytes and subsequent tissue injury. The cascade of signal transduction for this response becomes defined and includes CD14, receptors similar to Toll, NF-. kappa.B, and the production of cytokines. The decrease of the otitis sequelae can be achieved by an effective blockade of pneumococcal-induced inflammation. It has been shown that SOC inhibitors are effective in blocking the activation of NF-.kappa.B in Jurkat cells, and therefore can be considered as potential medical treatments of inflammatory conditions, such as RA and Crohn's disease, where the activation NF- .kappa.B plays a crucial role. The nuclear factor of activated T cell proteins (NFAT) is a family of transcription factors whose activation is controlled by calcineurin, a phosphatase of the calcium-dependent protein (Rao A et al., Annu. Rev. Immunol. 15: 707-47, 1997; Stankunas K et al., Cold Spring Harb. Symp. Quant. Biol. 64: 505-16, 1999).

Originally identified in T cells as inducers of cytokine gene expression, NFAT proteins play varied roles in cells outside the immune system (Horsley V and Pavlath GK, J. Cell Biol. 156: 771-4, 2002; Graef IA et al., Curr Opin Genet, Dev. 11: 505-12, 2001). Recently, using immunofluorescence / confocal microscopy, it was shown that cyclosporin A and tacrolimus block the nuclear translocation of calcineurin and NFAT in keratinocyte cultures (Al-Daraji WI et al., J. Invest.Dermatol., 118: 779-88 , 2002). The results showed that a variety of cell types in normal and psoriatic skin expressed calcineurin and? FAT1, although expression was particularly prominent in keratinocytes. The main cyclosporin A and the tracolimus that bind proteins cyclophilin A and FKBP12 were also expressed in keratinocytes and non-immune cells in the skin. The? FAT1 was predominantly nuclear in the epidermal, basal, normal keratinocytes. An increased nuclear localization of NFAT1 was observed in the suprabasal keratinocytes within the psoriatic lesional epidermis and to a lesser extent non-lesional compared to normal skin, which suggests an increased activation of calcineurin in the epidermal, psoriatic keratinocytes.

Agonists that induce differentiation of keratinocytes, specifically 12-0-tetradecanoyl-phorbol-13-acetate (TPA) plus ionomycin, raise intracellular calcium, induce nuclear translocation of NFAT1 and calcineurin in keratinocytes, and are inhibited by the treatment with cyclosporin A or tacrolimus. In contrast, in human dermal fibroblasts, TPA plus ionomycin or TPA do not significantly alter the proportion of NFAT1 associated with the nucleus. These results indicate that calcineurin is functionally active in human keratinocytes that induce the nuclear translocation of the? FAT1, and that the regulation of the? FAT1 nuclear translocation in the skin is cell type specific. The inhibition of this pathway in epidermal keratinocytes can be quantified, in part, by the therapeutic effect of cyclosporin A and tacrolimus on skin conditions such as psoriasis. SOC inhibitors which can effectively inhibit NFAT activation provide an alternative pharmacological treatment for inflammatory conditions such as psoriasis. Mast cells and / or basophils have been involved in the expression of a wide variety of biological responses, including immediate hypersensitivity reactions, host responses to parasites and neoplasms, angiogenesis, tissue remodeling, and non-specific inflammatory and fibrotic conditions. immunologically Recent findings suggest that an important mechanism by which mast cells influence such biological responses is through the production of a broad panel of multifunctional cytokines. In contrast, the degree to which basophils can produce cytokines is uncertain (Galli S J et al., Curr Opin Immunol 3: 865-72, 1991). The mediators associated with mast cells are generally classified into two groups: the preformed mediators, which are stored in the cytoplasmic granules of the cells and released during exocytosis, and the newly synthesized mediators, which are not stored but reproduced and secrete only after a proper stimulation of the cell. It has now been reported that the tumor necrosis factor alpha (TNF-alpha) / cachectin represents a new type of mediator associated with mast cells, in which the activation of IgE-dependent cells results in the rapid release of preformed stores from the cytokine followed by the synthesis and sustained release of large amounts of the newly formed TNF-alpha. It has also been shown that stimulation with a specific antigen induces higher levels of RA? M of TNF-alpha at skin sites sensitized with IgE in normal mice or mice WBB6F1-W / W1 'devoid of genetically reconstituted mast cells with mast cells in sites treated identically in WBB6F1-W / W1' mice that are devoid of mast cells. These findings identify mast cells as a biologically significant source of TNF-alpha / cachectin during IgE-dependent responses and define a mechanism by which stimulation of mast cells can be explained through the FC epsilon R.sup.l of the both rapid and sustained release of this cytokine (Gordon JR and Galli SJ, J. Exp. Med. 174: 103-7, 1991). Mast cells are widely considered to be important effector cells in the immune responses associated with Th2 cells and IgE. Recent work shows that they can also contribute significantly to the expression of innate immunity. In addition, survival in a model of acute bacterial infection, which depends on complement and mast cells, can be greatly improved by the long-term treatment of mice with the whole ligand (stem cell factor) at least in part due to the effects of such treatment on the number and / or function of mast cells. These findings not only indicate that mast cells may represent a critical component of host defense in their natural immunity but also suggest that mast cell function in this environment can be manipulated for therapeutic purposes (Galli S J et al., Curr Opin. Immunol., 11: 53-9, 1999). The release of pro-inflammatory mediators by degranulation of mast cells is considered a calcium-dependent process. Compounds, such as SOC inhibitors that prevent degranulation of mast cells, represent new potential medical treatments for inflammatory, allergic and immune conditions where mast cells are involved. In certain embodiments, the compounds, compositions and methods are useful for treating any condition arising from the increased activity of the lymphocyte activation pathway downstream of calcium entry such as NFAT (nuclear factor of activated T cells). In certain embodiments, the compounds are also useful for treating inflammation from other calcium-dependent processes, including, but not limited to, mast cell degranulation and leukocyte secretion, as well as calcium-dependent processing of adhesion molecules. , chemokines and cytokines by a variety of non-hemopoietic cells, including endothelial and epithelial cells. In addition, the compounds, compositions and methods of the present invention can also be used to prevent and / or treat inflammatory reactions or conditions., pulmonary (eg, asthma, allergic rhinitis, lung disease, obstructive, chronic, and respiratory fatigue syndrome in adults), musculoskeletal or inflammatory reaction (eg, exercise-induced injuries, rheumatoid arthritis, • psoriatic arthritis, osteoporosis and osteoarthritis), urogenital reaction or gastrointestinal, inflammatory (eg, enterocolitis, gastritis, Crohn's disease, interstitial cystitis, vaginitis, and ulcerative colitis), autoimmune disease or reactions (eg, type II diabetes, inflammatory bowel disease, and psoriasis), irritable bowel syndrome, neurogenic inflammation and rejection reactions to transplants. The compounds, compositions and methods of the present invention can also be used to prevent and / or treat inflammatory skin conditions (eg, atopic dermatitis, eczema, contact dermatitis and allergic dermatitis), hyperproliferative skin conditions (e.g. , psoriasis, basal cell carcinoma and squamous cell carcinoma), and skin irritation.

Such conditions are well known to those skilled in the art and are described, for example, in Champion et al., Eds. (1998) "Textbook of Dermatology", Blackwell Science, or in information provided by any of a number of organizations such as the American Academy of Dermatology (see, for example, http://www.dermfnd.org/) and the American Cancer Society (see, for example, http://www.cancer.org/). In addition, the compounds and compositions of the present invention can be used to treat any symptom with any of these conditions or conditions, such as inflammation, redness, itching, pimples, crusts, scabs, dryness, burns, exudation, fluids, for example , pus, suppuration, pustules, blisters, rashes, disfigurement, scars, dandruff, papules, plaques, lesions, thickenings, spills, protuberances, desquamation, bleeding, softenings, cuts, scratches, ailments, cramps, irritation, swelling, blisters, vesicles , prominences, scars, wrinkles, freckles, yellowing, dilation of blood vessels, loss of normal functions, and others. The compounds, compositions and methods of the present invention may also be useful for preventing and / or treating inflammatory, mucocutaneous diseases such as asthma and allergic rhinitis as well as their associated symptoms. Descriptions of such conditions can be found in the Asthma and Allergy Foundation of America (see, for example, http://www.aafa.org/), and are well known to those skilled in the art. Asthma is characterized by the paradoxical narrowing of the bronchi that results in breathing difficulties. Typical symptoms associated with asthma include, for example, wheezing, breathing difficulties, tightness of the chest, dry cough and shortness of breath after exercise. The compounds of the present invention can also be used to treat allergic rhinitis (hay fever). Allergic rhinitis results from an inflammatory reaction that occurs in the nasal passages in response to an allergic stimulus. Symptoms associated with allergic rhinitis include, for example, sneezing, nasal congestion, nasal itching, nasal discharge and itching of the palate of the mouth and / or ears. The compounds, compositions and methods of the present invention can also be used to prevent and / or treat skin aging, in particular extrinsic skin aging, as well as any symptoms associated with aging of the skin. Such symptoms include, for example, the appearance of wrinkles, and / or fine lines, skin and subcutaneous tissue decay, depressed skin, atrophy of the epidermis, increased dryness of the skin, decreased skin elasticity, frailty Increased capillaries, increased healing time after a wound, pigmented alterations with areas of hyper- and hypopigmentation, appearance of a variety of benign, premalignant, and malignant neoplasms, and the like.

In addition, at the histological level, aging results in a thinning and deterioration of the skin, as well as reduction in cells and blood supply, and a flattening in the junction between the dermis and the epidermis. In addition, the compounds, compositions and methods of the present invention can be used to prevent and / or treat photodamage in the skin and any associated symptoms. Photodamage on the skin occurs with aging caused by prolonged or repeated exposure to ultraviolet radiation. Signs of photodamage on the skin include, for example, wrinkles, yellowing, appearance of spots and moles, elastosis, appearance of lines, coriaceous or dry appearance of the skin, and premature aging of the skin. At the histological level, the photodamage on the skin can be reflected in the abnormal elastic fibers, thickened, entangled, diminished collagen, and increased content of glycosaminoglycans (see, Tanaka et al. Arch. Dermatol. Res. 285: 352-355, 2000). The compounds, compositions and methods of the present invention are efficient to prevent and / or treat inflammation and mucocutaneous irritation caused, for example, by the delivery of transdermal or transmucosal drugs, irritant drug release enhancers or irritant pharmaceutical substances. The compounds and compositions of the present invention can also be used as excipients to enhance the potency of anti-inflammatory drugs, such as corticosteroids, salicylates, colchicine, para-aminophenol, propionic acid, piroxicam, ketorolaco, ketoprofen, cyclooxygenase inhibitors, indomethacin , and similar. In still another aspect, the present invention provides methods for treating an atopic condition, such as atopic dermatitis, allergic rhinitis or asthma, comprising: administering to a patient an HMG CoA reductase inhibitor (open chain, lactone or combinations thereof) ) treating this the atopic condition. HMG-CoA reductase inhibitors include, but are not limited to, mevastin, lovastatin, fluvastatin, pravastatin, simvastatin, dalvastatin, cerivastatin, and atorvastatin. The HMG CoA reductase inhibitor (open chain, lactone or combinations thereof) can also be used to prevent and / or treat inflammatory skin conditions (e.g., atopic dermatitis, eczema, contact dermatitis and allergic dermatitis, a obstructive pulmonary disease and respiratory fatigue syndrome in adults), hyperproliferative skin conditions (eg, psoriasis, basal cell carcinoma and squamous cell carcinoma), and skin irritation. In addition, the HMG CoA reductase inhibitor (open chain, lactone or combinations thereof) can also be used to treat a gastrointestinal or urogenital, inflammatory reaction, such as inflammatory bowel disease, enterocolitis, gastritis, vaginitis, cystitis. interstitial Treatment of Viral Infections The anti-viral agents of the present invention (the compounds of the formulas I, II, III, and IV, and the pharmaceutically acceptable salts thereof), can be used to treat an infection by Herpes virus. (particularly of the two defined immunological types of Herpes simplex, HSV-1 and HSV-2), and Poliomyelitis virus (including the three immunologically distinguishable types thereof), in addition to Varicella zoster virus, Togavirus, Cytomegalovirus (CMV), Epstein-Barr virus (EBV) , Picornavirus, Rhinovirus, Human Papilloma Virus and Hepatitis Virus, among others. The anti-viral agents of the present invention are suitable for application in mammals (such as humans, horses, cattle, dogs and rodents). The route of administration is usually oral or parenteral, although it is possible to administer the anti-viral agents by other routes of administration, for example, by topical application, depending on whether the preparation is used to treat viral, internal or external infections, or application nasal. Topical application can be used for systemic treatment. Pharmaceutical Compositions In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more carriers (additives) and / or pharmaceutically acceptable diluents. As described in detail below, the pharmaceutical compositions of the present invention can be formulated especially for administration in solid or liquid form, including those adapted for the following: (1) oral administration, eg, purgative portions (aqueous solutions or suspensions or non-aqueous), tablets, for example, those designed for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application on the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection, such as, for example, a sterile solution or suspension, or sustained release formulation (3) topical application, for example, as a cream, ointment, or a controlled release patch or spray applied to the skin; (4) intravaginally or intra-rectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; u (8) nasally. The phrase "therapeutically effective amount" as used herein means the amount of a compound, material, or composition comprising a compound of the present invention which is effective to produce any desired therapeutic effect in at least one subpopulation of cells. in an animal in a reasonable benefit / risk ratio, applicable to any medical treatment. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and animals, without excessive toxicity, irritation, allergic response, or other problem or complication, in proportion to a reasonable benefit / risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate, or stearic acid), or solvent encapsulating material, involved in carrying or transporting the target compound from an organ, or part of the body, to another organ, or part of the body. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and waxes for suppositories; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) damping agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) solutions with buffered pH; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other compatible, non-toxic substances used in pharmaceutical formulations.

As stated above, certain embodiments of the present compounds may contain basic functional group, such as amino or alkylamino, and are, therefore, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this sense refers to the relatively non-toxic acid, inorganic and organic addition salts of the compounds of the present invention. These salts can be prepared in itself in the administration vehicle or in the manufacturing process of the dosage form, or by reacting separately a purified compound of the invention in its free base form with an organic or inorganic acid, suitable , and isolating the salt thus formed during the subsequent purification. Representative salts include salts of hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate, and the like. (See, for example, Berge et al (1977) "Pharmaceutical Salts", J. Pharm, Sci. 66: 1-19). The pharmaceutically acceptable salts of the objective compounds include non-toxic, conventional salts, or quaternary ammonium salts of the compounds, for example, of organic or inorganic, non-toxic acids. For example, such conventional, non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric , toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isothionic, and the like. In other cases, the compounds of the present invention may contain one or more functional groups, acidic, and, therefore, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these cases refers to the relatively non-toxic basic, inorganic and organic addition salts of the compounds of the present invention. These salts can also be prepared in situ in the delivery vehicle or the manufacturing process of the dosage form, or by separately reacting the purified compound in its free acid form with a suitable base, such as hydroxide, carbonate or bicarbonate. of a metal cation, pharmaceutically acceptable, with ammonium or with a primary, secondary or tertiary amine, pharmaceutically acceptable. Representative alkaline or alkaline earth salts include salts of lithium, sodium, potassium, calcium, magnesium, and aluminum, and the like. Representative organic amines for the formation of basic addition salts useful for the formation of basic addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., Supra). Wetting, emulsifying, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and flavoring agents, preservatives and preservatives may also be present in the compositions. antioxidants Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lectin, propylgalate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Formulations of the present invention include those suitable for oral, nasal, topical administration (including oral and sublingual), rectal, vaginal and / or parenteral. The formulations may conveniently be present in a unit dosage form and may be prepared by any method well known in the art. The amount of active ingredient that can be combined with a carrier material to produce a simple dosage form will vary depending on the host or host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a simple dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will vary from about 0.1 percent to about ninety-nine percent of the active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent up to about 30 percent. In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle-forming agents, for example, bile acids, and polymeric carriers, for example, polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, a formulation mentioned above makes orally available a compound of the present invention. Methods for preparing these formulations or compositions include the step of carrying in relation to a compound of the present invention with the carrier and, optionally, one or more non-essential ingredients. In general, the formulations are prepared by uniformly and intimately carrying them in relation to a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, forming the product. Formulations of the invention suitable for oral administration may be in the form of capsules, capsules, pills, tablets, dragees (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a tablet (using an inert base, such as gelatin and glycerin, or sucrose and acacia) ) and / or as mouth rinses and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention can also be administered as a bolus, electuary or paste.

In dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, troches and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate. , and / or any of the following: (1) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato starch or tapioca, alginic acid, certain silicates, and sodium carbonate; (5) retarding agents for solution, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surface agents, such as poloxalene and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surface agents; (8) absorbers, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type can also be employed as filling agents in soft and hard shell gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like. A tablet can be made by compression or molding, optionally with one or more non-essential ingredients. Compressed tablets can be prepared using binder (e.g., gelatin, or hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrating agent (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active or dispersing agent . Molded tablets can be made by molding them in a suitable machine, moistening a mixture of the pulverized compound with a liquid, inert diluent. The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, can optionally be labeled or prepared with coatings or shells, such as enteric coatings and other well-known coatings in the Pharmaceutical formulations technique. They can also be formulated to provide a slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in various proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be formulated for rapid release, for example, cold-dried.

They can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilization agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile, injectable medium, immediately. Before its use. These compositions may also optionally contain clouding agents and may be of a composition that they release only in the active ingredient (s), or preferably, in a certain part of the gastrointestinal tract, in a delayed manner. Examples of compositions included which may be used include polymeric substances and waxes. The active ingredient may also be in micro-encapsulated form, if appropriate, with one or more of the excipients described above. Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetate. of ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and esters of sorbitan fatty acid, and mixtures thereof. In addition to inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, flavoring and preservative agents. The suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be present as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers, comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum and release the active compound. Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or aerosol formulations containing such carriers which are known in the art to be appropriate. Dosage forms for topical or transdermal administration of a compound of this invention, include powders, aerosols, ointments, pastes, creams, lotions, gels, solutions, patches and inhalers. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservative, buffer, or propellant that may be required. Ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, acid silicic acid, talc and zinc oxide, or mixtures thereof. The powders and aerosols may contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.

The aerosols additionally contain propellants, such as chlorofluorohydrocarbons and volatile, non-substituted hydrocarbons, such as butane and propane. Transdermal patches have the added advantage of providing a controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The speed of such a flow can be controlled either by providing a speed controlling membrane or by dispersing the compound in a polymeric matrix or gel. Ophthalmic formulations, ointments, powders, solutions for the eyes and the like are also contemplated as being within the scope of this invention. The pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more aqueous or non-aqueous, isotonic, sterile, pharmaceutically acceptable solutions, dispersions, suspensions or emulsions, or sterile powders which can reconstitute into sterile injectable solutions or dispersions just before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which make the formulation isotonic with the blood of the desired recipient or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers that can be employed in the pharmaceutical compositions of the invention include, water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surface agents.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of the microorganisms in the target compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol-sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can occur through the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of a crystalline or amorphous material having a poor solubility in water.

The rate of absorption of the drug then depends on its rate of dissolution, which, in turn, may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of a drug form administered parenterally by dissolving or suspending the drug in an oil vehicle is achieved. - Forms of injectable deposit are formed by forming microencapsulated matrices of the objective compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the drug to the polymer, and the nature of the particular polymer employed, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). depot injectable formulations can also be prepared by trapping the drug in liposomes or microemulsions which are compatible with the tissue of the body.

When the compounds of the present invention are administered as drugs, to humans and animals, they may be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of the ingredient active in combination with a pharmaceutically acceptable carrier. The preparations of the present invention can be given orally, parenterally, topically, or rectally. They are, of course, given in suitable forms for each administration route. For example, they are administered in the form of tablets or capsules, by injection, inhalation, ocular lotion, ointment, suppositories, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal suppositories. Oral administrations are preferred. The phrases "parenteral administration" and "parenterally administered" as used herein means modes of administration other than enteral or topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal injection and infusion, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal. The phrases "systemic administration", "systematically administered", "peripheral administration" and "peripherally administered" as used herein means the administration of a compound, drug or other distinct material, directly into the central nervous system, in such a manner that it enters the patient's system and, therefore, undergoes metabolism and other similar processes, for example, subcutaneous administration. These compounds can be administered to humans or other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, an aerosol, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually. Regardless of the route of administration, the compounds of the present invention, which can be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. experts in the art. The current dosage levels of the active ingredients in the pharmaceutical compositions of this invention can be varied to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without that is toto the patient. The selected dosage level will depend on a variety of factors including the activity of the particular compound employed in the present invention, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism. of the particular compound used, the speed and degree of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound used, age, sex, weight, condition, general health and clinical history prior to the patient being treated, and similar factors well known in the medical arts. A physician or veterinarian having ordinary skill in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian could start with doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than those required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. . In general, an adequate daily dose of a compound of the invention will be that amount of the compound which is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. In general, when oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention are used for a patient, to indicate analgesic effects, they will vary from about 0.0001 to about 100 mg per kilogram of body weight per day. If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. The preferred dosage is one administration per day. While it is possible to administer a compound of the present invention alone, it is preferable to administer the compound as a pharmaceutical formulation (composition). The compounds according to the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceutical substances. In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more objective compounds, as described above, formulated together with one or more carriers (additives) and / or pharmaceutically acceptable diluents. As described in detail below, the pharmaceutical compositions of the present invention can be formulated especially for administration in solid or liquid form, including those adapted for the following: (1) oral administration, eg, purgative doses or solutions (solutions or aqueous or non-aqueous suspensions), tablets, boluses, powders, granules, pastes for application on the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous injection, such as, for example, a sterile solution or suspension (3) topical application, for example, as a cream, ointment, or spray applied to the skin, lungs, or mucous membranes; or (4) intravaginally or intra-rectally, for example, as a pessary, cream or foam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; u (8) nasally. The term "treatment" is intended to also cover prophylaxis, therapy and cure. The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as horses, cattle, pigs and sheep; and poultry and pets in general. The compounds of the invention can be administered as such or in mixtures with pharmaceutically acceptable carriers in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides, and glycopeptides. Conjunctive therapy, therefore, includes sequential, simultaneous and separate administration of the active compound so that the therapeutic effects of the first that is administered do not completely disappear when the subsequent one is administered. The addition of the active compound of the invention to animal feed is preferably achieved by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix in the complete ration. Alternatively, an intermediate concentrate or food supplement containing the active ingredient can be mixed in the food. The manner in which such premixes of whole foods and rations can be prepared and administered is described in reference books (such as "Applied Animal Nutrition," WH Freedman and CO., San Francisco, USA, 1969 or "Livestock Feeds and Feeding. "Books 0 and B, Corvallis, Ore., USA, 1977). Micelles Recently, the pharmaceutical industry introduced microemulsification technology to improve the bioavailability of some pharmaceutical agents, lipophilic (insoluble in water). The examples include Trimethrin (Dordunoo, S.K., et al., Drug Development and Industrial Pharmacy, 17 (12), 1685-1713, 1991 and REV 5901 (Sheen, P.C., et al., J Pharm Sci 80 (7), 712-714, 1991). Among other things, the microemulsion provides an improved bioavailability by preferably directing the absorption to the lymphatic system instead of the circulatory system, which therefore bypasses itself, and prevents the destruction of the compounds in the hepatobiliary circulation. In one aspect of the invention, the formulations contain micelles formed from a compound of the present invention and at least one amphiphilic carrier, in which the micelles have an average diameter of less than about 100 nm. More preferred embodiments provide micelles having an average diameter of less than about 50 nm, and even more preferred embodiments provide micelles having an average diameter of less than about 30 nm, or even less than about 20 nm. Although all suitable amphiphilic carriers are contemplated, the presently preferred carriers in general are those having the status Generally Recognized as Safe (GRAS), and which can both solubilize the compound of the present invention and microemulsify at a later stage when the solution enters. in contact with a complex aqueous phase (such as is found in the human gastrointestinal tract). Usually, amphiphilic ingredients that meet these requirements have HLB (hydrophilic to lipophilic balance) values of 2-20, and their structures contain straight chain aliphatic radicals in the range of C-6 to C-20. Examples are polyethylene glycolized fatty glycerides and polyethylene glycols. Particularly preferred amphiphilic carriers are the polyethylene glycolized fatty acid glycerides, such as those obtained from various fully or partially hydrogenated vegetable oils. Such oils may advantageously consist of glycerides of tri-, di- and mono-fatty acids and di- and mono-polyethylene glycol esters of the corresponding fatty acids, with a particularly preferred fatty acid composition including caustic acid 4-10, acid caprice 3-9, lauric acid 40-50, myristic acid 14-24, palmitic acid 4-14 and stearic acid 5-15%. Another useful class of amphiphilic carriers includes sorbitan and / or partially esterified sorbitol, with saturated or monounsaturated fatty acids (SPAN series) or the corresponding ethoxylated analogs (TWEEN series). Particularly commercially available amphiphilic carriers are contemplated, including the Gelucire, Labrafil, Labrasol, or Lauroglycol series (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di-oleate, PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc. (produced and distributed by a number of companies in the United States and around the world). Polymers Hydrophilic polymers suitable for use in the present invention are those that are readily soluble in water, which can be covalently attached to a vesicle-forming lipid, and which are tolerated in vivo without toxic effects (i.e., they are biocompatible) . Suitable polymers include polyethylene glycol (PEG), polylactic acid (also called polylactide), polyglycolic (also called polyglycolide), a polylactic-polyglycolic acid copolymer), and polyvinyl alcohol. Preferred polymers are those having a molecular weight of from about 100 or 120 daltons to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons. In a particularly preferred embodiment, the polymer is a polyethylene glycol having a molecular weight of from about 100 to about 5,000 daltons, and more preferably having a weight of from about 300 to about 5,000 daltons. In a particularly preferred embodiment, the polymer is polyethylene glycol of 750 daltons (PEG (750)). The polymers can also be defined by the number of monomers therein; A preferred embodiment of the present invention utilizes polymers of at least about three monomers, such polymers PEG consisting of three monomers (approximately 150 daltons). Other hydrophilic polymers which may be suitable for use in the present invention include polyvinyl pyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derived celluloses such as hydroxymethylcellulose or hydroxyethylcellulose. In certain embodiments, a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly (ortho) esters, poly (bical acid), poly (lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and combinations , mixtures, or copolymers thereof. Cyclodextrins Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8 glucose units, designated with the Greek letter .alpha., .beta, or .gamma., Respectively. It is not known that there are cyclodextrins with less than six glucose units. The glucose units are bound by alpha-1, 4-glycosidic bonds. As a consequence of the chair conformation of the sugar units, all the secondary hydroxyl groups (in C-2, C-3) are located in a part of the ring, while all the primary hydroxyl groups in C-6 are located in The other part. As a result, the outer faces are hydrophilic, making the cyclodextrins soluble in water. In contrast, the cavities of the cyclodextrins are hydrophobic, since they are aligned by the hydrogen of the C-3 and C-5 atoms, and by ether-like oxygens. These matrices allow the formation of complexes with a variety of relatively hydrophobic compounds, including, for example, steroid compounds such as 17.beta.-estradiol (see, for example, van Uden et al., Plant Cell Tiss., Org. Cult. 38: 1-3-113 (1994)). The formation of complexes occurs through Van der Waals interactions and through the formation of hydrogen bonds. For a general review of the chemistry of cyclodextrins, see, Wenz, Agnew. Chem. Int. Ed. Engl., 33: 803-822 (1994). The physico-chemical properties of the cyclodextrin derivatives depend strongly on the type and de of substitution. For example, its solubility in water ranges from insoluble (eg, triacetyl-beta-cyclodextrin) to 147% soluble (w / v) (G-2-beta-cyclodextrin). In addition, they are soluble in many organic solvents. The properties of cyclodextrins allow the control in the solubility of several components of the formulation increasing or decreasing its solubility. Numerous cyclodextrins and methods for their preparation have been described. For example, Parmeter (I), et al. (US Patent No. 3,453,259) and Gramera, et al. (U.S. Patent No. 3,459,731) describe electro-neutral cyclodextrins. Other derivatives include cyclodextrins with cationic properties [Parmeter (II), U.S. Patent No. 3,453,257], crosslinked, insoluble cyclodextrins (Solms, U.S. Patent No. 3,420,788), and cyclodextrins with anionic properties [Parmeter (III), U.S. Patent. 3,426,011]. Among the cyclodextrin derivatives with anionic properties, carboxylic acids, phosphorous acids, phosphonous acids, phosphonic acids, phosphoric acids, thiophosphonic acids, thiosulfinic acids, and sulfonic acids have been attached to the origin cyclodextrin [see, Parmeter (III), supra) ] In addition, sulfoalkyl ether cyclodextrin derivatives have been described by Stella, et al. (North American Patent No. 5,134,127).

Liposomes Liposomes consist of at least one double-layer lipid membrane that encloses an internal, aqueous compartment. Liposomes can be characterized by type and membrane size. Small unilamellar vesicles (SUVs) have a single membrane and typically vary between 0. 02 and 0.05 μm in diameter; large unilamellar vesicles (LUVS) are typically greater than 0.05 μm. Large oligolamellar vesicles and multilamellar vesicles have multiple layers of membranes, usually concentric and typically larger than 0.1 μm. Liposomes with several non-concentric membranes, ie, several smaller vesicles contained within a larger vesicle, are called multi-vesicular vesicles. One aspect of the present invention relates to formulations comprising liposomes containing a compound of the present invention, wherein the liposome membrane is formulated to provide a liposome with increased transport capacity. Alternatively or in addition, the compound of the present invention may be contained within, or absorbed in, the liposome double layer of the liposome. The compound of the present invention can be added with a lipid surface agent and carried within the internal space of the liposome; in these cases, the liposome membrane is formed to resist the destructive effects of the aggregate of active agent-surface agent. In accordance with one embodiment of the present invention, the lipid double layer of a liposome contains lipids derived with polyethylene glycol (PEG), such that the PEG chains extend from the inner surface of the double lipid layer into space interior encapsulated by the liposome, and extending from the outside of the double lipid layer to the surrounding environment. The active agents contained within the liposomes of the present invention are in solubilized form. Aggregates of surface agent and active agent (such as emulsions or micelles containing the active agent of interest) can be trapped within the interior space of the liposomes according to the present invention. A surface agent acts to disperse and solubilize the active agent, and can be selected from any suitable aliphatic, cycloaliphatic or aromatic surface agent, including, but not limited to, biocompatible lysophosphatidylcholines (LPCs) of various chain lengths (for example, from about C. sub.14 to about C. sub.20). Polymer-derived lipids such as PEG lipids can also be used for the formation of micelles when they act to inhibit the fusion of micelles / membranes, and when the addition of a polymer to the surface agent molecules decreases the CMC of the surface agent and aid in the formation of micelles. Surface agents with CMCs in the micromolar range are preferred; surface agents with higher CMC can be used to prepare micelles trapped within the liposomes of the present invention, however, the monomer of the surface agent of the micelles could affect the stability of the double layer of liposomes and would be a factor in the design of a liposome of a desired stability. Liposomes according to the present invention can be prepared by any of a variety of techniques known in the art. See, for example, U.S. Patent No. 4,235,871; PCT Published Applications WO 96/14057; New RRC, Liposomes: A Practical Approach, IRL Press, Oxford (1990), pages 33-104; Lasic DD, Liposomes from physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993. For example, the liposomes of the present invention can be prepared by spreading a lipid derivative with a hydrophilic polymer into preformed liposomes, such as by exposing preformed liposomes to compound micelles. of lipid-grafted polymers, at lipid concentrations corresponding to the final percent in mol of the desired lipid derivative in the liposome. Liposomes containing a hydrophilic polymer can also be formed by homogenization, hydration in the lipid field, or extrusion techniques, which are well known in the art. In another exemplary formulation process, the active agent is first dispersed by sonification in a lysophosphatidylcholine or other surface agent with low CMC (including lipids grafted with polymers) that easily solubilizes hydrophobic molecules. The resulting micellar suspension of the active agent is then used to rehydrate a dry lipid sample containing a suitable mole percent lipid grafted with polymer, or cholesterol. The lipid and active agent suspension is then formed into liposomes using extrusion techniques well known in the art, and the resulting liposomes are separated from the non-encapsulated solution by standard column separation. In one aspect of the present invention, liposomes are prepared having substantially homogeneous sizes in a range of selected sizes. One method of effective size classification involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a uniform pore size, selected; The pore size of the membrane will correspond roughly with the sizes of liposomes produced by the extrusion through that membrane. See, for example, US Patent No. 4,737,323 (April 12, 1988). Release Modifiers The release characteristics of a formulation of the present invention will depend on the encapsulation material, the concentration of the encapsulated drug, and the presence of release modifiers. For example, the release can be manipulated to be pH dependent, for example, by using a pH-sensitive coating that is released only at a low pH, such as in the stomach, or at a higher pH, such as in the intestine. An enteric coating can be used to prevent the release from occurring until after its passage through the stomach. Multiple coatings or mixtures of cyanamide can be used, encapsulated in different materials to obtain an initial release in the stomach, followed by a subsequent release in the intestine. The release can also be manipulated by the inclusion of salts or pore-forming agents, which can increase the absorption or release of water from the drug by diffusion of the capsule. It is also possible to use excipients that modify the solubility of the drug to control the rate of release. It is also possible to incorporate agents that improve the degradation of the matrix or that are released from the matrix. They can be added to the drug, added as a separate phase (i.e., as particles), or they can co-dissolve in the polymer phase depending on the compound. In all cases the amount should be between 0.1 and thirty percent (p / p of polymer). Types of degradation enhancers include organic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, carbonate of zinc, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine and surface agents such as Tween.RTM. and Pluronic .RTM .. Formation agents are added that add microstructure to the matrices (ie, water soluble compounds such as inorganic salts and sugars) as particles. The range should be between one and thirty percent (p / p of polymer). The uptake can also be manipulated by altering the residence time of the particles in the intestine. This can be achieved, for example, by covering the particle with, or selecting as the encapsulating material, a polymer adhesive to the mucosa. Examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (when used herein, polyacrylates refers to polymers that include acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates. ).

EXAMPLE The invention now generally described will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention . Example 1 A. (-) - 6-amino-2-hydroxyhexanoic acid [Chem. Pharm. Bull. 1976, 24, 621] An aqueous solution (100 ml) of sodium nitrite (25.9 g, 0.36 mol) was gradually added to a stirred solution of L-lysine hydrate (19.0 g, 0.097 mol) in 10% sulfuric acid (250 mL) at 45-50 ° C for a period of 2 hours. After the addition was complete, the solution was stirred at 25 ° C for 3 hours. Urea was added to the solution in order to decompose the nitric acid formed in the reaction process and the aqueous solution was poured into an ion exchange column (Amberlite IR-120, form H +, 200 ml). After the column was washed thoroughly with water, it was eluted with aqueous ammonium hydroxide until the eluent became negative to the ninhydrin test. The combined fractions were evaporated in vacuo, which gave a yellow oil, 7.5 grams.

H Hj »N,? SOH CBZ: NN O. - OCH 3 3 OH 3 OH B. Acid (S) -6- [[(phenylmethyl) carboni 1] amino] -2-hydroxyhexanoic acid The aminohydroxy acid (7.5 g, 51.0 mmoles) of Part A in a 1 N NaOH solution (50 ml) at 0 ° C (ice bath) was adjusted to pH 10 with concentrated HCl and treated with benzyl chloroformate (8.40 ml, 95%, 55.9 mmol) in 1 ml portions at 15 minute intervals. Throughout the reaction, the pH was maintained at a pH of 9.8-10.2 by the addition of an IN NaOH solution. When the addition was complete and the pH stabilized, the mixture was stirred at a pH of 10 to 0 ° C for an additional 45 minutes, then washed with a portion of ether. The aqueous solution was acidified to a pH of 1 with concentrated HCl and extracted with EtOAc (2x). The EtOAc extract was washed with brine, dried and evaporated to give 4 g of the product. C. (S) -6- [[(Phenylmethoxy) carbonyl] -amino] -2-hydroxyhexanoic acid methyl ester Crude hydroxy acid (4.0 g, 14.2 mm) from Part B and iododomethane (0.97 ml, 15.6 mmol) , 1.1 eq.) Were treated with K2CO3 (2.55 g, 18.5 mmol, 1.3 eq.) And the light yellow suspension was stirred for 4 hours at room temperature. The mixture was diluted with water and extracted with EtOAc. (2x), and the combined organic extracts were washed with water (2x), saturated NaHCO 3 and brine, then dried over anhydrous Na 2 SO 4 and evaporated to give 3 g (80%) of the methyl ester as a pale yellow, viscous oil. TLC (1: 1) EtOAc / hexane, Rf = 0.5.

D. (S) -Methyl-6- [(phenylmethoxy) carbonyl] amino] -2-triflyloxyhexanoate A solution of the CBZ hydroxy ester of Part C (3.0 g, mmol) and pyridine (0.71 g, 11 mmol) in methylene chloride (300 mL) at 0 ° C with triflic anhydride (3.1 g, 11 mmol) in methylene chloride (30 mL) for 1 hour. After subtraction of the pyridinium triflate salt by filtration, the crude product was purified by chromatography with silica gel to obtain the triflate (1.2 g, 31%). TLC: Rf 0.65 in dichloromethane / methanol (97: 3).

E. Protected DOTA analog The cyclin (50 mg, 0.29 mmol) in 10 mL of dry THF was treated with 1.6 M n-butyl-lithium (0.8 mL, 1.3 mmol) in hexane at 0 ° C under nitrogen. The reaction mixture was then stirred at room temperature for 5 minutes. The flask was then immersed in a bath with Dry Ice / acetone and (S) -methyl-6- [(phenylmethoxy) carbonyl] amino] -2-triflyloxyhexanoate (0.68 g, 1. 74 mmol) in THF (5 mL) and HMPA (1 mL) was added via syringe. The reaction mixture was allowed to reach room temperature where it was stirred for 1 hour.

The reaction mixture was diluted with 50 mL of methylene chloride and washed with 10 mL of water and dried. The solvent was removed by vacuum and the product was purified by chromatography (silica gel, methylene chloride / methanol, 90:10).

F. DOTA apologous The protected DOTA analog was stirred in trifluoroacetic acid (10 mL) at 25 ° C for two hours and the excess trifluoroacetic acid was purged with a stream of nitrogen. The crude oil was washed with ether to give the DOTA analogue. Example 2 A. 2, 3, 5, 6 - tetrafluoro phenyl trifluoroacetate (TFP-OTFA) Using a known procedure [Nucleic Acids Res. 1993, 21, 145], a mixture of 2,3,5,6-tetrafluorophenol (55.2 g, 0.33 mol), trifluoroacetic anhydride (60 mL, 0.42 mol) and boron trifluoride etherate (0.5 ml) was refluxed. , for 16 hours. The trifluoroacetic anhydride and trifluoroacetic acid were removed by distillation at atmospheric pressure. The trifluoroacetic anhydride fraction (bp (boiling point) 40 ° C) was returned to the reaction mixture together with 0.5 mL of boron trifluoride etherate and the mixture was refluxed for 24 hours. This process was repeated twice to ensure a complete reaction. After distillation at atmospheric pressure the desired product was collected at 62 ° C / 45 mm (45 ° C / 18 mm) as a colorless liquid: yield: 81.3 (93%); d = 1.52 g / mL; IR (CHCl3) 3010, 1815, 1525, 1485, 1235, tl80, and 955 cm "1 B. Synthesis of the Biotin Tetraf Luorofenyl Ester The preparation of the biotin TFP ester was obtained as described by Wilbur [Bioconj. 1997, 7, 692.] Biotin (1.0 g, 4.1 mmol) was dissolved in 20 mL of DMF (70 ° C) under an argon atmosphere.To the solution at 25 ° C, 1 mL was added. (8 mmoles) of triethylamine followed by the addition of 1.7 (6.1 mmoles) of 2,3,5,6-tetrafluorophenyl trifluoroacetate. The reaction was stirred at room temperature for 30 minutes and the solvent was removed under vacuum. The product was triturated in 10 mL of ether and filtered. The isolated product was dried under vacuum to give 1.3 (80%) of the biotin TFP ester as a colorless solid: mp (melting point): 185-187 ° C; XH NMR (DMS0-d6, 0) 1.4-1.8 (m, 6H), 2.5 (m, IH), 2.6-2.9 (m, 3H), 3.1 (m, IH), 4.2 (m, IH), 6.4 (d, 2H), 7.9 (m, 1 H); IR (KBr, cm-1) 3250, 2915, 1790, 1710, 1520, 1480, 1090.

C. 3- (Biotinamido) butyric acid Preparation was accomplished as described by Wilbur [Bioconj. Chem 1997, 8, 572]. To an amount of 0.13 g (1.3 mmoles) of 3-aminobutyric acid dissolved in 2 mL of DMF under argon atmosphere was added 0.4 mL (2.5 mmol) of triethylamine followed by 0.5 g (1.3 mmol) of biotin tetrafluorophenyl ester. The reaction was stirred at 25 ° C for 24 hours and the solvent was removed under vacuum. The residue was triturated with acetonitrile and filtered. The isolated solid was dried under vacuum to give 0.5 g (98%) of the product as a colorless solid, mp 161-163 ° C. XH NMR (DMSO-d6): O 7. 6 (m, 1H), 6.2 (d, J = 11.2 Hz, 2H), 3.9-4.2 (m, 3H), 2.6 (m, 2H), 2.35 (d, J = 12.6 Hz, 1H), 1.7-2.1 (m, 4H), 0.7-1.5 (m, 10H). D. Tetraf luorofenyl 3 - (Biotinamido) butyrate To 3- (biotinamido) butyric acid (1.0 3.1 mmol) dissolved in 10 mL of DMF under argon atmosphere 1.0 was added (3.65 mmole) of TFP-OTFA, followed by 0.1 mL of triethylamine. The reaction mixture was stirred at 25 ° C for 1 hour and the solvent was removed under vacuum. The residue was extracted into CH3C1 (4 x 20 mL). The CH3C1 extracts were washed with saturated aqueous NaHCO3 (2 x 10 mL) and water (2 x 10 mL). The CH3C1 solution was dried over anhydrous Na2SO4, and the solvent was removed by vacuum. The product was dried to give 1.1 g (80%) of a colorless solid, mp 137-139 ° C. ^? ? MR (DMSO-d6): d 7.7 (m, 2H), 6.2 (d, J = 13.2 Hz, 2H), 3.9-4.2 (m, 3H), 2.5-2.7 (m, 4H), 2.35 (d, J = 12.6 Hz, 1H), 1.85 (t, J = 7.0 Hz, 2H), 0.7-1.5 (m, 10H). Example 3 Biotin-DOTA To an amount of 0.5 g (0.65 mmoles) of the DOTA-amine analog acid dissolved in 20 mL of DMF under nitrogen atmosphere, 1 mL of triethylamine was added followed by 2.4 g (12.76 mmol) of the tetrafluorophenyl ester of 3 - (biotinamido) butyrate. The reaction was stirred at 25 ° C for 24 hours and the solvent was removed under vacuum. The residue was triturated with acetonitrile and filtered. The isolated solid was dried under high vacuum. The product was purified by reverse phase HPLC. Example 4 Gd-Biotin-DOTA Gadolinium chelation (Gd) was performed by incubating the Biotin-DOTA with GdCl3 in 50 mM glycine buffer / HCl, pH 3.5 at 80 ° C for 3 hours. The whole was purified by reverse phase HPLC.

Example 5 A. 6- (N-phthalimido) hexanoic acid A mixture of phthalic anhydride (56.4 g, 381 mmol), 6-aminocáprico acid (50 g, 381 mmol), and triethylamine (54 ml) in toluene (200 mL), refluxed for 1 hour in a 500 mL flask equipped with a Dean-Stark trap. The mixture was allowed to stand overnight at room temperature. The formed precipitate was filtered and washed with hexane followed by 1 N HCl, which gave 51 g (50%) of 6- (N-phthalimido) hexanoic acid; mp = 110-112 ° C.

B. 2-Bromo-6- (N-phthalimido) isopropyl hexanoate A mixture of 6- (N-phthalimido) hexanoic acid (10 g, 37.4 mmol), carbon tetrachloride (20 mL), and thionyl chloride (11.4 ml, 112.3 mmol) was refluxed for 1 hour. The mixture was cooled to room temperature and carbon tetrachloride (20 mL), NBS (8 g, 45 mmol), and 48% HBR (2 drops) were added. The mixture was refluxed for another two hours. Once cooled to room temperature, isopropanol (60 ml) was added to the mixture and stirring was continued at 25 ° C for 30 minutes. The volatiles were removed by roto-evaporation and the oil obtained was chromatographed on silica gel using ethyl acetate / hexane (10:90). Yield: 8.7 g (60%); XH NMR (CDC13): d (ppm) 1.19 (d, 3H), 1.35 (m, 2H), 1.68 (m, 4H), 2. 25 (dd, 2H), 4.9 (m, 1H), 7.8 (m, 2H), 7.85 (m, 2H).

C. 1, 4, 7, 10-Tetraazacyclododecan-1, 4, 7, 10 -tetra [2 -6- (N-phthalimido) -hexanoate of tetr ai sopropyl Cylinder (150 mg, 0.87 mmol), 2-bromine -6- (N-phthalimido) isopropyl hexanoate (2 g, 5.2 mmol), and potassium carbonate (720 mg, 5.2 mmol) in DMF (3 mL) were heated at 150 ° C for 16 hours. The mixture was diluted with methylene chloride (20 mL), washed with water (3 x 50 mL) and dried (Na 2 SO 4). The solvent was removed by roto-evaporation and the oil obtained was chromatographed on silica gel using methanol / methylene chloride (15:85), Yield: 0.34 g (30%); XH NMR (CDCl3): d (ppm) 1-4 (m, 80H), 4.8-5.1 (m, 4H), 7.5-7.9 (m, 16H) Example 6 A. Biotin tetraf luorofenyl ester Biotin (1 g, 4 mmol) in 20 mL of DMF was heated at 70 ° C until complete dissolution. The solution was cooled to room temperature and triethylamine (1 mL) was added followed by 2,3,3,6-tetrafluorophenyl trifluoroacetate (2 g, 8 mmol). The reaction was stirred for 30 minutes at 25 ° C and the solvents were removed under vacuum. The product was triturated in ether (20 mL) and filtered and dried to give 1.0 g (63%); mp 184-186 ° C, XH NMR (DMSO-d6): d (ppm) 1.4-1.8 (m, 6H), 2.5 (m, 1H), 2.6-2.9 (m, 34H), 3.1 (m, 1H) , 4.2 (m, 6H), 6.4 (d, 2H), 7.9 (m, 1H).

B. 1, 4, 7, 10-Tetraazacyclododecan-1, 4, 7, 10-tetra [2-6- (biotinamido) -hexanoate of tetrai sopropyl A solution of 1, 4, 7, 10-tetraazacyclododecan-1, 4 , 7,10-tetra [2-6- (N-phthalimido) hexisanate tetraisopropyl (100 mg, 0.076 mmol) and hydrazine hydrate (20 μL, 0.38 mmol) in methanol (3 mL), was refluxed for 1 hour. hour. The volatile materials were removed by roto-evaporation and the resulting oil was dissolved in methylene chloride (20 mL) and the solid materials were removed by filtration. After evaporation of the solvent, the oil, dissolved in DMF (10 mL), was treated with triethylamine (1 mL) and biotin tetrafluorophenyl ester (0.26 g, 0.16 mmol). The mixture was stirred for 16 hours. The solvent was removed under vacuum and the obtained residue was dissolved in methanol (5 mL) and made basic (pH 9) by the addition of a methanol / NaOH solution. The solvent was subtracted and the oil was chromatographed on silica gel (methanol / methylene chloride) (10/90) to give 77.5 mg (60%) of the product; mp =; XH NMR (CDC13): d (ppm) 1.4-1.8 (m, 32H), 2.3 (t, 16H), 2.7-3.2 (m, 12H), 4.3 (dd, 4H), 4.5 (dd, 4H), 5.2 (s, 4 H), 5.5 (s, 4H).

C. Tetra-hydrochloric acid salt of 1, 4, 7, 10-tetraazacyclododecan-1, 4, 7, 10 -tetra [2-6- (biotinamido)] hexanoic A solution of 1,4, 7, 10-tetraazacyclododecan-1, 4, 7, 10-tetra [2-6- (biotinamido) hexanoate of tetraisopropyl (50 mg) • in 5 mL of 6 N HCl, refluxed for 4 hours. The solvent was removed in vacuo to give the product. Example 7 Biodistribution of 1, 4, 7, 10-tetraazacyclododecan-1, 4, 7, 10-tetra [2-6- (biotinamido)] hexanoic acid radiolabelled with Tc-99m Figure 3 shows the normal inflammation-countermultiple relationship obtained one hour after the injection of the radiolabelled polybicylin with Tc-99m to 5 rats (average) with inflammation in the thigh. The inflammation was produced by an injection of turpentine to the thigh of the rat 24 hours before biodistribution. The rest of the agent was concentrated in the liver and kidneys. Incorporation by Reference All patents and publications cited herein are incorporated by reference. Equi to the Entity Those skilled in the art will recognize, or be able to ascertain using no more than one routine experiment, many equivalents to the specific embodiments of the invention, described herein. It is intended that such equivalents be encompassed by the following claims.

Claims (43)

1. CLAIMS 1.- A compound represented by the formula I: wherein R represents independently for each case "H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; n independently represents for each case 1, 2, 3, or 4; and X independently represents for each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NR1C (0)) m-alkyl] -, where m is 1, 2, 3, or 4, and R1 is H or alkyl 2. The compound of claim 1, characterized in that n is 23. - The compound of claim 1, characterized in that n is 2; and R is hydrogen. 4. The compound of claim 1, characterized in that X is an optionally substituted - [(alkyl-NRXC (0)) m-alkyl]. 5. The compound of claim 1, characterized in that X is 6. - The compound of claim 1, characterized in that n is 2; R is hydrogen; And it is -C (O) -; and X is 7. The compound of claim 4, characterized in that m is 1. 8. The compound of claim 4, characterized in that m is 2. 9. The compound of claim 1, characterized in that each alkyl is optionally substituted with at least a carboxylic acid. 10. A compound represented by formula II: p wherein R represents independently for each case H or alkyl; And independently represents for each case -C (0) - Ó -S (O) -; n represents independently for each case 1, 2, 3, or 4; M is a metal atom; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl -NRXC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl. 11. The compound of claim 10, characterized in that M is a transition metal. 12. The compound of claim 10, characterized in that M is selected from the group consisting of In-111, Tc-99m, 1-123, 1-125 F-18, Ga-67, Ga-68, 1-131 , Re-186, Re-188, Y-90, Bi-212, At-211, Sr-89, Ho-166, Sm-153, Cu-67, and Cu-64. 13. The compound of claim 10, characterized in that M is selected from the group consisting of Gd3 +, Mn2 +, Fe3 +, Cr3 +, dysprosium, holmium, and erbium. 14. The compound of claim 10, characterized in that M is selected from the group consisting of Gd3 +, Mn2 +, Fe3 +, and Cr3 +. 15. The compound of claim 10, characterized in that n is 2. 16. The compound of claim 10, characterized in that n is 2; R is hydrogen; and Y is -C (O) -. 17. The compound of claim 10, characterized in that X is - [(alkyl-NRxC (O)) m-alkyl] -. 18. The compound of claim 1, characterized in that X is OR 19. The compound of claim 10, characterized in that n is 2; R is hydrogen; And it is -C (O) -; and M is Ga3 +. 20. - The compound of claim 10, characterized in that n is 2; R is hydrogen; And it is -C (O) -; M is Tc-99m, 21. The compound of claim 17, characterized in that m is 1. 22. The compound of claim 17, characterized in that m is 2. 23. A compound represented by the formula III: m wherein R represents independently for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; n represents independently for each case 1, 2, 3, or 4; A is selected from the group consisting of an optionally substituted covalent bond, alkyl, heteroalkyl, alkenyl, - [(alkyl-NRxC (O)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl; X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRXC (O)) m-alkyl] -, where m is 1, 2, 3, or 4; and R1 is H or alkyl; and Z is -CH2C02H, an antibiotic, anti-viral, anti-tumor, anti-inflammatory, anti-infectious, antifungal, radionuclide, hormonal antagonist, heavy metal complexes, oligonucleotide, antisense, chemotherapeutic nucleotide, peptide, protein, polysaccharide, aminoglycoside, antibody and fragments, lipid construct, non-specific protein (non-antibody), compound containing boron, photodynamic agent, enediin, or a transcription-based drug. 24. The compound of claim 23, characterized in that n is 2; and R is hydrogen. 25. The compound of claim 23, characterized in tX is an optionally substituted - [(alkyl-NRxC (O)) m-alkyl]. 26. The compound of claim 23, characterized in tn is 2; R is hydrogen; And it is -C (0) -; and X is 27. - The compound of claim 25, characterized in that m is 1. 28.- The compound of claim 25, characterized in that it is 2. 29. - A compound represented by formula IV: IV wherein R represents independently for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; M is a metal atom; n represents independently for each case 1, 2, 3, or 4; A is selected from the group consisting of an optionally substituted covalent bond, alkyl, heteroalkyl, alkenyl, - [(alkyl-NR x C (0) m-alkyl] -, where m is 1, 2, 3, or 4; is H or alkyl, X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl, and Z is -CH2C02H, an antibiotic, anti-viral, anti-tumor, anti-inflammatory, anti-infectious, antifungal, radionuclide, hormonal antagonist, heavy metal complexes, oligonucleotide, antisense, nucleotide chemotherapeutic, peptide, protein, polysaccharide, aminoglycoside, antibody and fragments, lipid construct, non-specific protein (non-antibody), boron-containing compound, photodynamic agent, or enediin, or a transcription-based drug. The compound of claim 29, characterized in that M is selected from the group that System of In-111, Tc-, 99m, 1-123, 1-125 F-18, Ga-67, Ga-68, 1-131, Re-186, Re-188, Y-90, Bi-212, At-211, Sr-89, Ho-166, Sm-153, Cu-67, and Cu-64. 5. The compound of claim 29, characterized in that M is selected from the group consisting of Gd3 +, Mn2 +, Fe3 +, Cr3 +, dysprosium, holmium, and erbium. 32. A method for the treatment of a condition or disorder selected from the group consisting of inflammation, infection and cancer, characterized in that it comprises administering to a mammal in need of such treatment an effective amount of the compound of the formula I, II, III, or IV; wherein a compound represented by formula I is: 5 wherein R independently represents for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; n represents independently for each case 1, 2, 3, or 4; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl; wherein a compound represented by formula II is: p wherein R represents independently for each case H or alkyl; And independently represents for each case -C (0) - or -S (0) -; n represents independently for each case 1, 2, 3, or 4; M is a metal atom; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) ra-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl; wherein a compound of formula III is: m wherein R represents independently for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; n represents independently for each case 1, 2, 3, or 4; A is selected from the group consisting of an optionally substituted covalent bond, alkyl, heteroalkyl, alkenyl, - [(alkyl-NRxC (0) m -alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl, X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRXC (O)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl, and Z is -CH2C02H, an antibiotic, anti-viral, anti-tumor, anti-inflammatory, anti-infectious, antifungal, radionuclide, hormonal antagonist, heavy metal complexes, oligonucleotide, antisense, chemotherapeutic nucleotide , peptide, protein, polysaccharide, aminoglycoside, antibody and fragments, lipid construct, non-specific protein (non-antibody), compound containing boron, photodynamic agent, enediin, or a transcription-based drug, and wherein a compound of formula IV is: IV wherein R represents independently for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; M is a metal atom; n represents independently for each case 1, 2, 3, or 4; A is selected from the group consisting of an optionally substituted covalent bond, alkyl, heteroalkyl, alkenyl, - [(alkyl-NRxC (0) m-alkyl] -, where m is 1, 2, 3, or 4, and R1 is H or alkyl, X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NR x C (O)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl, and Z is -CH2C02H, an antibiotic, anti-viral, anti-tumor, anti-inflammatory, anti-infectious, antifungal, radionuclide, hormonal antagonist, heavy metal complexes, oligonucleotide, antisense, chemotherapeutic nucleotide , peptide, protein, polysaccharide, aminoglycoside, antibody and fragments, lipid construct, non-specific protein (non-antibody), compound containing boron, photodynamic agent, enediin, or a transcription-based drug. of claim 32, for treating an infection, characterized in that the infection is caused by bacteria selected from the group consisting of Staphylococcus, Streptococcus, Micrococcus, Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium, Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium, and Corynebacterium. 34. - The method of claim 32, for treating an infection, characterized in that the infection is caused by a virus selected from the group consisting of Herpes Virus, Poliomyelitis virus, Varicella-zoster virus, Togavirus, Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Picornavirus, Rhinovirus, Human papilloma virus and hepatitis virus. The method of claim 32, for treating an inflammatory condition, characterized in that said inflammatory condition or inflammatory reaction is a condition of the skin, wherein said skin condition is selected from the group consisting of atopic dermatitis, psoriasis, neurogenic inflammation, photodamage to the skin, a cell carcinoma, queratoris, and a keratinization disease, or is an inflammatory reaction or condition, pulmonary, wherein said inflammatory reaction or condition, pulmonary, is selected from the group consisting of asthma, rhinitis allergic, obstructive pulmonary disease, chronic, and respiratory asphyxia syndrome in adults; or is a reaction or inflammatory, musculoskeletal condition, wherein said condition or musculoskeletal, inflammatory reaction is a member selected from the group consisting of psoriatic arthritis, osteoarthritis, and osteoporosis; or is a condition or inflammatory reaction, gastrointestinal or urogenital, wherein said condition or gastrointestinal or urogenital reaction, inflammatory, is a member selected from the group consisting of inflammatory bowel disease, enterocolitis, gastritis, vaginitis, and interstitial cystitis, or in wherein said inflammation is caused by a condition or autoimmune reaction, wherein said autoimmune condition is a member selected from the group consisting of multiple sclerosis, type II diabetes, lupus, and rheumatoid arthritis, or wherein said inflammation is caused by a treatment of transplant. 36.- The method of claim 32, for treating cancer, characterized in that the cancer is located in the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, lower jaw, larynx, hypopharynx, salivary glands, paragangliomas, pancreas, stomach, skin, esophagus, liver and biliary tree, bones, intestine, colon, rectum, ovaries, prostate, lung, chest, central nervous system, or patient's brain. 37.- A method for generating a magnetic resonance image of a human or non-human animal body, characterized in that it comprises the steps of administering in the body of a subject in need of magnetic resonance imaging a compound of the formula II or IV and generate a magnetic resonance image; wherein a compound is represented by formula II is: p wherein R represents independently for each case H or alkyl; And independently represents for each case -C (O) - or -S (0) -; n represents independently for each case 1, 2, 3, or 4; M is a metal atom; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) m-alkyl] -, where it is 1, 2, 3, or 4; and R1 is H or alkyl; and wherein a compound of formula IV is: IV wherein R represents independently for each case H or alkyl; And independently represents for each case -C (0) - or -S (O) -; M is a metal atom; n represents independently for each case 1, 2, 3, or 4; A is selected from the group consisting of a covalent bond, optionally substituted alkyl, heteroalkyl, alkenyl, - [(alkyl NRxC (0) m-alkyl] -, wherein m is 1, 2, 3, or 4; and Rx is H or alkyl, X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and R1 is H or alkyl; and Z is -CH2C02H, an antibiotic, anti-viral, anti-tumor, anti-inflammatory, anti-infective, antifungal, radionuclide, hormone antagonist, heavy metal complex, oligonucleotide, antisense nucleotide chemotherapeutic , peptide, protein, polysaccharide, aminoglycoside, and antibody fragments, construct lipid, protein nonspecific (non-antibody), boron-containing compound, photodynamic agent, enediyne, or transcription-based drug. 38. The method of claim 37, characterized in that said subject is a human. e claim 37, characterized in that said compound of the formula II wherein M is selected from the group consisting of Gd3 +, Mn2 +, Fe3 +, and Cr3 +; and wherein a compound is represented by formula II is: p wherein R represents independently for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; n represents independently for each case 1, 2, 3, or 4; M is a metal atom; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and R1 is H or alkyl. The method of claim 37, characterized in that said compound of the formula II wherein M is Gd3 +; and wherein a compound represented by formula II is: n wherein R represents independently for each case H or alkyl; And independently represents for each case -C (0) - or -S (0) -; n represents independently for each case 1, 2, 3, or 4; M is a metal atom; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRXC (O)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl; 41. The compound of claim 37, characterized in that said compound of the formula II wherein M is selected from the group consisting of In-111, Tc-99m, 1-123, I-125 F-18, Ga-67 , Ga-68, 1-131, Re-186, Re-188, Y-90, Bi-212, At-211, Sr-89, Ho-166, Sm-153, Cu-67, and Cu-64; and wherein a compound represented by formula II is: n wherein R represents independently for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; n represents independently for each case 1, 2, 3, or 4; M is a metal atom; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl. 42. The method of claim 37, characterized in that said compound of the formula II wherein M is Tc-99m; and wherein a compound represented by formula II is: u wherein R represents independently for each case H or alkyl; And independently represents for each case -C (0) - or -S (O) -; n represents independently for each case 1, 2, 3, or 4; M is a metal atom; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl. 43.- A formulation, characterized in that it comprises a compound of formula I, II, III, or IV and a pharmaceutically acceptable excipient; wherein a compound represented by formula I is: wherein R independently represents for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; n represents independently for each case 1, 2, 3, or 4; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl; wherein a compound represented by formula II is: E wherein R represents independently for each case H or alkyl; And independently represents for each case -C (0) - or -S (0) -; n represents independently for each case 1, 2, 3, Ó 4; M is a metal atom; and X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl; wherein a compound of formula III is: ip, wherein R represents independently for each case H or alkyl; Y represents independently for each case -C (O) - or -S (O) -; n represents independently for each case 1, 2, 3, or 4; A is selected from the group consisting of an optionally substituted covalent bond, alkyl, heteroalkyl, alkenyl, - [(alkyl-NRXC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl; X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRxC (0)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl; and Z is -CH2C02H, an antibiotic, anti-viral, anti-tumor, anti-inflammatory, anti-infectious, antifungal, radionuclide, hormonal antagonist, heavy metal complexes, oligonucleotide, antisense, chemotherapeutic nucleotide, peptide, protein, polysaccharide, aminoglycoside, antibody and fragments, lipid construct, non-specific protein (non-antibody), compound containing boron, photodynamic agent, enediin, or a transcription-based drug; and wherein a compound of formula IV is: IV wherein R represents independently for each case H or alkyl; And independently represents for each case -C (0) - or -S (O) -; M is a metal atom; n represents independently for each case 1, 2, 3, or 4; A is selected from the group consisting of an optionally substituted covalent bond, alkyl, heteroalkyl, alkenyl, - [(alkyl- NRxC (0) m-alkyl] -, where m is 1, 2, 3, or 4; is H or alkyl, X independently represents in each case an optionally substituted alkyl, heteroalkyl, alkenyl, or - [(alkyl-NRXC (O)) m-alkyl] -, where m is 1, 2, 3, or 4; and Rx is H or alkyl, and Z is -CH2C02H, an antibiotic, anti-viral, anti-tumor, anti-inflammatory, anti-infectious, antifungal, radionuclide, hormonal antagonist, heavy metal complexes, oligonucleotide, antisense, chemotherapeutic nucleotide , peptide, protein, polysaccharide, aminoglycoside, antibody and fragments, lipid construct, non-specific protein (non-antibody), boron-containing compound, photodynamic agent, enediin, or a transcription-based drug.