MXPA01006151A - Vitronectin receptor antagonist pharmaceuticals - Google Patents

Vitronectin receptor antagonist pharmaceuticals

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Publication number
MXPA01006151A
MXPA01006151A MXPA/A/2001/006151A MXPA01006151A MXPA01006151A MX PA01006151 A MXPA01006151 A MX PA01006151A MX PA01006151 A MXPA01006151 A MX PA01006151A MX PA01006151 A MXPA01006151 A MX PA01006151A
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Mexico
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carbon atoms
alkyl
aryl
substituted
alkoxy
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MXPA/A/2001/006151A
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Spanish (es)
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David Harris Thomas
Rajopadhye Milind
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Dupont Pharmaceuticals Company*
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Publication of MXPA01006151A publication Critical patent/MXPA01006151A/en

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Abstract

The present invention describes novel compounds of formula:(Q)d-Ln-Ch, useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient. The present invention also provides novel compounds useful for monitoring therapeutic angiogenesis treatment and destruction of new angiogenic vasculature. The present invention further provides novel compounds useful for imaging atherosclerosis, restenosis, cardiac ischemia, and myocardial reperfusion injury. The present invention still further provides novel compounds useful for the treatment of rheumatoid arthritis. The pharmaceuticals are comprised of a targeting moiety that binds to a receptor that is upregulated during angiogenesis, and optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety. The imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, and X-ray contrast agent, or an ultrasound contrast agent.

Description

PHARMACEUTICAL SUBSTANCES VITRONECTIN RECEPTOR ANTAGONISTS FIELD OF THE INVENTION The present invention provides novel pharmaceutical substances useful for the diagnosis and treatment of cancer, methods for imaging tumors in a patient and methods for treating cancer in a patient. The pharmaceutical substances are constituted by an objective-choosing portion, which binds to the vitronectin receptor that is expressed in the tumor vasculature, an optional binding group and a therapeutically effective radioisotope or a diagnostically effective image-forming portion. The therapeutically effective radioisotope emits a gamma ray or an alpha particle sufficient to be cytotoxic. The image forming portion is a radioisotope that emits gamma rays or positrons, a contrast agent for magnetic resonance imaging, a contrast agent for X-rays or a contrast agent for ultrasound.
BACKGROUND OF THE INVENTION Cancer is the main public health concern in the United States and in the world. It is estimated that more REF: 129312 of a million new cases of invasive cancer will be diagnosed in the United States in 1998. The most prevalent forms of the disease are solid tumors of the lung, breast, prostate, colon and rectum. Cancer is typically diagnosed by a combination of in vitro tests and imaging procedures. Imaging procedures include X-ray computed tomography, magnetic resonance imaging, ultrasound imaging, and radionuclide scintigraphy. Frequently, a contrast agent is administered to the patient to improve the image obtained by X-ray CT, MRI and ultrasound, and the administration of a radiopharmaceutical that is localized in the tumors is what is required for the scintigraphy with radionuclides. Cancer treatment typically involves the use of external beam radiation therapy and chemotherapy, either alone or in combination, depending on the type of disease. Many chemotherapeutic agents are available, but generally all lack specificity for tumors versus normal tissue, resulting in considerable side effects. The effectiveness of these treatment modalities is also limited, as evidenced by the high mortality rates for many types of cancer, especially the most prevalent solid tumor diseases. There is still a need for a more effective and specific means of treatment. Despite the variety of imaging procedures available for the diagnosis of cancer, the need for improved methods remains. In particular, methods are needed that better differentiate between cancer and other pathological conditions or benign physiological abnormalities. One means of obtaining this desired improvement would be to administer to the patient a metapharmaceutical substance that is specifically located in the tumor by binding to a receptor that is expressed only in tumors or that is expressed to a significantly greater extent in tumors than in another tissue. The location of the metal-pharmaceutical substance can be detected externally either by its image-forming emission in the case of certain radiopharmaceutical substances or by its effect on the rate of water relaxation in the immediate vicinity, in the case of contrast agents formers of magnetic resonance imaging. This tumor-specific metalworking solution can also be used for the treatment of cancer when the metal-pharmaceutical substance is constituted by a radioisotope that emits particles. The radioactive decay of the isotope at the tumor site results in sufficient ionizing radiation to be toxic to the tumor cells. The specificity of this tumor solution minimizes the amount of normal tissue that is exposed to the cytotoxic agent and therefore can provide more effective treatment with fewer side effects. Previous efforts to obtain these desired improvements in cancer imaging and treatment have focused on the use of monoclonal antibodies labeled with radionuclides, fragments of antibodies or other proteins or polypeptides that bind to tumor cell surface receptors. The specificity of these radiopharmaceuticals is often very high, but has certain disadvantages. First, because of their high molecular weight, they usually clear up from the bloodstream very slowly, resulting in a prolonged blood pool in the images. In addition, due to their molecular weight, they do not extravasate easily to the tumor site and when they do so they only diffuse slowly through the extravascular space to the surface of the tumor cell. This results in a very limited amount of radiopharmaceutical reaching the receptors and therefore a very low signal intensity in the image formation and an insufficient cytotoxic effect for treatment. Alternative solutions for imaging and therapy in cancer have involved the use of small molecules, such as peptides, that bind to the surface receptors of tumor cells. A peptide that binds somatostatin receptor labeled with In-lll, In-111-DTPA-D-Phex-octeotide, is in clinical use in many countries for imaging tumors that express the somatostatin receptor (Baker, et al. al., Life Sci., 1991, 49, 1583-91 and Krenning, et al., Eur. J. Nucí, Med., 1993, 20, 716-31). Higher doses of this radiopharmaceutical have been investigated for the potential treatment of these cancers (Krenning, et al., Digestion, 1996, 57, 57-61). Several groups are investigating the use of Tc-99m labeled analogues of In-lll-DPTA-D-Phe1-octeotide for imaging and analogs labeled with e-186 for therapy (Flanagan, et al., U.S. Pat. 5,556,939, Lyle, et al., U.S. Patent 5,382,654 and Albert et al., U.S. Patent 5,650,134). Angiogenesis is the process by which new blood vessels are formed from preexisting capillaries or postcapillary venules.; it is an important component of diverse physiological processes that involve ovulation, embryonic development, wound repair and collateral vascular generation in the myocardium. It is also a central process in many pathological conditions such as tumor and metastasis growth, diabetic retinopathy and macular degeneration. The process begins with the activation of existing vascular endothelial cells in response to various cytokines and growth factors. The tumor releases cytokines or angiogenic factors and stimulates vascular endothelial cells by interacting with specific cell surface receptors for the factors. Activated endothelial cells secrete enzymes that degrade the basement membrane of the vessels. The endothelial cells then proliferate and invade the interior of the tumor tissue. Endothelial cells differentiate to form lumens, producing deviations of new vessels from pre-existing vessels. The new blood vessels then provide nutrients to the tumor allowing for additional growth and a route for metastasis. Under normal conditions, the proliferation of endothelial cells is a very slow process, but it increases in a short period of time during embryogenesis, ovulation and wound healing. This temporary increase in cell turnover is governed by a combination of many growth-stimulating factors and factors that suppress growth. In pathological angiogenesis, this normal balance is altered resulting in continued increased proliferation of endothelial cells. Some of the proangiogenic factors that have been identified include basic fibroblast growth factor (bFGF), angiogenin, TGF-alpha, TGF-beta and vascular endothelial growth factor (VEGF). While interferon-alpha, interferon-beta and thrombospondin are examples of angiogenesis suppressors. The proliferation and migration of endothelial cells in the extracellular matrix is mediated by the interaction with various cell adhesion molecules (Folkman, J., Nature Medicine, 1995, 1, 27-31). Integrins are a diverse family of enterodimeric cell surface receptors by which endothelial cells bind to the extracellular matrix, to each other and to other cells. Integrin vß3 is a receptor for a wide variety of extracellular matrix proteins with a tripeptide Arg-Gly-Asp and mediates cell adhesion to its ligand: vitronectin, fibronectin and fibrinogen, among others. Integrin vß3 is minimally essed in normal blood vessels, but is significantly activated in vascular cells within a wide variety of human tumors. The role of avß3 receptors is to mediate the interaction of endothelial cells and the extracellular matrix, and to facilitate the migration of cells in the direction of the angiogenic signal, the population of tumor cells. The angiogenesis induced by bFGF or TNF-alpha depends on the integrin vß3 agency, whereas the VEGF-induced angiogenesis depends on the avß3 integrin (Cheresh et al., Science, 1955, 270, 1500-2). The induction of ession of integrins 1 ^ 1 and 2ßx on the surface of endothelial cells is another important mechanism by which VEGF promotes angiogenesis (Senger, et al., Proc. Nati, Acad. Sci. USA, 1997, 84, 13612-7). Angiogenic factors interact with endothelial cell surface receptors such as the EGFR tyrosine kinase receptor, FGFR, PDGFR, Flk-1 / KDR, Flt-1, Tek, tie, neuropilin-1, endoglin, endosialin and Axi. The Flk-1 / KDR, neuropilin-1, and Flt-1 receptors recognize VEGF and these interactions play key roles in VEGF-induced angiogenesis. The receptor tyrosine kinase subfamily is also prominently essed during the formation of blood vessels. Due to the importance of angiogenesis in tumor growth and metastasis, many chemotherapeutic solutions have been developed to interfere with or avoid this process. One of these approaches involves the use of anti-angiogenic proteins such as angiostatin and endostatin. Angiostatin is a 38 kDa fragment of plasminogen that has been shown in animal models to be a potent inhibitor of endothelial cell proliferation (O'Reilly et. Al., Cell, 1994, 79, 315-328). Endostatin is a 20 kDa C-terminal fragment of collagen XVIII which has also been shown to be a potent inhibitor (O'Reilly et al., Cell, 1997, 88, 277-285). Systemic therapy with endostatin has been shown to result in strong antitumor activity in animal models. However, clinical trials in humans of these two chemotherapeutic agents of biological origin have been reduced by the lack of availability. Another approach to anti-angiogenic therapy is to use target portions choosing which interact with receptors on the surface of endothelial cells are expressed in the angiogenic vasculature to which are attached chemotherapeutic agents. Burrows and Thorpe (Proc. Nat. Acad. Sci. USA, 1993, 90, 8996-9000) describe the use of an antibody-immunotoxin conjugate to eradicate tumors in mouse model or by destroying the tumor vasculature. An antibody against the class II antigen of endothelial cells of the major histocompatibility complex is generated and then conjugated with the cytotoxic agent, the deglycosylated ricin A chain. The same group (Clin.Can.Res., 1995, 1, 1623-1634) investigated the use of antibodies generated against the endothelial cell surface receptor, endoglin, conjugated to the A chain of deglycosylated ricin. Both conjugates show potent antitumor activity in mouse models. However, it still suffers from drawbacks for systematic human use. As with most antibodies and other foreign and large proteins, there is a considerable risk of immunological toxicity which may limit or prevent administration to humans. In addition, although choosing the target vasculature may improve the local concentration of the bound chemotherapeutic agents, the agents must still be separated from the carrier antibody and must be transported or diffused to cells that are cytotoxic. Therefore, it is desirable to provide anti-angiogenic pharmaceutical substances and new tumor or vasculature imaging agents which do not exhibit this poor diffusion or transport, possible immunological toxicity, limited availability or lack of specificity. Another application of antiangiogenic therapy is to treat rheumatoid arthritis (RA). In RA, the inward growth of the highly vascularized cloth is caused by the excessive production of angiogenic factors by infiltrated macrophages, immune cells or inflammatory cells. Therefore, it is desirable to have new pharmaceutical substances that destroy the resulting highly vascularized cloth and thereby treat the disease. There is also an increasing interest in therapeutic angiogenesis to improve blood flow in regions in the body that have become ischemic or have a double perfusion. Several researchers are using locally administered growth factors to cause new vasculature to form either in the extremities or in the heart. The growth factors VEGF and bFGF are the most common for this application. Recent publications include: Takeshita, S., et al., J.
Clin. Invest., 1994, 93, 662-670; and Schaper, w. and Schaper, J., Collateral Circulation: Heart, Brain, Kidney, Limbs, Kluwer Academic Publishers, Boston, 1993. The main applications that are under investigation in many laboratories are to improve cardiac blood flow and to improve the flow of blood vessels. peripherals in the extremities. For example, Henry, T. et. to the. (J. Amer. College Cardiology, 1998, 31, 65A) describes the use of recombinant human VEGF in patients to improve myocardial perfusion by therapeutic angiogenesis. Patients who receive rhVEGF infusions are monitored by nuclear perfusion imaging 30 and 60 days after treatment to determine improvements in myocardial perfusion. Approximately 50% of patients show improvement by nuclear perfusion imaging while 5/7 show new collateralization by angiography. It is therefore desirable to discover a method for monitoring improved cardiac blood flow that is directed to the new collateral vessels themselves and not, as in nuclear perfusion imaging, a regional consequence of new collateral vessels. The detection, imaging and diagnosis of numerous vascular diseases need to be improved, including restenosis, atherosclerosis, damage by myocardial reperfusion and myocardial ischemia, attack or infarction. Recently it has been determined that in all of these morbid conditions, the vβ3 integrin receptor plays an important role. For example, in the complication of restenosis that occurs in "30-50% of patients who have undergone angioplasty or stent replacement, neointimal hyperplasia and final reocclusion is caused by active proliferation of vascular smooth muscle cells expressing vß3 ( Cardiovascular Res., 1997, 36", 408-428; DDT, 1997, 2, 187-199; Current Pharm. Design, 1997, 3, 545-584). Atherosclerosis degenerates from initial endothelial damage that results in recruitment and migration to the sub-monkey of monocytes at the site of damage. Growth factors are related which induce medial smooth muscle cells that proliferate and migrate to the intimal layer. The smooth muscle cells that migrate express vß3. In reperfusion injury, neutrophil transmigration is integrin-dependent and integrins moderate the initial infiltration within the viable borderline. The induction of a5ßl, a4ßl and avß5 in infiltrating neutrophils occurs within 3 to 5 hours after reperfusion as neutrophils move from the borderline area to the area of necrosis (Circulation, 1999, 100, 1- 275). -? 3 - Acute or chronic occlusion of the coronary artery is known to result in angiogenesis in the heart as native collateral vessels are recruited to try to alleviate the burn. However, even a gradual onset usually results in areas of infarction, since subsequent angiogenesis is not sufficient to prevent damage. Cardiac angiogenesis has been associated with increased expression of VEGF and FGF growth factors and the activation of growth factor receptors flt-1 and flk-l / KDR (Drugs, 1999, 58, 391-396).
BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention to provide anti-angiogenic pharmaceutical substances, consisting of a targeting portion, which binds to the vitronectin receptor that is expressed in the tumor neovasculature, an optional linker group and a radioisotope. Compounds that bind to the vitronectin receptor direct the radioisotope to the tumor neovasculature. The radioisotope that emits beta or alpha particles emits a cytotoxic amount of ionizing radiation which results in cell death. The penetration capacity of the radiation eliminates the requirement that the cytotoxic agent be diffused or transported inside the cell to be cytotoxic.
Another objective of the present invention is to provide pharmaceutical substances for treating rheumatoid arthritis. These pharmaceutical substances comprise an objective-choosing portion, which binds to a receptor that is activated during angiogenesis, an optional binding group and a radioisotope that emits cytotoxic radiation (ie, beta particles, alpha particles and Auger or Coster-Kronig electrons). ). In rheumatoid arthritis, the inward growth of highly vascularized cloth is caused by the excessive production of angiogenic factors by infiltrating macrophages, immune cells or inflammatory cells. Therefore, the radiopharmaceuticals of the present invention that emit cytotoxic radiation can be used to destroy the resulting new angiogenic vasculature and treat the disease. Another object of the present invention is to provide imaging agents, comprising vitronectin receptor binding compounds conjugated to an image forming portion, such as a gamma or positron emitting radioisotope, an image-forming contrast agent by magnetic resonance, an X-ray contrast agent or an ultrasound contrast agent. These imaging agents are useful for tumor neovasculature imaging, therapeutic angiogenesis interventions in the heart, natural angiogenic processes in response to acute or chronic occlusion of coronary vessels, restenosis and post-angioplasty, atherosclerosis and plaque formation and damage by reperfusion. Another objective of the present invention is to provide compounds useful for preparing the pharmaceutical substances of the present invention. These compounds are constituted by a non-peptidic quinolone which contains a portion that chooses its target which binds to a receptor that is activated during angiogenesis or during cardiovascular diseases, Q, an optional linker group, Ln and a chelating moiety or metal binding, Ch. The compounds may have one or more protecting groups attached to the metal binding or chelating portion. The protecting groups provide improved stability to the reagents for long-term storage and are removed either immediately before or concurrently to the synthesis of the radiopharmaceuticals. Alternatively, the compounds of the present invention are comprised of a peptide or a portion that selects its target mimetic peptide that binds to a receptor that is activated during angiogenesis or during cardiovascular diseases, Q, an optional linking group, Ln and a surfactant, Sf. The pharmaceutical substances of the present invention may be used for diagnostic, therapeutic or both purposes. The diagnostic radiopharmaceuticals of the present invention are radiopharmaceuticals consisting of a diagnostically useful radionuclide (i.e., a radioactive metal ion having gamma or positron emission which can image). The therapeutic radiopharmaceuticals of the present invention are pharmaceutical substances consisting of a therapeutically useful radionuclide, a radioactive metal ion that emits ionizing radiation such as beta particles, alpha particles and electrons from Auger or Coster-Kronig. The pharmaceutical substances comprise a radioactive metal ion that emits gamma rays or positrons, are useful for tumor imaging and by gamma scintigraphy or positron emission tomography. Pharmaceutical substances comprising a radioactive metal ion emitting gamma rays or positrons are also useful for imaging therapeutic angiogenesis, natural angiogenic processes in response to acute or chronic occlusion of coronary vessels, post-angioplasty restenosis, atherosclerosis and information from plaque, as well as reperfusion damage by gamma scintigraphy or positron emission tomography. Pharmaceutical substances comprising a radioactive, particle-emitting metal ion are useful for treating cancer by delivering a cytotoxic dose of radiation to tumors. Pharmaceutical substances comprising a radioactive metal ion emitting particles are also useful for treating rheumatoid arthritis to destroy the formation of angiogenic vasculature. Pharmaceutical substances comprising a paramagnetic metal ion are useful as contrast agents for magnetic resonance imaging. Pharmaceutical substances comprising one or more atoms that absorb x-rays or "heavy" atoms of atomic number 20 or greater, are useful as X-ray contrast agents. Pharmaceutical substances that compensate for a microbubble of a biocompatible gas, a liquid carrier and a surfactant microsphere, are useful as contrast agents for ultrasound.
DETAILED DESCRIPTION OF THE INVENTION [1] Therefore, in a first embodiment, the present invention provides a novel compound comprising: a portion that chooses its target and a chelator, wherein the portion that chooses its target joins the chelator, which is a non-peptidic of quinolone and binds to a receptor that is activated during angiogenesis and a compound that has 0-1 linkers between the portion that chooses its target and the chelator. [2] In a preferred embodiment, the receptor is avß3 or avß5 integrin and the compound is of the formula: (Q) d-Ln-Ch or (Q) d-Ln- (Ch) d, wherein Q is a compound of the formula (Ii; (II) which includes stereoisomeric forms thereof, or mixtures of the stereoisomeric forms thereof, or pharmaceutically acceptable salt forms or precursor thereof, wherein: Rle is selected from: Ae is -CH2- or -N (R10e) -; Ale and Bß are independently -CH2- or -N (R10e) -; Dß is -N (R10e) - or -S-; Ee-Fe is -C (R2e) = C (R3e) - or -C (R2e) 2C (R3e) 2-; Jß is -C (R2e) - O -N-; Ke, Le and Mee are independently -C (R2e) - or -C (R3e) -; R2e and R3e are independently selected from: H, alkoxy of 1 to 4 carbon atoms, NRlleR12e, halogen, N02, CN, CF3, alkyls of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 at 7 carbon atoms, cycloalkyl (3 to 7 carbon atoms) alkyl of 1 to 4 carbon atoms, aryl (alkyl of 1 to 6 carbon atoms) -, alkyl (1 to 6 carbon atoms) carboni 1 or, (C 1-6 alkoxy) carbonyl, arylcarbonyl and aryl substituted with 0-4 of R7e, alternatively, when R2e and R3e are substituents on adjacent atoms, can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic ring system or 5-7 membered aromatic or heterocyclic ring system aromatic, the carbocyclic or heterocyclic ring is substituted with 0-2 groups selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, cyano, amino, CF3 and N02; R2ae is selected from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms), aryl, aryl (C 1 -C 4 alkyl) -, (C 2 -C 7 alkyl) carbonyl, arylcarbonyl, (C 2 -C 7 alkoxy) carbonyl, cycloalkoxy (3 to 7 C atoms) carbon) carbonyl or, bicycloalkoxy (from 7 to 11 carbon atoms), aryloxycarbonyl, aryl (alkoxy of 1 to 10 carbon atoms) carbonyl, alkyl (of 1 to 6 carbon atoms) carbonyloxy (alkoxy of 1 to 4 carbon atoms) carbon) carbonyl, arylcarbonyloxy (C 1 -C 4 alkoxy) carbonyl, and cycloalkyl (3 to 7 carbon atoms) caroni 1 oi (C 1 -C 4 alkoxy) carbonyl; R7e is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 4 carbon atoms carbonyl, C02R18ae, S02Rlle, SO2ÑR10eRlle, OR10e and N (Rlle) R12e; U "is selected from: - (CH2) ne-, - (CH2) ne0 (CH2) me-, - (CH2) neN (R12) (CH2) rae-, -NH (CH2) ne-, - (CH2) neC (= 0) (CH2) me-, - (CH2) neS (O) pe (CH,) me-, - (CH2) neNHNH (CH2) me-, -N (R10e) C (= 0) -, -NHC (= 0) (CH2) nß-, -C (= 0) N (R10e) -, and -N (R10e) S (O) De-; Gß is N or CR19e; We is -C (= 0) -NR (R10e) - (alkylene of 1 to 3 carbon atoms) -, in which the alkylene group is substituted by R8e and by R9e: R8e and R9e are selected, independently of: H , C02R18be, C (= 0) R18be, C0NR17R18be, alkyl of 1 to 10 carbon atoms substituted with 0-1 of R6e, alkenyl of 2 to 10 carbon atoms substituted with 0-1 of R6e, alkynyl of 2 to 10 atoms of carbon substituted with 0-1 of Ree, cycloalkyl of 3 to 8 carbon atoms substituted with 0-1 of RSe, cycloalkenyl of 5 to 6 carbon atoms substituted with 0-1 of R6e, (C 1 -C 10 alkyl) carbonyl, cycloalkyl (3 to 10 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, phenyl substituted with 0-3 of R 6β, naphthyl substituted with 0-3 of RSe, a heterocyclic ring of 5-10 members containing 1-3 heteroatoms of N, O or S, wherein the heterocyclic ring may be saturated, partially saturated or completely saturated, the heterocyclic ring is substituted with 0-2 of R7e , alkoxy of 1 to 10 carbon atoms substituted with 0-2 of R7e, hydroxy, nitro, -N (RXOe) Rlle, -N (R16e) R17e, aryl (0 to 6 carbon atoms) carbonyl, aryl ( alkyl of 3 to 6 carbon atoms), heteroaryl (alkyl of 1 to 6 carbon atoms), CONR18aeR20e, S02R18ae, and S02NR1 188aaeeRt-): 20e with the proviso that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 of R7e; RSe is selected from: H, alkyl of 1 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, nitro, alkylcarbonyl of 1 to 10 carbon atoms, -N (Rlle) R12e, cyano, halo, CF3 , CHO, C02R18be, C (= 0) R18be, C0NR17eR18be, OC (= O) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= O) R1 NR10eC (= O) OR2 NR10ßC (= 0) NR l1ü0eeRnlle NR llOueerRj lie NR10eSO2R21e, S (0) pRlle, SO2NR10eRlle, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) meMe, and -NMe2, aryl (alkyl of 1 to 4 carbon atoms) -, the aryl is substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3 , S (0) peMe, and -NMe2 and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, 0 or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 of R7e; R10ß is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, aryl, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl (alkyl of 1 to 4 carbon atoms) carbon) and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R6e; Rlle is selected from: H, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, alkoxy of 1 to 6 carbon atoms, benzyloxy, aryl, heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl, alkyl of 1 to 10 carbon atoms substituted with 0-2 of R4e; R4e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 10 carbon atoms) carbonyl or, aryl, heteroaryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0-2 substituents which are independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02, alternatively, when R10e and Rllβ are both substituents on the same nitrogen atom (as in -NR10eRlle) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1, 2, 3, 4-tetrahydro- l-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, ti azolidinyl and 1-piperazinyl; the heterocycle is substituted with 0-3 groups which are selected from: alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 6 carbon atoms) carbonyl, (C3-C7-cycloalkyl) carbonyl, C1-C6-alkoxy) carbonyl, aryl (C1-C4 alkoxy) carbonyl, alkylsulfonyl of 1 to 6 carbon atoms and aryisulfonyl; R12e is selected from: H, C 6 -alkyl, trif-enylmethyl, methoxymethyl, methoxy-3-enylmethyl, trimethylsilylethoxymethyl, (C 1 -C 6 -alkyl) carb on i 1, (C 1 -C 6 -alkoxy) carbon) caroni 1 or, (C 1-6 alkyl) aminocarbonyl, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1) to 4 carbon atoms) -, aryl, heteroaryl (C 1-6 alkyl) carbonyl, heteroarylcarbonyl, aryl (C 1-6 alkyl) -, (C 1 -C 6 alkyl) carbonyl, arylcarbonyl, alkylsulfonyl of 1 to 6 carbon atoms, aryisulfonyl, aryl (C 1 -C 6 alkyl) sulphonyl, heteroarylsulfonyl, heteroaryl (alkyl of 1 to 6) carbon atoms) sulfonyl, aryloxycarbonyl and aryl (C 1 -C 6 alkoxy) carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, CF3 and nitro; R16e is selected from: -C (= 0) OR18ae, -C (= 0) R18be, -C (= 0) N (R18be) 2, -C (= 0) NHS02R18ae, -C (= 0) NHC (= 0) R18be, -C (= 0) NHC (= 0) 0R18ae, -C (= 0) NHS02NHR18be, -S02R18ae, -S02N (R18be) 2 and -S02NHC (= 0) 0R18be; R17e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms), (alkyl of 1 to 4 carbon atoms) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms); R18ae is selected from: alkyl of 1 to 8 carbon atoms optionally substituted with a bond to Ln, cycloalkyl of 3 to 11 carbon atoms optionally substituted with a bond Ln, aryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond L n, heteroaryl (alkyl of 1 to 6 carbon atoms) -optionally substituted with a bond to L n, -alkyl of 1 to 6 carbon atoms-heteroaryl optionally substituted with a bond to L n, diaryl (alkyl of 1 to 6 carbon atoms) optionally substituted with a bond to L n, heteroaryl optionally substituted with a bond to L n, phenyl substituted with 3-4 of R 19 β and optionally substituted with a bond to L n, naphthyl substituted with 0-4 of R 19 β and optionally substituted with a link to Ln, and a link to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19e; íete is H or R18ae; R19e is selected from: H, halogen, CF3, C02H, CN, N02 / -NRlleR12e, 0CF3, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl from 3 to 11 carbon atoms, cycloalkyl (3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 6 carbon atoms) -, alkoxy of 1 to 6 atoms of carbon, alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-O-, aryl-S02-, heteroaryl and heteroaryl-S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen , halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms; R20e is selected from: hydroxy, alkyloxy of 1 to 10 carbon atoms, cycloalkyloxy of 3 to 11 carbon atoms, aryloxy, aryl (alkyl of 1 to 4 carbon atoms) oxy, alkyl (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyl ( alkyl of 1 to 2 carbon atoms) oxy-, cycloalkyl (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy, cycloalkoxy (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1) at 2 carbon atoms) oxy-, cycloalkoxy of 3 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyloxy (alkyl) 1 to 2 carbon atoms) oxy-, arylcarbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 1 to 5 carbon atoms) (alkyl of 1 to 5 carbon atoms) ) carbonyloxy (1 to 2 carbon atoms) oxy, (5- (C 1-5 alkyl) -1,3-dioxa-cyclopenten-2-one-yl) methyloxy, (5-aryl-1) , 3-dioxa-cyclopenten-2-one-yl) methyloxy, and (R10β) (Rlle) N- (alkoxy of 1 to 10 carbon atoms) -; R21e is selected from: alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl, aryl (alkyl of 1 to 6 carbon atoms) to 4 carbon atoms) -, and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R7β; R22e is selected from: -C (= 0) -R18be, -C (= 0) N (R18bβ) 2, -C (= 0) NHS02R18ae -C (= 0) NHC (= 0) R18be, - (= 0 ) NHC (= 0) 0R18ae, and -C (= 0) NHS02NHR18be; Ye is selected from: -COR20e, -S03H, -P03H, -C0NHNHS02CF3, -C0NHS02R18ae, -C0NHS02NHR18be, -NHC0CF3, -NHC0NHS02R18ae, -NHS02R18ae, -OP03H2, -0S03H, -P03H2, -S02NHC0R18aß, -S02NHC02R18ae, me is 0-2 ne is 0-4, p3 is 0-2 rß is 0-2. with the following condition: nß and me are chosen so that the number of atoms that connect to Rl and Ye is in the range of 8-14; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; d 'is 1-100; Ln is a linking group having the formula: ((W) h- (CR6R7) g) x- (Z) k- ((CR6aR7a) g, - (W) h,)? L; is independently selected, each time it is presented, from the group: O, S, NH, NHC (= 0), C (= 0) NH, NR8C (= 0), C (= 0) NR8, C (= 0), C (= 0) 0, OC (= 0), NHC (= S) NH, NHC (= 0) NH, S02, S02NH, (0CH2CH2) s, (CH2CH20) a,, (0CH2CH2CH2) 3", (CH2CH2CH20) t, and (aa) t,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, cycloalkyl of 3 to 10 carbon atoms substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which is independently selected from N, S and 0 and substituted with 0-3 of R10; R6, R6a, R7, R7a and R8 are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, P03H, alkylated from 1 to 5 carbon atoms substituted with 0-3 of R10, aryl substituted with 0-3 of R10, benzyl substituted with 0-3 of R10 and alkoxy of 1 to 5 carbon atoms substituted with 0-3 of R10, NHC (= 0) R11, C ^ ONHR11, NHC (= 0) NHR11 , NHR11, R11 and a binding to Ch; R10 is independently selected, each time it is presented, from the group: a link to Ch, COOR11, C (= 0) NHRX1, NHC (= 0) R11, OH, NHR11, S03H, P03H, -0P03H2, -0S03H, aryl substituted with 0-3 of R11, alkyl of 1 to 5 carbon atoms substituted with 0-1 of R12, alkoxy of 1 to 5 carbon atoms substituted with 0-1 of R12 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S, and O and substituted with 0-3 of R11; R11 is independently selected, each time it occurs, from the group: H, alkyl substituted with 0-1 of R12, aryl substituted with 0-1 of R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0, and substituted with 0-1 of R12, cycloalkyl of 3 to 10 carbon atoms substituted with 0-1 of R12, polyalkylene glycol substituted with 0-1 of R12, carbohydrate substituted with 0- 1 of R12, cyclodextrin substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, polycarboxyalkyl substituted with 0-1 of R12, polyazaalkyl substituted with 0-1 of R12, peptide substituted with 0-1 of R12, in wherein the peptide is comprised of 2-10 amino acids, 3,6-0-disulfo-BD-galactopyranosyl, bis (phosphonomethyl) glycine or a bond for Ch; R12 is a link to Ch; k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; h 'is selected from 0, 1, and 2; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; g 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and ; s is selected from O, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; s' is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and ; s "is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and ; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; t 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and , x is selected from 0, 1, 2, 3, 4 and 5; x 'is selected from 0, 1, 2, 3, 4 and 5; Ch is a unit that joins metal, which has a formula that is selected from the group: A1, A2, A3, A4, A5, A6, A7 and A8 are independently, whenever they occur, of the group: NR13, NR13R14, S, SH, S (Pg), O, OH, PR13, PR13R14, P ( 0) R1SR16, and a link to Ln; E is a bond, CH, or a spacer group that is independently selected, each time it is presented, from the group: 1 to 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of 3 to 10 carbon atoms substituted with 0-3 of R17, heterocycloalkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, wherein the heterocycle group is a of 5-10 membered heterocyclic ring containing 1-4 heteroatoms which are independently selected from N, S and 0, aryl (from 6 to 10 carbon atoms) -alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, alkyl (of 1 to 10 carbon atoms) -aryl of 6 to 10 carbon atoms-substituted with 0-3 of R17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are selected independently of N, S and O and which are replaced with 0-3 of R17; R13 and R14 are each independently selected from the group: a bond to Ln, hydrogen, alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of 1 to 10 carbon atoms. carbon substituted with 0-3 of R17, heterocycloalkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, wherein the heterocycle group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are selected independently of N, S and O, aryl (from 6 to 10 carbon atoms) -alkyl of 6 to 10 carbon atoms-alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, alkyl (from 1 to 10 carbon atoms) -aromethyl of 6 to 10 carbon atoms-substituted with 0-3 of R17, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and O and substituted with 0-3 of R17, and an electron, with the proviso that when one of R13 or R14 is an electron, the other also be an electron; alternatively, R13 and R14 combine to form = C (R20) (R21); R1S and R16 are each independently selected from the group: a bond to Ln, -OH, alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of 3 to 10 carbon atoms substituted with 0-3 of R17, heterocycloalkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, wherein the heterocycle group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and O, aryl (from 6 to 10 carbon atoms) -alkyl from 1 to 10 carbon atoms substituted with 0-3 of R17, alkyl (of 1 to 10 carbon atoms) aryl of 6 to 10 carbon atoms-substituted with 0-3 of R17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are selected independently of N, S and O, and substituted with 0-3 of R17; R17 is independently selected, each time it is presented from the group: a bond to Ln, = 0, F, Cl, Br, I, -CF3, -CN, -C02R18, -C (= 0) R18, -C (= 0) N (R18) 2, -CHO, -CH2OR18, -0C (= 0) R18, -OC (= 0) ORx -OR1 -0C (= 0) N (R18) 2, -NR19C (= 0) R18, -NR19C (= 0) OR1 NR19C (= 0) N (R18) -NR19S02N (R18) -NR ^ SO ^ 1 • S03H, -SOjR1 -SR18, -S (= 0) R18a, -S0'22N "(* R" • 18) '22, 1 -N (R18) 2, -NHC (= S) NHR18, = N0R18, N02, -C (= 0) NHOR > 1188, _-rC > l (MNtHTNNTTRD l1ß8üRl1ß8aa, -0CH2C02H, 2- (1-morpholino) ethoxy, alkyl of 1 to 5 carbon atoms, alkenyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylmethyl of 3 to 6 atoms of carbon, alkoxyalkyl of 2 to 6 carbon atoms, aryl substituted with 0-2 of R18 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and O; R18, R18a and R19 are independently selected, each time they occur, from the group: a bond to Ln, H, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, alkoxy of 1 to 6 carbon atoms, halide, nitro, cyano and trifluoromethyl; Pg is a thiol protecting group: R20 and R21 are independently selected from the group: H, alkyl of 1 to 10 carbon atoms, -CN, -C02R2S, -C (= 0) R25, -C (= 0) N (R2S) 2, 1-alkene of 2 to 10 carbon atoms substituted with 0-3 of R23, 1-alkyne of 2 to 10 carbon atoms substituted with 0-3 of R23, aryl substituted tuido with 0-3 of R23, a saturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and 0 and substituted with 0-3 of R23, and a carbocycle of 3 to 10 carbon atoms saturated substituted with 0-3 of R23; alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form: R22 and R23 are independently selected from the group: H, R24, alkyl of 1 to 10 carbon atoms substituted with 0-3 of R24, alkenyl of 2 to 10 carbon atoms substituted with 0-3 of R24, alkynyl of 2 to 10 carbon atoms substituted with 0-3 of R24, aryl substituted with 0-3 of R24, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and O and substituted with 0 -3 of R24, and carbocycle of 3 to 10 carbon atoms substituted with 0-3 of R24; alternatively, R22 and R23 taken together form a fused aromatic portion of a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and O; a and b indicate the positions of the optional double bonds and n is 0 or 1; R24 is independently selected, each time it is presented, from the group: = 0, F, Cl, Br, I, -CF3, -CN, -C02RSC (= 0) R25, -C (= 0) N (R2S ) 2, -N (R25) 3+, -CH20R25, -OC (= 0) R25 -0C (= 0) R2Sa, -0R2S, -0C (= 0) N (R25) 2, -NR26C (= 0) R25, -NR26C (= 0) 0R25a -NR2SC (= 0) N (R25) -NR2eS02N (R25) -NR26S02R2 S03H, S02R2 -SR25, -S (= 0) R25a, -S02N (R25) 2, -N (R25) 2, = N0R2S, -C (= 0) NHOR25 -0CH2C02H and 2- (1-morpholino) ethoxy; and R: R and R are each independently selected, each time they occur from the group: hydrogen and alkyl of 1 to 6 carbon atoms; and a pharmaceutically acceptable salt thereof. [3] In a more preferred embodiment, the present invention provides a compound therein: Q is a compound of the formula (IV): (IV) which includes stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or precursor forms thereof, wherein: Rle is selected from: R2e and R3e are independently selected from: H, alkoxy of 1 to 4 carbon atoms, NRlleR12e, halogen, N02, CN, CF3, alkyl of 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (3 to 7 carbon atoms) -alkyl of 1 to 4 carbon atoms, aryl (alkyl of 1 to 6 carbon atoms) -, (alkyl of 1 to 6 carbon atoms) carbonyl, (C 1-6 alkoxy) carbonyl, arylcarbonyl and aryl substituted with 0-4 of R 7e, alternatively, when R 2e and R 3e are substituents on adjacent atoms, can be taken together with the carbon atoms which are attached to form a 5 to 7 membered carboxylic ring system or 5-7 membered heterocyclic aromatic or non-aromatic ring system, the carboxylic or heterocyclic ring is substituted with 0-2 groups which are selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, cyano, amino, CF3 and N02; R2 e is selected from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms), aryl, aryl (C 1 -C 4 alkyl) -, (C 2 -C 7 alkyl) carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy) carbonyl, cyclic coxi carboni 1 or 3 to 7 carbon atoms, bicycloalkoxycarbonyl of 7 to 11 carbon atoms, aryloxycarbonyl, aryl (alkoxy of 1 to 10 carbon atoms) carbonyl, alkyl (of 1 to 6 carbon atoms) ca rb on i 1 oi (C 1 -C 4 alkoxy) carbonyl, arylcarbonyloxy (C 1 -C 4 alkoxy) carbonyl and cycloalkyl (3 to 7 C atoms) c arb oni 1 oi (alkoxy of 1) to 4 carbon atoms) carbonyl; R7e is selected from: H, hydroxy, alkyl of 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 4 carbon atoms) ), carbonyl, C02R18ae, S02Rlle, S02NR10eRlle, OR10e and N (Rlle) R12e; U * is selected from: - (CH2) ne-, - (CH2) ne0 (CH2) me-, -NH (CH2) ne-, -N (R10e) C (= O) -, -NHC (= 0) (CH2) ne- and -C (= 0) N (R10e) -; Ge is N or CR19e; R8e is selected from: H, C02R18be, C (= 0) R18be, C0NR17eR18be, alkyl of 1 to 10 carbon atoms substituted with 0-1 of R6e, alkenyl of 2 to 10 carbon atoms substituted with 0-1 of R6e, alkynyl of 2 to 10 carbon atoms substituted with 0-1 of RSβ, cycloalkyl of 3 to 8 carbon atoms substituted with 0-1 of R6e, cycloalkenyl of 5 to 6 carbon atoms substituted with 0-1 of R6e, (alkyl) from 1 to 10 carbon atoms) carbonyl, cycloalkyl (3 to 10 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, phenyl substituted with 0-3 of R6e, naphthyl substituted with 0-3 of R6e, a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, 0 or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 of R7β; R9e is selected from: alkyl of 1 to 10 carbon atoms substituted with 0-1 of R6β, alkoxy of 1 to 10 carbon atoms substituted with 0-2 of R7e, H, nitro, N (Rlle) R12e, OC (= O) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= O) R10e, NR10eC (= 0) OR21e, NR10eC (= 0) NR10eRlle, NR10eS02NR10eRlle, NR1DeS02R21e, hydroxy, OR22e, -N (R10e) Rlle, - N (R16e) R17e, aryl (0 to 6 carbon atoms) carbonyl, aryl (alkyl of 1 to 6 carbon atoms) heteroaryl (alkyl of 1 to 6 carbon atoms), CONR18aeR20e, S02R18ae and S02NR18aeR0ß, with the condition that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or independently substituted with 1-2 of R7e; RSe is selected from: H, alkyl of 1 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, nitro, alkylcarbonyl of 1 to 10 carbon atoms, -N (Rllβ) R12e, cyano, halo, CF3 , CHO, C02R18be, C (= 0) R18be, CONR17eR18be, OC (= 0) R ^ 0e, OR10e, OC (= O) NR j1l0OeeRrjUe NR]! C (= 0) R3 NR1! C (= 0) 0R: NR10eC (= 0) NR lOenlle NR1 'SO-jNR > 110e! Rp lJie NR1DeS02R- < S (0) peRlle, SO2NR10eRlle, aryl substituted with 0-3 groups selected from halogen, alkoxy of 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) meMe and -NMe2, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) meMe and -NMe2, aryl (alkyl of 1 to 4 carbon atoms) carbon) -, aryl which is substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) peMe, and -NMe2 and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, 0 or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 R7e; R10e is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, aryl, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl (alkyl of 1 to 4 carbon atoms) carbon) and alkyl of 1 to 10 carbon atoms substituted with 0-2 of RSe; Rlle is selected from: H, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, alkoxy of 1 to 6 carbon atoms, benzyloxy, aryl, heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R4e; Re is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, heteroaryl , aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0-2 substituents which are independently selected from the group consisting of of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02, R12e is selected from: H, alkyl of 1 to 6 carbon atoms, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl , trimethylsilylethoxymethyl, (C 1-6 alkyl), carbonyl, (C 1-6 alkoxy), carbonyl, (C 1-6 alkyl) aminocarbonyl, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 4 carbon atoms) - , aryl, heteroaryl (alkyl of 1 to 6 carbon atoms) carbonyl, heteroarylcarbonyl, aryl (C 1-6 alkyl) -, (C 1-6 alkyl), carbonyl, arylcarbonyl, alkylsulfonyl of 1 to 6 carbon atoms, aryisulfonyl, aryl (alkyl of 1 to 6 carbon atoms) sulfonyl, heteroarylsulfonyl, heteroaryl (C1-C6 alkyl) sulfonyl, aryloxycarbonyl, and aryl (alkoxy of 1 to 6 carbon atoms) carbonyl, wherein the aryl groups are substituted with 0-2 substituents which are selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo CF3 and nitro; R16e is selected from: -C (= 0) OR18ae, -C (= 0) R18be, -C (= 0) N (R18be) 2, -S02R18ae, and -S02N (R18be) 2; R17ß is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -; R18aß is selected from: alkyl of 1 to 8 carbon atoms optionally substituted by a bond to Ln, cycloalkyl of 3 to 11 carbon atoms optionally its thionides with an enol ace to Ln, aryl (alkyl of 1 to 6 carbon atoms) ) - optionally substituted with a bond to Ln, heteroaryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to Ln, (at the rate of 1 to 6 as well as carbon) ilo optionally substituted with a bond to Ln, viaryl (alkyl of 1 to 6 carbon atoms) optionally substituted with a bond to Ln, heteroaryl optionally substituted with a bond to Ln, phenyl substituted with a 3-4 of R19e and optionally substituted with a bond to Ln, naphthyl substituted with 0-4 of R19e and optionally substituted with a bond to Ln, and a bond to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19β; R18 e is H or R18ae; R19e is selected from: H, halogen, CF3, C02H, CN, N02, -NRlleR12e, OCF3r alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cyclopalkyl (3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 6 carbon atoms) -, (alkoxy of 1 to 6 carbon atoms) alkyl), alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-O-, aryl-S02-, heteroaryl and heteroaryl-S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen , halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms; R20e is selected from: hydroxy, alkyloxy of 1 to 10 carbon atoms, cycloalkyloxy of 3 to 11 carbon atoms, aryloxy, aryl (alkyl of 1 to 4 carbon atoms) oxy, alkyl (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyl ( alkyl of 1 to 2 carbon atoms o) oxy-, cyc 1 or 1 to 1 to 1 (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10) carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyl (alkyl of 1 to 2 atoms) carbon) oxy-, aryloxycarbonyloxy (1 to 2 carbon atoms) oxy-, arylcarbonyloxy (1 to 2 carbon atoms) oxy-, alkoxy (1 to 5 carbon atoms) (alkyl from 1 to 5) carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy, (5- (alkyl of 1 to 5 carbon atoms) -1, 3-dioxa-cyclopenten-2-one-yl) methyloxy, (5 - aryl-1,3-dioxa-cyclopenten-2-a-yl) methyloxy, and (R10e) (Rlle) N-alkoxy of 1 to 10 carbon atoms); R21e is selected from: alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl, aryl ( 1 to 4 carbon atoms) -, and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R7e; R22e is selected from: -C (= 0) -R18be, -C (= 0) N (R18be) -C (= 0) NHS02R1 -C (= 0) NHC (= 0) R18be, -C (= 0) NHC (= 0) 0R18ae and -C (= 0) NHS02NHR18be; it is 0-2; nß is 0-4; and p 'is 0-2; with the following condition: nß u me are chosen so that the number of atoms that connect to R1 and -COR20e in the formula (IV) is in the range of 8-14; d is selected from 1, 2, 3, 4 and 5; d 'is 1-50; W is independently selected, each time it is presented, from the group; 0, NH, NHC (= 0), C (= 0) NH, NR8C (= 0), C (= 0) NR8, C (= 0), C (= 0) 0, 0C (= 0), NHC (= S) NH, NHC (= 0) NH, S02, (0CH2CH2) s, (CH2CH20) s, (0CH2CH2CH2) s ", (CH2CH2CH20) t and (aa) t,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-1 of R10, cycloalkyl of 3 to 10 carbon atoms substituted with 0-1 of R10 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0, and substituted with 0-1 of R10; Rβ, RSa, R7, R7a and R8 are independently selected, each time they occur from the group: H, = 0, COOH, S03H, alkyl of 1 to 5 carbon atoms substituted with 0-1 of R10, aryl substituted with 0 -1 of R10, benzyl substituted with 0-1 of R10 and alkoxy of 1 to 5 carbon atoms substituted with 0-1 of R10, NHC (= 0) R11, C (= 0) NHRxl, NHC (= 0) NHR11 , NHR11, R11 and a bond to Ch; k is 0 or 1; s is selected from 0, 1, 2, 3, 4 and 5; s' is selected from 0, 1, 2, 3, 4 and 5; s "is selected from 0, 1, 2, 3, 4 and 5; t is selected from 0, 1, 2, 3, 4 and 5; A1, A2, A3, A4, A5, A6, A7 and A8 are independently , each time they are presented, from the group: NR13, NR13R14, S, SH, S (Pg), OH and a link to Ln; E is a link, CH, or a separating group that is selected independently, each time it is presents, from the group: alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of 3 to 10 carbon atoms substituted with 0-3 of R17 and a ring system 5-10 membered heterocyclic containing 1-4 heteroatoms which are independently selected from N, S and O and which are substituted with 0-3 of R17; R13 and R14 are each independently selected from the group: a bond to Ln, hydrogen , alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S Y O and substituted with 0-3 of R17, and an electron, with the proviso that when one of R13 or R14 is an electron, the other is also an electron; alternatively, R13 and R14 combine to form = C (R20) (R21); R17 is independently selected, each time it is presented, from the group: a bond to Ln, = 0, F, Cl, Br, I, -CF3, -CN, C02R18, -C (= 0) R18, -C (= 0) N (R18) 2, -CH2OR18, -0C (= 0) R18, -0C (= 0) 0R18a, -OR18, -0C (= 0) N (R18) 2, -NR19C (= 0) R18, -NR19C (= 0) 0R18a, -NR19C (= 0) N (R18) 2, -NR19S02N (R18) 2, -NR19S02R18a, -S03H, -S02R18a, -S (= 0) R18a, -S02N (R18) 2 , -N (R18) 2, -NHC (= S) NHR18, = N0R18, -C (= 0) NHNR18R18a, -0CH2C02H, and 2- (1-morpholino) ethoxy; R18, R18a and R19 are independently selected, each time they occur, from the group: a bond to Ln, H and alkyl of 1 to 6 carbon atom and R2i are independently selected from the group: H, alkyl of 1 to 5 carbon atoms, -C02R25, 1-alkene of 2 to 5 carbon atoms substituted with 0-3 of R23, 1-alkyne of 2 to 5 carbon atoms substituted with 0-3 of R23, aryl substituted with 0-3 of R23 and an unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R23, alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form: R22 and R23 are independently selected from the group: H and R24; alternatively, R22, R23 taken together, form a 5-10 membered fused or heterocyclic aromatic ring system containing 1-4 heteroatoms that are independently selected from N, S, and O; R24 is independently selected, each time it is presented, from the group: -C02R25, -C (= 0) N (R2S) 2, -CH2OR25, -OC (= 0) R25, -OR25, -S03H, -N (R2S ) 2, and -0CH2C02H; and R25 is independently selected, each time they occur from the group: H and alkyl of 1 to 3 carbon atoms. [4] In an even more preferred embodiment, the present invention provides a compound that includes tereoisomeric forms thereof, or mixtures of the stereoisomeric forms thereof, or pharmaceutically acceptable salts or forms of precursors thereof, wherein: Rle is selected from: R2e and R3e are independently selected from: H, alkoxy of 1 to 4 carbon atoms, NRlleR12e, halogen, N02, CN, CF3, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms), aryl (alkyl of 1 to 6 carbon atoms) -, alkyl (1 to 6 carbon atoms) carbonyl, (C 1-6 alkoxy) carbonyl, arylcarbonyl and aryl substituted with 0-4 of R 7e, alternatively, when R 2 and R 3e are substituents on adjacent atoms, can be taken together with the carbon atoms to which they are attached to forming a 5-7 membered carbocyclic ring or 5-7 membered aromatic or non-aromatic heterocyclic ring system, the carbocyclic or heterocyclic ring is substituted with 0-2 groups selected from alkyl of 1 to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, halo, cyano, amino, CF3 and N02; R2ae is selected from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms), aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (C2-C7 alkyl) carbonyl, arylcarbonyl, (C2-C10 alkoxy) carbonyl, cycloalkoxycarbonyl or C3 to C7, bicycloalkoxycarbonyl with 7 to 11 atoms carbon, aryloxycarbonyl, aryl (C 1 -C 10 alkoxy) carbonyl, alkyl (C 1 -C 6) carbonyloxy (C 1 -C 4 alkoxy) carbonyl, arylcarbonyloxy (C 1 -C 4 -alkoxy) carbon) carbonyl, and cycloalkyl (3 to 7 carbon atoms) carboni 1 ox i (a 1 c ox i of 1 to 4 carbon atoms) carbonyl; R7e is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 4 carbon atoms) carbon) carbonyl, C02R18aß, S02Rlle, SO2NR10βRllβ, 0R10e and N (Rlle) R12e; U * is selected from: - (CH2) ne-, -NH (CH2) n-, -N (R10e) C (= O) -, and - HC (= 0) (CH2) ne; Gß is N or CR19e; R8e is H; R9e is selected from: H, nitro, -N (Rlle) R12e, OC (= 0) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= 0) R10e, NR10eC (= 0) OR21e, NR10eC (= 0 ) NR10eRlle, NR10eSO2NR10eRlle, NR10eS02R21e, hydroxy, 0R22e, -N (R10e) Rlle, -N (R16e) R17e, aryl (C0-4 alkyl) carbonyl, aryl (C1-C4 alkyl), heteroaryl (C 1 -C 4 alkyl), CONR18aeR20e, S02R18ae and S02NR18aβR20e, with the proviso that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 of R7e; R10e is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, (cycloalkyl of 3 to 6 carbon atoms) methyl, aryl (alkenyl of 1 to 4 carbon atoms) carbon) and alkyl of 1 to 4 carbon atoms substituted with 0-2 of R6e; R6e is selected from: H, alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, nitro, alkylcarbonyl of 1 to 4 carbon atoms, -N (Rlle) R12ß, cyano, halo, CF3 , CHO, C02R18be, C (= 0) R18be, C0NR17eR18be, OC (= O) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= O) R10e, NR10eC (= 0) OR21e, NR10eC (= 0) NR10eRlle , NR10eSO2NR10eRlle, NR10eSO2R21e, S (0) pRlle, S02NR10eRlle, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, CF3, S (0) meMe, and -NMe2, aryl (alkyl of 1 to 4 carbon atoms) -, the aryl is substituted with 0-3 groups which are selected from halogen, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, carbon, CF3, S (0) peMe, and -NMe2 and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, 0 or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 of R7e; Rllβ is selected from: H, hydroxy, alkoyl of 1 to 4 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (cycloalkyl of 3 to 6 carbon atoms) methyl, alkoxy of 1 to 4 carbon atoms, benzyloxy, aryl, heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl and alkyl of 1 to 4 carbon atoms substituted with 0-2 of R4ß; R4ß is selected from: H, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, heteroaryl , aryl (alkyl of 1 to 4 carbon atoms) -, and heteroaryl (alkyl of 1 to 4 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0-2 substituents which are independently selected from the group consisting of of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02, R12e is selected from: H, alkyl of 1 to 4 carbon atoms, (alkyl of 1 to 4 carbon atoms) carbonyl, (C 1 -C 4 alkoxy) carbonyl, phenyl (C 1 -C 4 alkyl) -phenylsulfonyl, phenyloxycarbonyl and phenyl (1 to 4-alkoxy) 4 carbon atoms) carbonyl, wherein the phenyl groups are substituted with 0-2 substituents which are selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, halo, CF3 and nitro; R16e is selected from: -C (= 0) OR18ae, -C (= 0) R18be, -C (= 0) N (R18be) 2, -S02R18ae and -S02N (R18be) 2; R17e is selected from: H, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl (of 3 to 6 carbon atoms), (alkyl of 1 to 4 carbon atoms) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms); R18ae is selected from: alkyl of 1 to 8 carbon atoms optionally substituted with a bond to Ln, cycloalkyl of 3 to 11 carbon atoms optionally substituted with a bond to Ln, aryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to L n, heteroaryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to L n, (alkyl of 1 to 6 carbon atoms) heteroaryl optionally substituted with a bond to L n, diaryl ( 1 to 6 carbon atoms) optionally substituted with a bond to Ln, heteroaryl optionally substituted with a bond to Ln, phenyl substituted with 3-4 of R19e and optionally substituted with a bond to Ln, naphthyl substituted with 0-4 of R19e and optionally substituted with a bond to Ln, and a bond to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19β; R18be is H or R18ae; R19e is selected from: H, halogen, CF3, C02H, C0, N02, -NRlleR12e, OCF3, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl (of 3 to 6 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms) -, alkoxy of 1 to 6 carbon atoms carbon, alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-O-, aryl-S02-, heteroaryl and heteroaryl-S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms; R2De is selected from: hydroxy, alkyloxy of 1 to 6 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, aryloxy, aryl (alkyl of 1 to 4 carbon atoms) oxy, alkyl (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyl ( alkyl of 1 to 2 carbon atoms) oxy-, cycloalkyl (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy of 3 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyloxy (alkyl) of 1 to 2 carbon atoms) oxy-, arylcarbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 1 to 5 carbon atoms) (alkyl of 1 to 5 carbon atoms) ca rbonyloxy (1 to 2 carbon atoms) oxy, (5- (C 1-5 alkyl) -1,3-dioxa-cyclopenten-2-one-yl) methyloxy, (5-aryl-1, 3-dioxa-cyclopenten-2-one-yl) methyloxy, and (R10e) (Rlle) N- (alkoxy of 1 to 10 carbon atoms) -; R21ß is selected from: alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms (cycloalkyl of 3 to 6 carbon atoms) methyl, aryl, aryl (alkyl of 1 to 6 carbon atoms) to 4 carbon atoms) -, and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R7e; R22e is selected from: -C (= 0) -R18be, -C (= 0) N (R18be) 2, -C (= 0) NHS02R18ae, -C (= 0) NHC (= 0) R18be, -C ( = 0) NHC (= 0) 0R18ae, and -C (= 0) NHS02NHR18be; mß is 0-2 nß is 0-4 pe is 0-2 Ch is A1 is selected from the group: OH and a bond to Ln; A2, A4 and A6 are each N; A3, A5 and A8 are each OH; A7 is a link to Ln or NH-link to Ln; E is an alkyl of 2 carbon atoms substituted with -1 of R1 R17 is = 0; alternatively, Ch is A1, is selected from the group: OH and a bond to Ln; A2, A3 and A4 are each N; Thus, A6 and A8 are each OH; A7 is a link to Ln; E is an alkyl of 2 carbon atoms substituted with -1 of R1 R17 is = 0; 2 alternatively, Ch is ^ > TO A1 is NHa or N = C (R20) (R21); E is a link; A2 is NHR13; R13 is a heterocycle substituted with R17, the heterocycle is selected from pyridine and pyrimidine; R17 is selected from a bond to Ln, C (= 0) NHR18 and C (= 0) R18 R18 is a bond to Ln; R24 is selected from the group: -C02R25, -0R2S, -S03H and -N (R2S) 2; and R25 is independently selected, each time it is presented from the group: hydrogen and methyl. [5] In another even more preferred embodiment, the present invention provides a compound that includes the enantiomeric or diastereomeric forms thereof, or mixtures of the enantiomeric or diastereomeric forms thereof, or pharmaceutically acceptable salt or pharmaceutically acceptable salt thereof thereof, wherein Q is selected from the group: 3- [7- [(imidazolin-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-yl-rb-onylamino] -2- (3, 5) -dimethylisoxazol-4-ylsulfonylamino) propionic acid, 3- [7- [(imidazolin-2-ylamino) methyl] -l-methyl-6,8-difluoroquinoline-4-yne-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid , 3- [7- [(imidazolin-2-ylamino) methyl] -l-methyl-6,8-difluor oquinol in4-ona-3-yl-c-arboni-1-amino] -2- (n-butyloxycarbonylamino) propionic acid , 3- [7- [(imidazolin-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (n-butylsulphonylamino) propionic acid, 3- [7] - [(tetrahydropyrimid-2-i lamino) methyl] -1-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1-methyl -6, 8 -dif luoroquinolin4 -ona-3-ylcarbonylamino] -2- (n-butyloxycarbonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1-methyl-6,8-dif luoroquinolin-4-one-3-ylcarbonylamino] -2- (phenylsulphonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (n-Butylsulfonyl) aminopropionic, 3- [7- [(2-aminothiazol-4-yl) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino] ) propionic acid, 3- [7- [(imidazole-2-ylamino) methyl] -l-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl)] sulfonylamino) propionic, 3- [7- (tetrahydropyrimid-2-ylamino) methyl] -1-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2, 4, 6) -trimethylphenyl) sulfonylamino) ropionic acid, 3- [7- ((imidazol-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (3,5-dimethylisoxazole) 4-ylsulphonylamino) propionic acid, 3- [7- [(imidazol-2-ylamino) methyl] -l-methyl-6,8-difluoroquinoline-4-yl-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, acid 3- [7- [(imidazol-2-ylamino) methyl] -l-methyl-6,8-difluor or qui nol in4-ona-3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) ) sulfonyl amino) propionic acid, 3- [7- [(imidazol-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino) -2 ((4-biphenyl) sulf onylamino) ropionic, 3- [7- [(imidazol-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (1-naphthylsulfonylamino) propionic acid, 3- [7- [(benzimidazol-2-ylamino) methyl] -1-methyl-6,8-difor luor oquinclin4 -one -3-II carboni lamino] -2- (2,4,6-trimethylphenyl) sulfonylamino) propionic , 3- [7- t (4-Methylimidazol-2-ylamino) methyl] -1-methyl-6,8-dif luoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethyl-phenyl) sulfonylamino) -roiopionic acid; - [7- [(4,5-dimethylimidazol-2-ylamino) methyl] -1- methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4, 6-trimethylphenyl) sulfonylamino) propionic acid, 3- [7- [(4, 5, 6, 7 -ethohydrobenz imidazol-2-ylamino) methyl] -1- methyl -6,8-difluor oqu 1 i n4 -one-3-carbonylamino] -2 - ((2,4,6-trimethyl-phenyl) sulfonylamino) propionic acid, 3- [7- [(pyridin-2-ylamino) methyl] -l-methyl-6 , 8-di fl uor oquinol in4-ona-3-ylcarbonylamino] -2- ((2,4,6-trimethylf-enyl) sulfonylamino) propionic acid, 3- [7- (2-aminopyridin-6-yl) -l- methyl-6, 8-diflu luo r oqu ino 1 i n4 - ona - 3 - i 1 carboni lamí nol - 2 - ((2,4,6-trimethyl enyl) sulfonylamino) propionic acid, 3- [7- [( 7-azabenzimidazol-2-yl) methyl] -1-methyl-6,8-dif luoroquinolin-4-one-3-ylcarbonylamino] -2 - ((2,4,6-trimethylphenyl) sulfonylamino) ropionic acid, 3- [ 7- [(benzimidazol-2-ylamino) methyl] -1- (2-f-enylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] propionic acid, 3- [7 - [(pyridin-2) lamino) methyl] - 1 - (2 -f-enylethyl) - 6, 8 -dif lu oroquinolin-4-amino-3-ylcarbonylamino] propionic acid, 3- [7- [(imidazolin-2-ylamino) methyl] -1- (2-f-enylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] propionic acid , 3- [7- [(imi-zol-2-yl-amino) -methyl] -1- (2-p-enylethyl) -6,8-dif-luoroquinolin-4-one-3-ylcarbonylamino] -propionic acid, 3- [7] - [(imidazolin-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3- [7- [(imidazolin- 2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (n-butyloxycarbonylamino) propionic acid, 3- [7- [(imidazolin-2-ylamino ) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (phenylsulfonylamino) propionic acid, 3- [7- [(imidazolin-2-ylamino) methyl] -1 - (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (n-butylsulphonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1- (2 - phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1- (2-phenylethyl) -6, 8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (n-butyloxycarbonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinoline4 - ona-3-carbonylamino] -2- (phenylsulfonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-dif luoroquinolin-4-one-3 -carbonylamino] -2- (n-butylsulfonyl) aminopropionic acid, 3- [7- [(2-amino-thiazol-4-yl) methyl] -1- (2-phenylethyl) -6,8-difluoroquinoline 4- ona-3-ylcarbonylamino] -2- (phenylsulphonylamino) propionic acid, 3- [7- [(2-aminothiazol-4-yl) methyl] -1- (2-phenylethyl) -6,8-difluoroquinoline 4-one] -3-carbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3 - [7 - [(imidazolin-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinoline-4-one-3-carbonylamino no] -2- ((2,4,6-Trimethylphenyl) sulfonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1- (2-phenylethyl) -6,8- dif-luoroquinolin-4-one-3-ylcarbonylamino] -2 - ((2,4,6-trimethylphenyl) sulfonylamino) propionic acid, 3 [7- [(imidazol-2-ylamino) methyl] -1- (2-phenyl) ethyl) 6, 8 -dif luoroquinolin-4-yl-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, [7- [(imidazol-2-ylamino) methyl] -1- (2-phenylethyl) -6,8- difluoroquinolin-4-one-3-ylcarbonylamino] -2- (phenylsulphonylamino) propionic acid, 3- [7- [(imidazol-2-yl-amino) -methyl] -1- (2-p-ethyl-ethyl) -6,8-dif luoroquinolin4 -one-3-ylcarbonylamino] -2 - ((2,6-dichlorophenyl) sulfonylamino) propionic acid, 3- [7- [(imidazol-2-ylamino) methyl] -1- (2-phenyl ethyl) - 6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethyl-il-enyl) -sulfonylamino) -roprionic acid, 3 - [7 - [(imidazol-2-ylamino) methyl] - 1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylami no] -2- ((4-biphenyl) sulfonylamino) propionic acid, 3- [7- [(benzimidazol-2-ylamino) methyl] -1- (2-f-enylethyl) -6-, 8-difluoroquinoline-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethyl-phenyl) -sulfonylamino) -propionic acid, 3- [7- [(4-methylimidazol-2-ylamino) -methyl] -1] - (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) sulfonylamino) propionic acid, 3- [7- [(4,5) - dimethylaminozol-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) sulfonylamino) propionic acid 3- [7- [(4,5,6,7-tetrahydrobenz imidazol-2-ylamino) methyl] -1- (2-f-enylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] - 2 - ((2,4,6-trimethylphenyl) sulfonylamino) propionic, 3- [7- [(pyridin-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3 - ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) sulfonylamino) propionic acid, 3- [7- (2-aminopyridin-6-yl) -1- (2-phenylethyl) -6,8-dif] luor oquinol i n4 -one-3-ylcarb onylamino] -2- ((2,4,6-trimethylphenol) l) onylamino) propionic sulfide, and 3- [7- [(7-azabenzimidazol-2-yl) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2 acid ( (2,4,6-trimethylphenyl) sulfonylamino) propionic acid. [6] In another even more preferred embodiment, the present invention provides a compound selected from the group: 2 - (((4- (4 - (((3- (2- (2- (3 - (6 - ((L-aza-2- (2-sulfophenyl) vinyl) amino) (3-pyridyl)) carbonyl amino) propoxy) ethoxy) -ethoxy) rovyl) amino) sulfonyl) phenyl) phenyl) -sulfonyl) amino) - 3- ((7- ((imidazol-2-ylamino) methyl) -1-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) clothingnoic; 3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) -2- (4- (4- (3- (2- (2)} - (3- (2- (1, 4, 7, 1 0-tetraaza-4, 7, l 0 -tris (carboxylmethyl) cyclododecyl) acetylamino) -propoxy) ethoxy) ethoxy) propyl) amino) sulfonyl) -phenyl) phenyl) sulf onyl) amino) propanoic; 2- (((4- (3- (N- (3- (2- (2- (3- ((6- ((1-aza-2- (2-sulf of enyl) vinyl) amino]) ( 3-pyridyl)) carbonylamino) -ropoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l -methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic; 3 - ((1- (3 - ((6 - ((1-aza-2- (2-sulfo-enyl) vinyl) amino) (3-pyridyl)) carbonylamino) propyl) -7- ((imide zol- 2-yl-amino) -methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2 - (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic acid; 3 - ((1 - (3 - ((6 - ((1-aza-2 - (2-sulfo-enyl) vinyl) amino) (3-pyridyl)) carbonylamino) propyl) -7- (((1-) hydroxyimidazole-2-yl) amino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic; 3- ((1- (3- (3- (N- (3- (2- (2- (3- ((6- ((1-aza-2- (2-sulfophenyl) vinyl) amino)) ( 3-pyridyl)) carbonylamino) propoxy) ethoxy) -ethoxy) propyl) carbamoyl) propanoylamino) propyl) -7 ((imidazol-2-ylamino) methyl) -4 -oxo (3-hydroquinolyl)) carbonylamino) -2 - ( ((2,4,6-Trimethylphenyl) sulfonyl) amino) propanoic; 2- (2-aza-2- (5- (N- (1, 3-bis (3- (2- (2- (3- (3- (N- (3- (3- (N- ( 3-carboxy-2- (((2,4,6-trimethylphenyl) sulfonyl) amino) -ethyl) carbamoyl) -7- ((imidazol-2-ylamino) methyl) 4-oxohydroquinolyl) propyl) carbamoyl) propanoylamino) propoxy) -ethoxy) ethoxy) propyl) carbamoyl) (2-pyridyl)) amino) vinyl) benzenesulfonic; 25 «H HN J." O ß-cyclodextrin ? \ 1 N or n = 114, bird 2- (((4- (3- (N- (3- (2- (2- (3- (2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (carboxymethyl)} cyclododecyl acetylamino) -6-aminohexanoyl amino) propoxy) ethoxy) ethoxy) -propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) -carbonylamino) propanoic acid; acid conjugate 2- (((4- (3- (N- (3- (2- (2- (3 - (2 (1, 4, 7, 10 -tetraaza-4, 7, 10 -tris (carboxymethyl) ) -cyclododecylacetylamino) -6- (2 (bis- (phosphomethyl) amino) -acetylamino) hexanoylamino) propoxy) -ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) • l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic acid; 2- (((4- (3- (N- (3- (2- (2- (3- (2- (2- ((2- ((2- (bis (carboxymethyl) -amino) ethyl)) (carboxymethyl) amino) ethyl) - (carboxymethyl) amino) acetylamino) -3-sulfopropyl) propoxy) ethoxy) -ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethyl-phenyl) -sulfonyl) -amino) -3 - (( 7- ((imidazol-2-ylamino) methyl) -1-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic acid; fifteen or a pharmaceutically acceptable salt form thereof. [7] In a further preferred embodiment, the present invention provides a kit comprising a compound of claim 2, or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier. [8] In a further preferred embodiment, the kit further comprises one or more auxiliary ligands and a reducing agent. [9] In a further preferred embodiment, the auxiliary ligands are tricine and TPPTS.
[10] In another additional preferred embodiment, the reducing agent is tin (II).
[11] In a second embodiment, the present invention provides a novel diagnostic or therapeutic, metapharmaceutical composition, comprising: a metal, a chelator, capable of chelating the metal and a target-choosing portion, wherein the target-choosing portion it binds to the chelator, and is a non-peptidic quinolone and binds to a receptor that is activated during angiogenesis and the compound has 0-1 linkers between the target-choosing portion and the chelator.
[12] In a preferred embodiment, wherein the metapharmaceutical substance is a diagnostic radiopharmaceutical, the metal is a radioisotope selected from the group: 99mTc, 95Tc, L? An, 62Cu, 64Cu, 67Ga, and s8Ga, and the Binding group is present between the portion that chooses the non-peptidic target and the chelator.
[13] In another preferred embodiment, the targeting targeting portion is a non-peptidic quinolone and the receptor is vß3 or avß5.
[14] In another preferred embodiment, the radioisotope is 99mTc or 95Tc, the radiopharmaceutical further comprises a first auxiliary ligand and a second auxiliary ligand capable of stabilizing the radiopharmaceutical.
[15] In another preferred embodiment, the radioisotope is nTc.
[16] In another preferred embodiment, the radiopharmaceutical is selected from the group: 99mTc ((2 - (((4- (4- (((3 - (2- (2 - ((6- (diazenido (3-pyridyl)) carbonylamino) -ropoxy) -toxy) -ethoxy) propylamino) sulfonyl) phenyl) phenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -1-methyl-4 -oxo (3-hydroquinolyl)) carbonylamino) -propanoic acid (tricine) (TPPTS); 99raTc ((2- (((4- (3- (N- (3- (2- (2- (3- ( (6- (diazenido) (3-pyridyl)) carbonylamino) propoxy) ethoxy) -ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) -amino) -3 - ((7- ((imidazole -2-amino) methyl) -1-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic) (tricine) (TPPDS); 99mTc (3 - ((1 - (3 - ((6 - ( diazenido) (3-pyridyl)) carbonylamino) propyl) -7- ((imidazol-2-ylamino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) ) sulfonyl) amino) propanoic) (tricine) (TPPTS); 99mTc (3 - ((1- (3 - ((6-) (diazenido) (3-pyridyl)) carbonylamino) ropil) -7 - (((1-hydroxy imidazol-2-yl) amino) methyl) -4 -oxo- (3-hydroquinolyl)) carbonylamino) -2 - (( (2, 4, 6-trimethylphenyl) sulf onyl) amino) propanoic) (tricine) (TPPTS); 99mTc (3- ((1- (3- (3- (N- (3- (2- (2- (3- ((6- (diazenido) (3-pyridyl)) carbonylamino) propoxy) ethoxy) -ethoxy ) propyl) carbamoyl) propanoylamino) ropil) -7 ((imidazol-2-ylamino) methyl) -4 -oxo (3 hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) amino propane) (tricine) (TPPTS); 99raTc (2- (2- (5- (N- (l, 3-bis (3- (2- (2- (3- (3- (N- ( 3- (3- (N- (3-carboxy-2- (((2,4,6-trimethylphenyl) sulphonyl) amino) -ethyl) carbamoyl) -7- ((imidazol-2-ylamino) methyl) 4-oxohydroquinolyl) propyl) carbamoyl) propanoylamino) propoxy) -ethoxy) -ethoxy) propyl) carbamoyl) (2-pyridyl) diazenido)) (tricine) (TPPTS); 99mTc (3 - { [1- ( 3- { 2- [(6- (diazenido) (3-pyridyl)) carbonylamino] (2R) -3-sulfopropyl) ropil) -7- [(imidazol-2-ylamino) methyl] -4-oxo ( 3-Hydroquinolyl) lcarbonylamino. (2S) -2- { [(2,4,6-trimethylphenyl) sulfonylcholine}. Propanoic) (tricine) (TPPTS).
[17] In another preferred embodiment, the radioisotope is LIn.
[18] In another preferred embodiment, the radiopharmaceutical is selected from the group:
[19] In another preferred embodiment wherein the metapharmaceutical substance is a radioafharmaceutical therapeutic substance, the metal is a radioisotope that is selected from the group: 186Re, 188Re, 153Sm, 166Ho, 177Lu, 149Pm, 90Y, 212Bi, 103Pd, 109Pd, 159Gd, 140La, 198Au, 199Au, 169Yb, 175Yb, 165Dy, 16ßDy, S7Cu, 10SRh, l?: LAg and 192Ir and the linking group is present between the target nb peptide targeting moiety and the chelator.
[20] In another preferred embodiment the targeting portion is a non-peptidic quinolone and the receptor is avß3 or
[21] In another preferred embodiment, the radioisotope is 1S3Sm.
[22] In another preferred embodiment, the radioisotope is
[23] In another preferred embodiment, the radiopharmaceutical is selected from the group:
[24] In another preferred embodiment, the radioisotope is 90 Y
[25] In another preferred embodiment, the radiopharmaceutical is selected from the group;
[26] In another preferred embodiment, wherein the metapharmaceutical substance is a contrast agent for MRI, the metal is a paramagnetic metal ion selected from the group: Gd (III), Dy (III), Fe (III) and Mn. (II), the target-choosing portion is a non-peptidic quinolone and the linking group is present between the targeting portion and the chelator.
[27] In another preferred embodiment, the target-choosing portion is a non-peptidic quinolone and the receptor is
[28] In another preferred embodiment, the metal ion is Gd (III) '
[29] In another preferred embodiment, the contrast agent is
[30] In another preferred embodiment, wherein the metapharmaceutical substance is an X-ray contrast agent, the metal is selected from the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au , Au, Yb, Dy, Cu, Rh, Ag, and Ir, the portion that chooses obj ective is a non-peptidic quinolone, the receptor is avß3 or avßs and the linking group is present between the targeting portion and the chelator.
[31] In another preferred embodiment, the present invention provides a novel method for targeting and treating rheumatoid arthritis in a patient, comprising: administering a therapeutic radiopharmaceutical of claim 19 capable of localizing a novel angiogenic vasculature in a patient , by injection or infusion.
[32] In another preferred embodiment, the present invention provides a novel method for treating cancer in a patient, comprising: administering to a patient in need thereof a therapeutic radiopharmaceutical substance of claim 19 by injection or infusion.
[33] In another preferred embodiment, the present invention provides a novel method for imaging therapeutic angiogenesis in a patient, comprising: (1) administering a diagnostic radiopharmaceutical, an MRI contrast agent, or an agent of X-ray contrast, of claim 11 to a patient, by injection or infusion; (2) forming an image of the patient's area where the desired formation of new blood vessels is located.
[34] In another preferred embodiment, the present invention provides a novel method for cancer imaging in a patient, comprising: (1) administering a diagnostic radiopharmaceutical of claim 12 to a patient by injection or infusion; (2) image the patient using flat gamma scintigraphy or SPECT, or positron emission tomography.
[35] In another preferred embodiment, the present invention provides a novel method of cancer magnet formation in a patient, comprising: (1) administering an MRI contrast agent of claim 26; and (2) forming images of the patient using magnetic resonance imaging.
[36] In another preferred embodiment, the present invention provides a novel method of cancer imaging in a patient, comprising: (1) administering an X-ray contrast agent of claim 30; and (2) image the patient using computed tomography; J_ tr
[37] In a third embodiment, the present invention provides a novel compound comprising: a target portion and a surfactant, wherein the target portion is attached to the surfactant, which is a non-peptide and binds to a receptor that is activated during angiogenesis and the compound has 0-1 linking groups between the objective portion and the surfactant.
[38] In a preferred embodiment, the targeting portion comprises a non-peptidic quinolone and the linking group is present between the targeting portion and the surfactant.
[39] In another preferred embodiment, the receptor is the avß3 or avßs integrin and the compound is of the formula: (Q) d-Lnsf wherein Q is a compound of the formula (II) (II) which includes stereoisomeric forms thereof, or mixtures of the stereoisomeric forms thereof, or pharmaceutically acceptable salt forms or precursor thereof, wherein: Rle is selected from: - Ae is -CH2- O -N (R10e) -; 20 Ale and Be are independently -CH 2 - or -N (R 10 β) -; De is -N (R10e) - or -S-, - Ee-Fe is -C (R2e) = C (R3e) -O-C (R2e) 2C (R3e) 2-; Jß is -C (R2e) - or -N-; Ke, Le and Me are independently -C (R2e) - or -C (R3e) -; R 2 β and R 3 β are independently selected from: H, alkoxy of 1 to 4 carbon atoms, NRlleR12e, halogen, N02, CN, CF3, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (from 3 to 7 carbon atoms) alkyl of 1 to 4 carbon atoms, aryl (alkyl of 1 to 6 carbon atoms) carbonyl-, (alkyl of 1 to 6 carbon atoms) carbon) carboni 1 or, (alkoxide 1 to 6 to atoms of carbon) carbonyl, arylcarbonyl and aryl substituted with 0-4 of R7e, alternatively, when R2e and R3e are substituents on adjacent atoms, can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic ring system or 5-7 membered aromatic or heterocyclic ring system aromatic, the carbocyclic or heterocyclic ring is substituted with 0-2 groups selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, cyano, amino, CF3 and N02; R2ae is selected from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms), aryl, aryl (C 1 -C 4 alkyl) -, (C 2 -C 7 alkyl) carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy) carbonyl, cycloalkoxy (C 3 -C 10) at 7 carbon atoms) carbonyl or, bicycloalkoxy (from 7 to 11 carbon atoms) carbonyl, aryloxycarbonyl, aryl (alkoxy of 1 to 10 carbon atoms) carbonyl, alkyl (from 1 to 6 carbon atoms) carboni 1 ox i (a 1 c ox i of 1 to 4 carbon atoms) carbonyl, arylcarbonyloxy (alkoxy of 1 to 4 carbon atoms) carbonyl, and cycloalkyl (of 3 to 7 carbon atoms) ca rb on i 1 oxy (C 1 -C 4 alkoxy) carbonyl; R7e is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 4 carbon atoms) carbon) carbonyl, C02R18ae, S02Rlle, S02NR10eRlle, OR10e and N (Rlle) R12e; U * is selected from: - (CH2) ne-, - (CH2) neO (CH2) me-, - (CH2) neN (R12) (CH2) me-, -NH (CH2) ne-, - (CH2) neC (= 0) (CH2) me-, - (CH2) neS (O) pe (CH2) me-, - (CHa) neNHNH (CH2) me-, -N (R10e) C (= 0) -, - NHC (= 0) (CH2) ne-, -C (= 0) N (R10e) -, and -N (R10e) S (0) p-; Gß is N or CR19e; . We is -C (= 0) -NR (R10e) - (alkylene of 1 to 3 carbon atoms) -, in which the alkylene group is substituted by R8e and by R9e: R8e and R9e are independently selected from: H, C02R18be, C (= 0) R18be, CONR17R18be, alkyl of 1 to 10 carbon atoms substituted with 0-1 of R6e, alkenyl of 2 to 10 carbon atoms substituted with 0-1 of RSe, alkynyl of 2 to 10 carbon atoms carbon substituted with 0-1 of R6e, cycloalkyl of 3 to 8 carbon atoms substituted with 0-1 of R6e, cycloalkenyl of 5 to 6 carbon atoms substituted with 0-1 of R6e, (alkyl of 1 to 10 carbon atoms carbonyl, cycloalkyl (3 to 10 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, phenyl substituted with 0-3 of RSß, naphthyl substituted with 0-3 of R6e, a heterocyclic ring of 5-10 members containing 1-3 heteroatoms of N, 0 or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 of R7e, alkoxy of 1 to 10 carbon atoms substituted with 0-2 of R7β, hydroxy, Nitro, -N (R10e) Rlle, -N (R16e) R17e, aryl (C 0 -C 6 alkyl) carbonyl, aryl (C 3 -C 6 alkyl), heteroaryl (C 1 -C 6 alkyl) carbon), CONR18aeR0e, S02R18ae, and S02NR18aeR20e, with the proviso that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 of R7e; R6 is selected from: H, alkyl of 1 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, nitro, alkylcarbonyl of 1 to 10 carbon atoms, -N (Rlle) R12e, cyano, halo, CF3, CHO, C02R18be, C (= 0) R18b, CONR17eR18be, OC (= O) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= O) R10e, NR10eC (= 0) OR21e, NR10eC (= 0) NR10eRlle, NR10eS02NR10eNRlle, NR10eS02R21e, S (0) pRlle, S02NR10ßRllβ, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) meMe, and -NMe2, aryl (alkyl of 1 to 4 carbon atoms) -, the aryl is substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3 , S (0) peMe, and -NMe2 and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, 0 or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 of R7e; R10e is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, aryl, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl (alkyl of 1 to 4 carbon atoms) and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R6β; Rllß is selected from: H, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, alkoxy of 1 to 6 carbon atoms carbon, benzyloxy, aryl, heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R4β; R4e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 10 carbon atoms) carbonyl, aryl, heteroaryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0-2 substituents which are independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02, alternatively, when R10e and Rlle are both substituents on the same nitrogen atom (as in -NR10eRlle) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1, 2, 3, 4-tetrahydro- l-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, ti azolidinyl and 1-piperazinyl; the heterocycle is substituted with 0-3 groups which are selected from: alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 6 carbon atoms) carbonyl, (C3-C7-cycloalkyl) carbonyl, C1-C6-alkoxy) carbonyl, aryl (C1-C4 alkoxy) carbonyl, alkylsulfonyl of 1 to 6 carbon atoms and aryisulfonyl; R12e is selected from: H, alkyl of 1 to 6 carbon atoms, trif enylmethyl, methoxymethyl, methoxyifenylmethylmethyl, trimethylsilylethyloxymethyl, (C 1 -C 6 alkyl) carbonyl, (C 1 -C 6 alkoxy) carbonyl 1 or, (C 1-6 alkyl) aminocarbonyl, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4) carbon atoms) -aryl, heteroaryl (alkyl of 1 to 6 carbon atoms) carbonyl heteroarylcarbonyl, aryl (alkyl of 1 to 6 carbon atoms) - (alkyl of 1 to 6 carbon atoms) carbonyl, arylcarbonyl alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl aryl (C 1-6 alkyl) sulphonyl or heteroarylsulfonyl, heteroaryl (C 1-6 alkyl) sulfonyl, aryloxycarbonyl and aryl (C 1-6 alkoxy) carbonyl, wherein such aryl groups are substituted with 0-2 substitutes These are selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, CF3 and nitro; R16e is selected from: -C (= 0) OR18ae, -C (= 0) R18be, -C (= 0) N (R18be) 2, -C (= 0) NHS02R18ae, -C (= 0) NHC (= 0) R18be, -C (= 0) NHC (= 0) 0R18ae, -C (= 0) NHS02NHR18be, -S02R18ae, -S02N (R18be) 2 and -S02NHC (= 0) 0R18be; R17e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms), (alkyl of 1 to 4 carbon atoms) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms); R? ß e is selected from: alkyl of 1 to 8 carbon atoms optionally substituted with a bond to L n, cycloalkyl of 3 to 11 carbon atoms optionally substituted with a bond L n, aryl (alkyl of 1 to 6 carbon atoms) optionally substituted with a link Ln, heteroaryl (alkyl of 1 to 6 carbon atoms) -optionally substituted with a bond to L n, (alkyl of 1 to 6 carbon atoms) heteroaryl optionally substituted with a bond to L n, diaryl (alkyl) from 1 to 6 carbon atoms) optionally substituted with a bond to L n, heteroaryl optionally substituted with a bond to L n, phenyl substituted with 3-4 of R 19e and optionally substituted with a bond to L n, naphthyl substituted with 0-4 of R 19e and optionally substituted with a bond to Ln, and a bond to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19e; iß e is H or R18ae; R19e is selected from: H, halogen, CF3, C02H, CN, N02, -NRlleR12e, OCF3, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl from 3 to 11 carbon atoms, cycloalkyl (3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 6 carbon atoms) -, alkoxy of 1 to 6 carbon atoms carbon, alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-O-, aryl-S02-, heteroaryl and heteroaryl-S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms; R20e is selected from: hydroxy, alkyloxy of 1 to 10 carbon atoms, cycloalkyloxy of 3 to 11 carbon atoms, aryloxy, aryl (alkyl of 1 to 4 carbon atoms) oxy, alkyl (of 2 to carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 atoms) carbon) carbonyl (1 to 2 carbon atoms) oxy-, cycloalkyl (3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy, cycloalkoxy (3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyl (alkyl of 1 to 2 carbon atoms) oxy -, aryloxycarbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, arylcarbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 1 to 5 carbon atoms) (alkyl of 1 to 5 carbon atoms) carbonyloxy (1 to 2 carbon atoms) oxy, (5- (C 1-5 alkyl) -1,3-dioxa-cyclopenten-2-one-yl) methyloxy, (5-aryl-1, 3-dioxa-cyclopenten-2-one-yl) methyl oxy, and (R10e) (Rlle) N- (alkoxy of 1 to 10 carbon atoms) -; R21e is selected from: alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl, aryl (alkyl of 1 to 6 carbon atoms) to 4 carbon atoms) -, and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R7e; R22e is selected from: -C (= 0) -R18be, -C (= 0) N (R18be) 2, -C (= 0) NHS02R18ae, C (= 0) NHC (= 0) R18 e, - (= 0) NHC (= 0) 0R18ae, and -C (= 0) NHS02NHR Ye is selected from: -COR20e, -S03H, -P03H, -CONHNHS02CF3, -CONHS02R18ae, -CONHS02NHR18be, -NHCOCF3, -NHCONHS02R18ae, -NHS02R18ae, -OP03H2, -OS03H, -P03H2, -S02NHC0R18ae, -S02NHC02R18ae, mß is 0-2 ne is 0-4, p * is 0-2, re is 0-2, with the following condition: ne and me are chosen so that the number of atoms that connect Rle and Ye is in the range of 8-14; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Ln is a linking group having the formula: ((W) h- (CR6R7) g) x- (Z) k- ((CR6aR7a) g, - (W) h.) X,; W is independently selected, each time it is presented, from the group: O, S, NH, NHC (= 0), C (= 0) NH, NR8C (= 0), C (= 0) NR8, C (= 0) ), C (= 0) 0, OC (= 0), NHC (= S) NH, NHC (= 0) NH, S02, S 02NH / (O CH2 CH2) 20 _200, (CH2 CH2 O) 20_200, ( O CH2 CH2 CH2) 20.200, (CH2CH2CH20) 20_200, and (aa) t.; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, cycloalkyl of 3 to 10 carbon atoms substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which is independently selected from N, S and 0 and substituted with 0-3 of R10; Rs, R6a, R7, R7a and R8 are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, P03H, alkyl of 1 to 5 carbon atoms substituted with 0-3 of R10, aryl substituted with 0-3 of R10, benzyl substituted with 0-3 of R10 and alkoxy of 1 to 5 carbon atoms substituted with 0-3 of R10, NHC (= 0) R11, C (= 0) NHR11, NHC (= 0) NHR11, NHR11, R11 and a binding to Sf; R10 is independently selected, each time it is presented, from the group: a bond to Sf, COOR11, C (= 0) NHR11, NHC (= 0) RX1, OH, NHR11, S03H, P03H, ~ -OP03H2, -OS03H, aryl substituted with 0-3 of R11, alkyl of 1 to 5 carbon atoms substituted with 0-1 of R12, alkoxy of 1 to 5 carbon atoms substituted with 0-1 of R12 and a heterocyclic ring system of 5-10 members containing 1-4 heteroatoms that are independently selected from N, S, and O and substituted with 0-3 of R "; R11 is independently selected each time it is presented, from the group: H, alkyl substituted with 0-1 of R12, axyl substituted with 0-1 of R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S, and O, and substituted with 0-1 of R12, cycloalkyl of 3 to 10 carbon atoms substituted with 0-1 of R12, polyalkylene glycol substituted with 0-1 of R12, carbohydrate substituted with 0-1 of R12, cyclodextrin substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, polycarboxyalkyl substituted with 0-1 of R12, polyaza alkyl substituted with 0-1 of R12, peptide substituted with 0-1 of R12, wherein the peptide is consisting of 2 to 10 amino acids, 3,6-O-disulfo-BD-galactopyranosyl, bis (phosphonomethyl) glycine and a bond to Sf; R12 is a link to Sf; k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; h 'is selected from 0, 1, and 2; g is selected from 0, 1, -2, 3, 4, 5, 6, 7, 8, 9 and ; g 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and ; t 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and ; x is selected from 0, 1, 2, 3, 4 and 5; it is selected from 0, 1, 2, 3, 4 and 5; Sf is a surfactant which is a lipid or a compound of the formula: i- A E "/ A9 A9 is selected from the group: OH and OR27; A10 is OR27; R 27 is C (= 0) alkyl of 1 to 20 carbon atoms; E1 is alkylene of 1 to 10 carbon atoms substituted with 1-3 of R28; R28 is independently selected, each time it is presented, from the group: R30, -P03H-R3 °, = 0, -C02R29, -C (= 0) R29, -C (= 0) N (R29) 2, -CH20R29 , -OR29, -N (R29) 2, alkyl of 1 to 5 carbon atoms and alkenyl of 2 to 4 carbon atoms; R29 is independently selected, each time it is presented, from the group: R30, H, alkyl of 1 to 6 carbon atoms, phenyl, benzyl and trifluoromethyl; R30 is a link to Ln; and a pharmaceutically acceptable salt thereof. [40] In another preferred embodiment, the compound is of the formula: wherein Q is a compound of the formula (IV) (IV) which includes stereoisomeric forms thereof, or mixtures of the stereoisomeric forms thereof, or a pharmaceutically acceptable salt or precursor forms thereof, wherein: Rle is selected from: R2e and Re are independently selected from: H, alkoxy of 1 to 4 carbon atoms, NRlleR12e, halogen, N02, CN, CF3, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 at 7 carbon atoms, cycloalkyl (3 to 7 carbon atoms) -alkyl of 1 to 4 carbon atoms, aryl (alkyl of 1 to 6 carbon atoms) -, (alkyl of 1 to 6 carbon atoms) carbonyl , (C 1-6 alkoxy) carbonyl, arylcarbonyl and aryl substituted with 0-4 of R 7e, alternatively, when R 2e and R 3e are substituents on adjacent atoms, can be taken together with the carbon atoms which are attached to forming a 5 to 7 membered carbocyclic ring or 5 to 7 membered heterocyclic aromatic or non-aromatic ring system, the carbocyclic or heterocyclic ring is substituted with 0-2 groups which are selected from alkyl of 1 to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, halo, cyano, amino, CF3 and N02; R2ae is selected from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) -alkyl of 1 to 4 carbon atoms, aryl, aryl (C 1-4 alkyl) -, (C 2 -C 7 alkyl) carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy) carbonyl, cycloalkoxy carbonyl 3 7 carbon atoms, bicycloalkoxy carbonyl of 7 to 11 carbon atoms, aryloxy carbonyl, aryl (alkoxy of 1 to 10 carbon atoms) carbonyl, alkyl (of 1 to 6 carbon atoms) carbonyloxy (alkoxy of 1 to 4 carbon atoms) carbon) carbonyl, arylcarbonyloxy (C 1 -C 4 alkoxy) carbonyl and cycloalkyl (3 to 7 carbon atoms) carbonyloxy (C 1 -C 4 -alkoxy) carbonyl; R7e is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 4 carbon atoms) carbon), carbonyl, C02R18ae, S02Rlle, SO2NR10eRlle, OR10e and N (Rlle) R12e; Ue is selected from: - (CH2) ne-, (CH,) neO (CH2) me NH (CH2) ne-, -N (R10e) C (= O) -, -NHC (= 0) (CH2) ne - and -C (= 0) N (R10e) -; Ge is N or CR19e; R8e is selected from: H, C02R18be, C (= 0) R18be, CONR17be, alkyl of 1 to 10 carbon atoms substituted with 0-1 of RSe, alkenyl of 2 to 10 carbon atoms substituted with 0-1 of R6e, alkynyl of 2 to 10 carbon atoms substituted with 0-1 of R6e, cycloalkyl of 3 to 8 carbon atoms substituted with 0-1 of R6e, cycloalkenyl of 5 to 6 carbon atoms substituted with 0-1 of R6e, (alkyl) from 1 to 10 carbon atoms) carbonyl, cycloalkyl (3 to 10 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, phenyl substituted with 0-3 of R6e, naphthyl substituted with 0-3 of R6e, a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, O or S, wherein the heterocyclic ring may be partially saturated or fully unsaturated saturator, the heterocyclic ring is substituted with 0-2 of R7e; R9e is selected from: alkyl of 1 to 10 carbon atoms substituted with 0-1 of R6e, alkoxy of 1 to 10 carbon atoms substituted with 0-2 of R7e, H, nitro, N (Rlle) R12e, OC (= O) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= 0) R10e, NR10eC (= 0) 0R21e, NR10eC (= 0) NR10eRlle, NR10eSO2NR10eRlle, NR10eSO2R21e, hydroxy, OR2 -N (R 1100e \) pRlle -N (R 1X6e \ - RD l7e aryl (C 0 -C 6 alkyl) carbonyl, aryl (C 1 -C 6 alkyl) heteroaryl (alkyl) 1 to 6 carbon atoms), CONR18aeR20e, S02R18ae and SO2NR18aeR20e, with the proviso that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 of R7e; R6e is selected from: H, alkyl of 1 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, nitro, alkylcarbonyl of 1 to 10 carbon atoms, -N (Rlle) R12e, cyano, halo, CF3, CHO, C02R18be, C (= 0) R18be, CONR17eR18be, OC (= O) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= O) R10e, NR10eC (= O) OR21e, NR10eC (= 0) NR10eRlle, NR10eSO2NR10eRlle, NR10eSO2R1e, S (0) peRlle, SO2NR10eRlle, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) meMe and -NMe2, aryl (alkyl of 1 to 4 carbon atoms) -, the aryl is substituted with 0-3 groups which are selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) peMe and -NMe2, and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, O or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the ring heterocyclic is substituted with 0-2 R7e; R10e is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, aryl, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl (alkyl of 1 to 4 carbon atoms) carbon) and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R6e; Rlle is selected from: H, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl of 3 to 11 carbon atoms) methyl, alkoxy of 1 to 6 carbon atoms, benzyloxy, aryl, heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl and alkyl of 1 to 10 carbon atoms substituted with 0 -2 of R4e; R4e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, heteroaryl , aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0-2 substituents which are independently selected from the group consists of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02, R12e is selected from: H, alkyl of 1 to 6 carbon atoms, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl, (C 1-6 alkyl), carbonyl, (C 1-6 alkoxy), carbonyl, (C 1-6 alkyl) aminocarbonyl, alkenyl of 3 to 6 carbon atoms , cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 atoms) carbon) -, aryl, heteroaryl (C 1-6 alkyl), carbonyl, heteroarylcarbonyl, aryl (C 1-6 alkyl) -, (C 1-6 alkyl), carbonyl, arylcarbonyl , alkylsulfonyl of 1 to 6 carbon atoms, aryisulfonyl, aryl (C 1-6 alkyl) sulfonyl, heteroarylsulfonyl, heteroaryl (C 1-6 alkyl) sulfonyl, aryloxycarbonyl and aryl (C 1-6 alkoxy) carbon) carbonyl, wherein the aryl groups are substituted with 0-2 substituents which are selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, CF3 and nitro; R16e is selected from: -C (= 0) OR18ae, -C (= 0) R18be, -C (= 0) N (R18be) 2 '• S02R18ae, and S02N (R18 e) R17e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -; R18 e is selected from: alkyl of 1 to 8 carbon atoms optionally substituted with a bond to Ln, cycloalkyl of 3 to 11 carbon atoms optionally substituted with a bond to Ln, aryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to L n, heteroaryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to L n, (alkyl of 1 to 6 carbon atoms) heteroaryl optionally substituted with a bond to L n, biaryl ( alkyl of 1 to 6 carbon atoms) optionally substituted with a bond to L n, heteroaryl optionally substituted with a bond to L p, phenyl substituted with a 3-4 of R 19e and optionally substituted with a bond to L n, naphthyl substituted with 0-4 of R19e and optionally substituted with a bond to Ln, and a bond to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19e; R18be e s H 0 Rlßaß. R19e is selected from: H, halogen, CF3, C02H, CN, N02, -NRlleR12e, 0CF3? alkyl of 1 to 8 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1) to 4 carbon atoms) -, aryl (alkyl of 1 to 6 carbon atoms) -, (alkoxy of 1 to 6 carbon atoms), alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-O-, aryl- S02-, heteroaryl and heteroaryl-S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups which are selected from hydrogen, halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms. carbon; R20e is selected from: hydroxy, alkyloxy of 1 to 10 carbon atoms, cycloalkyloxy of 3 to 11 carbon atoms, aryloxy, aryl (alkyl of 1 to 4 carbon atoms) oxy, alkyl (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyl ( alkyl of 1 to 2 carbon atoms) oxy-, cycloalkyl (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyloxy ( alkyl of 1 to 2 carbon atoms) oxy-, arylcarbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 1 to 5 carbon atoms) (alkyl of 1 to 5 carbon atoms) no) carbonyloxy (1 to 2 carbon atoms) oxy, (5- (C 1-5 alkyl) -1,3-dioxa-cyclopenten-2-one-yl) methyloxy, (5-aryl) 1, 3-dioxa-cyclopenten-2-one-yl) methyloxy, and (R10e) (Rlle) N- (alkoxy of 1 to 10 carbon atoms); R21e is selected from: alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl, aryl ( 1 to 4 carbon atoms) -, and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R7e; R22e is selected from: -C (= 0) -R18be, -C (= 0) N (R18be) 2 / -C (= 0) NHS02R18ae, -C (= 0) NHC (= 0) R18be, -C ( = 0) NHC (= 0) OR18ae and -C (= 0) NHS02NHR18be; it is 0-2; pe is 0-4; and pe is 0-2; with the following condition: ne and me are chosen so that the number of atoms that connect to R1 and -COR20e in the formula (IV) is in the range of 8-14; it is independently selected, each time it is presented, from the group; 0, S, NH, NHC (= 0), C (= 0) NH, NR8C (= 0), -C (= 0) NR8, C (= 0), C (= 0) 0, 0C (= 0), NHC (= S) NH, NHC (= 0) NH, S02, S02NH, (0CH2CH2) 20-2oo '(CH2CH02) 20_200, (OCH2CH2CH2) 20.200, (CH2CH2CH2O) 20.200 and (aa) t ,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-1 of R10, cycloalkyl of 3 to 10 carbon atoms substituted with 0-1 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are selected independently of N, S and O, and substituted with 0-1 of R10; R6, R6a, R7, R7a and R8 are independently selected, each time they occur from the group: H, = 0, COOH, S03H, alkyl of 1 to 5 carbon atoms substituted with 0-1 of R10, aryl substituted with 0 -1 of R10, benzyl substituted with 0-1 of R10 and alkoxy of 1 to 5 carbon atoms substituted with 0-1 of R10, NHC (= 0) R1: 1, C (= 0) NHR11, NHC (= 0 ) NHR11, NHR11, R11 and a bond to S £; k is 0 or 1; Sf is a surfactant which is a lipid or a compound of the formula: A9 is OR27; A10 is OR27; R27 is C (= 0) alkyl of 1 to 15 carbon atoms; E1 is alkylene of 1 to 4 carbon atoms substituted with 1-3 of R28; R28 is independently selected, each time it is presented, from the group: R30, -P03H-R30, = 0, -C02R29, -C (= 0) R29, -CH20R29, -OR29 and alkyl of 1 to 5 carbon atoms; R29 is independently selected, each time it is presented, from the group: R30, H, alkyl of 1 to 6 carbon atoms, phenyl and benzyl; R30 is a link to Ln; and a pharmaceutically acceptable salt thereof. [41] In another more preferred embodiment, the present invention provides a novel ultrasound contrast agent composition, comprising: (a) a compound of claim 39, comprising: a quinolone that binds to the avß3 integrin, a surfactant and a linking group between the quinolone and the surfactant; (b) a parenterally acceptable carrier; and (c) an ecogenic gas. [42] In another more preferred embodiment, the present invention provides a novel composition of contrast agent for ultrasound, which further comprises: 1,2-dipalmitoyl-sn-glycero-3-phosphidodic acid, 1,2-dipalmitoyl-sn- glycero-3-phosphatidylcholine and N- (methoxypolyethylene glycol 5000 carbamoyl) -1, 2-dipamitoyl-sn-glycero-3-phosphatidylethanolamine. [43] In another more preferred embodiment, the echogenic gas is a perfluorocarbon of 2 to 5 carbon atoms. [44] In another preferred embodiment, the present invention provides a method for cancer imaging in a patient, comprising: (1) administering, by injection or infusion, a composition of ultrasound contrast agents of claim 41 to a patient, and (2) patient image formation using sonography. [45] In another preferred embodiment, the present invention provides a method of imaging new blood vessels, in a patient, comprising: (1) administering, by injection or infusion, a composition of contrast agent for ultrasound of claim 41 to a patient; (2) forming an image of the patient's area where the desired formation of the new blood vessels is located. [46] In another preferred embodiment, the present invention provides a method for forming a therapeutic image of angiogenesis in a patient, comprising: (1) administering by injection or infusion, an ultrasound contrast agent composition of claim 41 to a patient; (2) forming an image of the patient's area where the desired formation of new blood vessels is located. [47] In another preferred embodiment, the present invention provides a method for forming an image of atherosclerosis in a patient, comprising: (1) administering by injection or infusion an ultrasound contrast agent composition of claim 41 to a patient; (2) form an image of the patient's area where the atherosclerosis is located. [48] In another preferred embodiment, the present invention provides a method for restenosis imaging in a patient, comprising: (1) administering, by injection or infusion, an ultrasound contrast agent composition of claim 41 to a patient; (2) image the area of the patient where the restenosis is located.
[49] In another preferred embodiment, the present invention provides a method for imaging cardiac ischemia in a patient, comprising: (1) administering, by injection or infusion, an ultrasound contrast agent composition of claim 41 to a patient; (2) image the area of the myocardium where the ischemic region is located. [50] In another preferred embodiment, the present invention provides a method for imaging reperfusion damage to the myocardium in a patient, comprising: (1) administering, by injection or infusion, a composition of contrast agent for ultrasound of the claim 41 to a patient; (2) image the area of the myocardium where the reperfusion damage is located. [51] In another preferred embodiment, the present invention provides a novel therapeutic radiopharmaceutical composition, comprising: (a) a therapeutic radiopharmaceutical of claim 19; and (b) a parenterally acceptable carrier. [52] In another preferred embodiment, the present invention provides a novel diagnostic pharmaceutical composition, comprising: (a) a diagnostic radiopharmaceutical, an MRI contrast agent or an X-ray contrast agent of claim 11; and (b) a parenterally acceptable carrier. [53] In another preferred embodiment, the present invention provides a method of treating restenosis in a patient, comprising: (1) administering to a patient, either systemically or locally, a therapeutic radiopharmaceutical of claim 19 capable of localizing in the • restenotic area and provide an effective dose of radiation. [54] In another preferred embodiment, the present invention provides a method for imaging atherosclerosis in a patient, comprising: (1) administering a diagnostic radiopharmaceutical, a contrast agent for MRI or an X-ray contrast agent, of claim 11, to a patient by injection or infusion; (2) form an image of the patient's area where the atherosclerosis is located. [55] In another preferred embodiment, the present invention provides a method for restenosis imaging in a patient, comprising: (1) administering a diagnostic radiopharmaceutical, an MRI contrast agent, or a lightning contrast agent X of claim 11 to a patient by injection or infusion; (2) forming an image of the patient's area where the restenosis is located. [56] In another preferred embodiment, the present invention provides a method for imaging cardiac ischemia in a patient, comprising: (1) administering a diagnostic radiopharmaceutical, a contrast agent for MRI, or a contrast agent for lightning X of claim 11 to a patient by injection or infusion; (2) image the area of the myocardium where the ischemic region is located. [57] In another preferred embodiment, the present invention provides a method for imaging reperfusion damage of the myocardium in a patient, comprising: (1) administering a diagnostic radiopharmaceutical, a contrast agent for MRI or an agent for X-ray contrast, of claim 11, to a patient, by injection or infusion; (2) image the area of the myocardium where the reperfusion damage is located. Another aspect of the present invention is diagnostic equipment for the preparation of radiopharmaceuticals useful as agents for imaging cancer. The diagnostic kits of the present invention comprise one or more bottles containing the non-pyrogenic and sterile formulation constituted of a predetermined amount of a reagent of the present invention and optionally other components such as one or two auxiliary ligands, reducing agents, ligands of transfer, buffers, lyophilization aids, stabilization aids, solubilization and bacteriostatic aids. The inclusion of one or more optional components in the formulation will often improve the ease of synthesis of the radiopharmaceutical by the practicing end user, the ease of manufacturing the equipment, the shelf life of the equipment or the stability and shelf life of the equipment. the radiopharmaceutical substance. The inclusion of one or two auxiliary ligands is required for diagnostic kits comprising a reagent containing a hydrazine or hydrazone binding moiety. One or more bottles containing all or part of the formulation can be found independently in the form of a sterile solution or a lyophilized solid. Another aspect of the present invention contemplates a method for cancer imaging in a patient, which involves: (1) synthesizing a radiopharmaceutical of the diagnosis of the present invention, using a reagent of the present invention, capable of localizing in tumors; (2) administering the radiopharmaceutical to a patient by injection or infusion; (3) image the patient using flat scintigraphy or gamma SPECT, or positron emission tomography. Another aspect of the present invention contemplates a method for imaging cancer in a patient, which involves: (1) administering a paramagnetic metallo-pharmaceutical substance of the present invention capable of localization in tumors to a patient by injection or infusion; (2) forming the patient's image using magnetic resonance imaging. Another aspect of the present invention contemplates a method for cancer imaging in a patient, which involves: (1) administering to a patient by injection or infusion an X-ray contrast agent of the present invention capable of localization in tumors; and (2) forming the patient image using X-ray computed tomography. Another aspect of the present invention contemplates a method for cancer imaging in a patient, which involves: (1) administering to a patient by injection or infusion a contrast agent for ultrasound of the present invention capable of localization in tumors; and (2) patient image formation using sonography. Another aspect of the present invention contemplates a method for treating cancer in a patient, which involves: (1) administering to a patient by injection or infusion a therapeutic radiopharmaceutical of the present invention capable of localization in tumors.
DEFINITIONS The compounds described herein may have asymmetric centers. Unless indicated otherwise, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C = N double bonds and the like may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that the compounds of the present invention contain asymmetrically substituted carbon atoms and that they can be isolated in optically active or racemic form. It is well known in the art how to prepare optically active forms, for example by resolution or separation of racemic forms or by synthesis from optically active starting materials. It is known that two distinct isomers (cis and trans) of the peptide bond are present; both may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. The D and L isomers of a particular amino acid are designated herein using the conventional 3-letter abbreviation of the amino acids, as indicated by the following examples: D-Leu, or L-Leu. When any variable occurs more than once in any substituent or in any formula, its definition, whenever it is presented, is independent of the definition in another place where it is presented. Thus, for example, if it is shown that a group is substituted with 0-2 of R52, such a group can optionally be substituted with up to 2 of R52, and R52, each time it is presented, is independently selected from the defined list of R52. possible. In addition, by way of example for the group -N (R53) 2, each of the two substituents R53 in N is independently selected from the defined list of possible R53s. Combinations of substituents or variables are permissible only if such combinations result in stable compounds. When it is shown that a bond for a substituent crosses the bond connecting two atoms in a ring, then this substituent can be attached to any atom in the ring. The term "non-peptidic" preferably means less than three amide bonds in a core of the backbone of the target portion, or preferably less than three amino acids or amino acid mimetics in the target portion.
The term "metapharmaceuticals" means a pharmaceutical substance comprising a metal. Metal is the cause of the image forming signal in diagnostic applications and the source of cytotoxic radiation in radiotherapeutic applications. Radiopharmaceuticals are metalworking substances in which the metal is a radioisotope. By "reactants" is meant a compound of this invention capable of directing the transformation into a metapharmaceutical substance of this invention. The reagents can be used directly for the preparation of the metapharmaceutical substances of this invention or can be a component in an equipment of this invention. The term "binding agent" means a metapharmaceutical substance of this invention that has affinity and that is capable of binding to the vitronectin receptor. The binding agents of this invention have a Ki < lOOOnM. By the terms "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a mixture of ration, and its formulation in an agent effective pharmacist The term "substituted", as used herein, means that one or more hydrogens in the designated atom or group are substituted with a selection of the indicated group, with the proviso that the normal valency of the atoms or of the designated groups is not exceeded and that the substitution results in a stable compound. When a substituent is keto (ie, = 0), then the 2 hydrogens on the atom are substituted. The term "link" as used herein means a single or double bond. The term "salt" as used herein, is used as defined in the CRC Handbook of Chemistry and Physics, 65th Edition, CRC Press, Boca Raton, Fia, 1984, as any substance which generates ions, in addition to the hydrogen or hydroxyl ions. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed modified compounds to make acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and similar. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions or dosage forms which, within the scope of reasonable medical judgment, are suitable for use in contact with the tissues of humans and animals without toxicity, irritation, allergic response or other excessive problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the described compounds wherein the The parent compound is modified by making the acid or base salts thereof Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids and the like Pharmaceutically acceptable salts include non-toxic salts conventional or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic 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 salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric , toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acid portion, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of two; generally non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference. As used herein, the term "alkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to methyl, ethyl , n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl; the terms "cycloalkyl" or "carbocycle" are intended to include saturated and partially unsaturated ring groups including mono-, bi- or polycyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl; the terms "bicycloalkyl" or "bicyclic" are intended to include saturated bicyclic ring groups such as [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane (decalin), [2.2.2] bicyclooctane and so on . As used herein, the term "alkene" or "alkenyl" is intended to include hydrocarbon chains having the specified number of carbon atoms of straight or branched configuration and one or more unsaturated carbon-carbon bonds which may be present at any stable point along the chain, such as ethenyl, propenyl and the like. As used herein, the term "alkyne" or "alkynyl" is intended to include hydrocarbon chains having a specified number of carbon atoms of either linear or branched configuration and one or more triple unsaturated carbon-carbon bonds. which can occur at any stable point along the chain, such as propargyl and the like. As used herein, the terms "aryl" or "aromatic residue" is meant to mean phenyl or naphthyl, which, when substituted, may be substituted at any position. As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable monocyclic or bicyclic ring of 5-7 membered or 7 to 10 membered bicyclic heterocyclic which is saturated, partially unsaturated or unsaturated ( aromatic) and which consists of carbon atoms and 1 to 4 heteroatoms which are independently selected from the group consisting of N, O and S and which includes any bicyclic group in which any of the heterocyclic rings defined in the above merge to a benzene ring. The nitrogen and sulfur heteroatoms can optionally be oxidized. The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein can be substituted at the carbon or nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle optionally can form a quaternary salt. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heterocycle is not greater than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic ring. or 7 to 10 membered bicyclic heterocyclic, which consists of carbon atoms and 1 to 4 heteroatoms which are independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not greater than 1. Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, -piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1, 2, 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl-, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aJi-c arbazolyl, • -carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5, 2 -dithiazinyl, dihydrofuro [2, 3 - £ >;] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isogininnyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl. , Oxazolyl, oxazolidinilperimidinilo, phenanthridinyl, phenanthrolinyl, fenarsazinilo, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, piridoxazol , pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1, 2,5-thiadiazinyl, 1,2 3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1, 2, 3 -triazolyl, 1, 2,4-triazolyl, 1,2,5-triazolyl, 1, 3, 4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl or isatinoyl. Also included are fused ring compounds and spiro containing, for example, the above heterocycles. As used herein, "the term" alkaryl "means an aryl group having an alkyl group of 1 to 10 carbon atoms, the term" aralkyl "means an alkyl group of 1 to 10 carbon atoms having a group aryl, the term "arylalkaryl" means an aryl group having an alkyl group of 1 to 10 carbon atoms having an aryl group, and the term "heterocycloalkyl" means an alkyl group of 1 to 10 carbon atoms having a heterocycle A "polyalkylene glycol" is a polyethylene glycol, p-polypropylene glycol or polybutylene glycol having a molecular weight of less than about 5000, which ends in either a hydroxy or alkylether moiety A "carbohydrate" is a polyhydroxyaldehyde, ketone, alcohol or acid, or derivatives thereof, which includes polymers thereof, which have acetal type polymeric linkages A "cyclodextrin" is a cyclic oligosaccharide Examples of cyclodextrins include, but are not mimic a-cyclodextrin, hydroxyethyl-cyclodextrin, hydroxypropyl-cyclodextrin, beta-cyclodextrin, hydroxypropyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2,6 di-O-methyl-β-cyclodextrin, sulfated β-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl -? - cyclodextrin, hydroxyethyl -? - Cyclodextrin and? -sulfated cyclodextrin.
As used herein, the term "polycarboxyalkyl" means an alkyl group having between 2 and about 100 carbon atoms and a plurality of carboxyl substituent; and the term "polyazaalkyl" means a linear or branched alkyl group having from 2 to about 100 carbon atoms, interrupted or substituted with a plurality of amine groups. A "reducing agent" is a compound that reacts with a radionuclide, which is typically obtained as a high-oxidation state compound, relatively unreactive, to decrease its oxidation state by transferring electrons to the radionuclide, thereby making it more reagent. Reducing agents useful in the preparation of radiopharmaceuticals and in diagnostic equipment useful for the preparation of such radiopharmaceuticals include, but are not limited to stannous chloride, stannous fluoride, formamidine sulfinic acid, ascorbic acid, cysteine, phosphines and cuprous salts or ferrous Other reducing agents are described in Brodack et. al., PCT Application 94/22496, which is incorporated herein by reference. A "transfer ligand" is a ligand that forms an intermediate complex with a metal ion that is stable enough to avoid unwanted side reactions but labile enough to convert to a meta-phar- maceutical substance. The formation of the intermediate complex is kinetically favored, while the formation of the metapharmaceutical substance is favored thermodynamically. Transfer ligands useful in the preparation of metapharmaceutical substances and in diagnostic equipment for the preparation of diagnostic radiopharmaceuticals, include but are not limited to gluconate, glucoheptonate, mannitol, glucarate, N, N, N ', N' - acid. ethylenediaminetetraacetic, pyrophosphate and methylene diphosphonate. In general, the transfer ligands are composed of oxygen or nitrogen donor atoms. -The term "donor atom" refers to the atom attached directly to a metal by a chemical bond. The "auxiliary" and "ligand" ligands are ligands that are incorporated into a radiopharmaceutical during its synthesis. They serve to complete the coordination sphere of the radionuclide together with the chelator or the radionuclide binding unit of the reactive. For radiopharmaceuticals comprised of a binary ligand system, the coordination sphere of the radionuclide consists of one or more chelators or linking units of one or more reagents or one or more auxiliary substances or associates, provided there is a total of two types of ligands, chelators or union units. For example, a radiopharmaceutical consisting of a chelator or a binding unit of a reagent or two of the same auxiliaries or associates and a radiopharmaceutical consisting of two chelators or binding units from one or two reagents and an auxiliary or binding agent both are considered to be constituted of binary ligand systems. For radiopharmaceuticals comprised of a ternary ligand system, the coordination sphere of the radionuclide is composed of one or more chelators or units of attachment of one or more reagents and one or more of two different types of auxiliaries or associates, with the proviso that there is a total of three types of ligands, chelators or union units. For example, it is considered that a radiopharmaceutical comprised of a chelator or a binding unit of a reagent and two different auxiliaries or associates is constituted by a ternary ligand system. The auxiliaries or associates useful in the preparation of radiopharmaceuticals and in the diagnostic equipment useful for the preparation of radiopharmaceuticals are constituted by one or more atoms of oxygen, nitrogen, carbon, sulfur, phosphorus., arsenic, selenium and tellurium. A ligand can be a transfer ligand in the synthesis of a radiopharmaceutical and also serve as an adjuvant or as a co-ligand in another radiopharmaceutical. The fact that a ligand is referred to as transfer or auxiy or binding depends on whether the ligand remains in the coordination sphere of the radionuclide in the radiopharmaceutical, which is determined by the coordination chemistry of the radionuclide and the chelator and unit of binding of the reagent or reagents. A "chelator" or "binding unit" is the portion of a group in a reagent that binds to a metal ion through the formation of chemical bonds with one or more donor atoms. The term "binding site" means the site in vivo or in vitro that binds to a biologically active molecule. A "diagnostic equipment" or "equipment" comprises a collection of components, called the formulation, in one or more flasks that are used by the practicing end user in a clinical or pharmacy facility to synthesize diagnostic radiopharmaceuticals. The equipment provides all the necessary components to synthesize and use the diagnostic radiopharmaceutical except those that are commonly available to the practicing end user, such as water or saline by injection, a solution of the radionuclide, equipment for heating the equipment during the synthesis of the radiopharmaceutical, if so required, and the equipment necessary to administer the radiopharmaceutical to the patient, such as syringes and protections, as well as imaging equipment. The therapeutic radiopharmaceuticals, the X-ray contrast agent radiopharmaceuticals, the ultrasound contrast agent pharmaceutical substances and the metal-pharmaceutical substances for magnetic resonance imaging contrast contrast are provided to the final user in their final form in a formulation typically contained in a bottle, either as a lyophilized solid or as an aqueous solution. The end user reconstitutes the lyophilized material with water or saline and withdraws the dose from the patient or only withdraws the dose from the aqueous solution formulation, as provided. A "lyophilization aid" is a component that has favorable physical properties for lyophilization, such as vitreous transition temperature, and is added to the formulation to improve the physical properties of the combination of all components of the lyophilization formulation. A "stabilization aid" is a component that is added to the metapharmaceutical substance or diagnostic equipment either to stabilize the metal-pharmaceutical substance or to prolong the shelf life of the equipment before it is used. Stabilization aids can be antioxidants, reducing agents or radical scavengers and can provide improved stability by reacting preferentially with species that degrade other components of the meta-phar maceutical. A "solubilization aid" is a component that improves the solubility of one or more other components in the medium required for the formulation. A "bacteriostatic" is a component that inhibits the growth of bacteria in a formulation either during storage before use or after the diagnostic equipment is used to synthesize a radiopharmaceutical. The following abbreviations are used herein: Acm acetamidomethyl b-Ala, beta-Ala or bAla 3-aminopropionic acid ATA 2-aminothiazole-5-acetic acid or 2-aminothiazole-5-acetyl group Boc t-butyloxycarbonyl CBZ, Cbz or Z Carbobenzyloxy Cit citrulline Dap 2, 3-diaminopropionic acid DCC dicyclohexylcarbodiimide DIEA diisopropylethylamine DMAP 4 -dimethylaminopyridine EOE ethoxyethyl HBTU 2- (lH-benzotriazol-1-yl) - 1 hexafluorophosphate, 1, 3, 3-tetramethyluronium hynic group boc-hydrazinonicotinil or acid 2 - [[[5 - [carbonyl] - 2-pir idini 1] hi dr az ono] me ti 1] - benzenesulfonic NMeArg or MeArga-N-methyl arginine NMeAsp aN-methyl aspartic acid NMM N-methylmorpholine OcHex O-cyclohexyl OBzl O-benzyl oSu O-succinimidyl TBTU 2- (lH-benzothiazol-1-yl) -1, 1,3,3-tetramethyluronium THF tetrahydrofuranyl THP tetrafluoroborate Tetrahydropyranyl Tosyl Tos Trityl The following three letter abbreviations for amino acids are used herein; in this one, conventional one-letter abbreviations for amino acids are NOT used: Ala alanina Arg arginina Asn aspargina Asp aspartic acid Cys cysteine Gln glutamine Glu glutamic acid Gly glycine His histidine lie isoleucine Leu leucine Lys lysine Met methionine Nle norleucine Orn ornithine Phe phenylalanine Phg phenylglycine Pro proline Sar sarcosine Serine Thr threonine Trp tryptophan Tyr tyrosine Val valine As used herein, the term "bubbles", as used herein, refers to vesicles which are generally characterized by the presence of one or more membranes or walls surrounding an internal void that is filled with a gas or a precursor thereof. Exemplary bubbles include, for example, liposomes, micelles and the like. As used herein, the term "lipid" refers to a synthetic or naturally occurring amphipathic compound which comprises a hydrophilic component and a hydrophobic component. The lipids include, for example, fatty acids, neutral fats, phosphatides, glycolipids, aliphatic alcohols and waxes, terpenes and steroids. As used herein, the "lipid composition" refers to a composition which comprises a lipid compound. Exemplary lipid compositions include suspensions, emulsions and vesicle compositions.
As used herein, the term "lipid formulation" refers to a composition which comprises a lipid compound and a bioactive agent. As used herein, the term "vesicle" refers to a spherical entity which is characterized by the presence of an internal void. Preferred vesicles are formulated from lipids, including the various lipids described herein. In any given vesicle, the lipids may be in the form of a monolayer or bilayer, and the lipids in the mono- or bilayer may be used to form one or more mono- or bilayers. In the case of more than one mono- or two-layer, the mono- or bilayers are generally concentric. Lipid vesicles described herein include such entities commonly referred to as liposomes, micelles, bubbles, microbubbles, microspheres, and the like. Therefore, the lipids can be used to form a unilamellar vesicle (comprised of a monolayer or bilayer), an oligolamellar vesicle (comprised of from about 2 to about 3 monolayers or bilayers) or a multilamellar vesicle (comprised of more than about 3 monolayers or bilayers). The internal void of the vesicles can be filled with a lipid including, for example, an aqueous liquid, a gas, a gaseous precursor or a solid or a solute material, including, for example, a bioactive agent, as desired . As used herein, the term "vesicular composition" refers to a composition which is formulated from lipids and which comprises vesicles. As used herein, the term "vesicular formulation" refers to a composition which comprises vesicles and a bioactive agent. As used herein, the term "liposomes" refers to a generally spherical group or aggregate of amphiphmatic compounds that include lipid compounds, typically in the form of one or more concentric layers, e.g., bilayers. It can also refer to lipid vesicles in the present. Angiogenesis is the process of forming new capillary blood vessels from the existing vasculature. It is an important component of various physiological processes that include ovulation, embryonic development, wound repair and collateral vascular generation in the myocardium. It is also central to many pathological conditions such as tumor growth and metastasis, diabetic retinopathy and macular degeneration. The process begins with the activation of existing vascular endothelial cells in response to various cytokines and growth factors. Activated endothelial cells secrete enzymes that degrade the basement membrane of the vessels. The endothelial cells then proliferate and migrate into the extracellular matrix, forming first tubules and then new blood vessels. Under normal conditions, the proliferation of endothelial cells is a very slow process, but it increases during a short period of time, during embryogenesis, ovulation and wound healing. This temporary increase in cell turnover is governed by a combination of numerous growth stimulating factors and growth suppression factors. In pathological angiogenesis, this normal equilibrium is disrupted resulting in a continuous increased endothelial cell proliferation. Some of the proangiogenic factors that have been identified include basic fibroblast growth factor (bFGF), angiogenin, TGF-alpha, TGF-beta and vascular endothelial growth factor (VEGF), while interferon-alpha, interferon- beta and thrombospondin are examples of angiogenesis suppressors. Angiogenic factors interact with endothelial cell surface receptors such as the EGFR, FGFR, PDGFR, Flk-1 / KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin and Axi receptor tyrosine kinases. The Flk-l / KDR, neuropilin-1 and Flt-1 receptors recognize VEGF and these interactions play key roles in 15'3 VEGF-induced angiogenesis. The Tie subfamily of tyrosine kinase receptors is also prominently expressed during the formation of blood vessels. The proliferation and migration of endothelial cells in the extracellular matrix is mediated by the interaction with various cell adhesion molecules. Integrins are a diverse family of heterodimeric cell surface receptors by which endothelial cells bind to the extracellular matrix, to each other and to other cells. The angiogenesis induced by bFGF or TNF-alpha depends on the integrin agency avb3, whereas the angiogenesis induced by VEFG depends on the integrin avb5 (Cheresh et al., Science, 1995, 270, 1500-2). The induction of expression of the integrins albl and a2bl on the surface of endothelial cells is another important mechanism by which angiogenesis is promoted by VEGF (Senger, et al., Proc. Nati, Acad. Sci USA, 1997, 94, 13612-7). The pharmaceutical substances of the present invention are comprised of an objective, non-peptide targeting portion for the vitronectin receptor that is expressed or active in angiogenic tumor vasculature. The ultrasound contrast agents of the present invention comprise various targeting portions of vitronectin receptor attached to or incorporated in a microbubble of a biocompatible gas, a liquid carrier and a surfactant microsphere, and further comprising an optional linker portion, Ln , between the target-choosing portions and the microbubble In this context, the term "liquid carrier" means a solution and the term "surfactant" means an amphiphilic material which produces a reduction in interfacial tension in a solution. In EP0727225A2 a list of suitable surfactants for forming microspheres of surfactant is described, which is incorporated by reference. The term surfactant microsphere includes nanospheres, liposomes, vesicles and the like. The biocompatible gas can be air, or a fluorocarbon such as perfluoroalkane of 3 to 5 carbon atoms, which provides the difference in echogenicity and therefore the contrast in ultrasound imaging. The gas is encapsulated or contained in the microsphere to which the biodirector group is attached, optionally a linking group. The union can be covalent, ionic or by van der Waals forces. Specific examples of such contrast agents include per-fluorocarbons encapsulated with lipids, with a plurality of peptides, polypeptides or peptidomimetics. <which join the tumor nevusculatory receptor. The X-ray contrast agents of the present invention are comprised of one or more targeting portions of vitronectin receptor bound to one or more "X-ray absorbing" or "heavy" atoms, of atomic number 20 or greater, which further comprise an optional binding moiety, Lp, between the target-choosing moieties and the X-ray absorbing atoms. The heavy atom frequently used in X-ray contrast agents is iodine. Recently, contrast agents for X-rays consisting of metal chelates have been described (Wallac, R., US Pat. No. 5,417,959) and polychelates composed of a plurality of metal ions (Love, D., US Pat. No. 5,679,810) more recently, complexes of multinuclear groups have been described as contrast agents for X-rays (U.S. Patent 5,804,161, PCT WO 91/14460 and PCT WO 92/17215). The MRI contrast agents of the present invention are comprised of one or more target-choosing portions of vitronectin receptor linked to one or more paramagnetic metal ions and further comprising an optional linker moiety, Ln, between the target-choosing portions and the paramagnetic metal ions. Paramagnetic metal ions are present in the form of metal complexes or metal oxide particles. US 5,412,148 and 5,760,191 describe examples of chelators for paramagnetic metal ions for use in contrast agents by MRI. US 5,801,228, US 5,567,411 and United States 5,281,704, describe examples of polychelants useful for forming complexes of more than one paramagnetic metal ion, for use in MRI contrast agents. US 5,520,904 discloses particulate compositions comprised of paramagnetic metal ions, for use as contrast agents for MRI. The pharmaceutical substances of the present invention have the formulas (Q) d-L n- (Ch-X), (Q) d-L n- (Ch-X 1) d,, (Q) d-L n- (X 2) dy ( Q) d-Ln- (X3), wherein Q represents a non-peptide that binds to a receptor expressed in angiogenic tumor vasculature, d is 1-10, Ln represents an optional linking group, Ch represents a metal chelator or a portion X represents a radioisotope, X1 represents a paramagnetic metal ion, X2 represents a paramagnetic metal ion or a heavy atom containing a solid and insoluble particle, d '' is- 1-100 and X3 represents a microsphere of surfactant of a gas ecogenic The interaction of the non-peptide recognition sequences of the vitronectin receptor binding portion of the pharmaceutical substances with the avß3 receptor results in the localization of the pharmaceutical substances in the angiogenic tumor vasculature, which expresses the avß3 receptor. The pharmaceutical substances of the present invention can be synthesized in various ways. One form involves the synthesis of the non-peptide portion that chooses the target, Q, and the direct binding of one or more of the portions, Q, to one or more metal chelators or binding portions, Ch, or to a paramagnetic metal ion or atom heavy that contains a solid particle, or a microbubble of ecogenic gas. Another approach involves the joining of one or more portions, Q, to the linking group, Ln, which is then attached to one or more metal chelators or binding portions Ch or a paramagnetic metal ion or a heavy atom containing a solid particle, or a microbubble of ecogenic gas. Another approach involves the synthesis of a non-peptide, Q, which presents a fragment of the linking group, Ln, one or more of which are then joined to the rest of the linking group and after one or more metal chelators or binding portions, Ch , or to a paramagnetic metal ion or heavy atom that contains a solid particle, or to a microbubble of ecogenic gas. Non-peptide vitronectin binding portions, Q, optionally have a linking group, L n or a fragment of the linking group, which can be synthesized using standard or conventional synthetic methods, known to those skilled in the art. Preferred methods include, but are not limited to, the methods described in the following. The binding of the linking groups, Ln to the non-peptides, Q; chelators or binding units, Ch, to the non-peptides, Q, or to the linking groups, Ln; and the non-peptides that present a fragment of the linking group to the rest of the linking group, in combination with the formation of the portion, (Q) d_Ln, and then to the portion Ch; everything can be done by standard techniques. These include, but are not limited to amidation, esterification, alkylation and the formation of ureas or thioureas. The procedures for carrying out these linkages can be found in Brinkley, M., Bioconjugate Chemistry 1992, 3 (1),. which is incorporated herein by reference. Many methods can be used to join the non-peptides, Q, to a paramagnetic metal ion or a heavy atom containing solid particles, X2, by a person skilled in the art of surface modification of solid particles. In general, the portion that chooses target Q or the combination (Q) dLn is attached to a coupling group that reacts with a constituent of the surface of the solid particle. The coupling groups may be any of numerous silanes which react with hydroxyl groups on the surface, on the surface of the solid particle, as described in copending US Patent Application Serial No. 09 / 356,178 and also they may include polyphosphonates, polycarboxylates, polyphosphates or mixtures thereof which are coupled to the surface of the solid particles, as described in U.S. 5,520,904. Many reaction schemes can be used to join the non-peptides, Q, to the surfactant microsphere, X3. These are illustrated in the following reaction schemes wherein Sf represents a portion of surfactant that forms the surfactant microsphere.
Acylation reaction: Sf-C (= 0) -Y + Q-NH2 or > Sf-C (= 0) -NH-Q Q-OH or Sf-C (= 0) -0-Q And it's an outgoing group or an active one Disulfide coupling: Sf-SH + Q-SH > Sf-S-S-Q Sulfonamide coupling: Sf-S (= 0) 2-Y + Q-NH 2 > Sf-S (= 0) 2-NH-Q Reductive ammunition: Sf-CHO + Q-NH2 > Sf -NH-Q In these reaction schemes, the substituents Sf and Q can also be inverted. The linking group Ln can serve several purposes. First, it provides a separation group between the metallic chelator or the binding portion, Ch, the paramagnetic metal ion or the solid particle containing the heavy atom, X2, and the surfactant microsphere, X3, and one or more of the non-peptides, Q, so as to minimize the possibility that the Ch-X, C-X1, X2 and X3 portions interfere with the interaction of Q recognition sequences with angiogenic tumor vasculature receptors. The need to incorporate a linking group into a reagent depends on the identity of Q, Ch-X, Ch-X1, X2 and X3. If Ch-X, Ch-X1, X2 and X3 can not be bound to Q without substantially decreasing affinity for the receptors, then a linking group is used. A linking group also provides a means to independently bind non-multiple peptides, Q, to a group that binds Ch-X, Ch-X1, X2 or X3. The linking group also provides a means for incorporating a pharmacokinetic modifier into the pharmaceutical substances of the present invention. The pharmacokinetic modifier serves to direct the biodistribution of the injected pharmaceutical substance in addition to the interaction with the target portions, Q, with the vitronectin receptors that are expressed in the tumor neovasculature. A wide variety of functional groups can serve as pharmacokinetic modifiers and include, but are not limited to carbohydrates, polyanylene glycols, peptides or other polyamino acids and cyclodextrins. The modifiers can be used to improve or decrease the hydrophilicity or to improve or decrease the rate of clearance in blood. Modifiers can also be used to direct the route of elimination of pharmaceutical substances. Preferred pharmacokinetic modifiers are those that result in moderate to rapid clearance in blood and improved renal excretion. The metal chelator or the binding portion, Ch, is selected to form stable complexes with the metal ion chosen for the particular application. Chelators or binding portions for diagnostic radiopharmaceuticals are selected to form stable complexes with radioisotopes having gamma-ray emissions or positrons that can image, such as 99mTc, 95Tc, 111In, S2Cu, 60Cu, 64Cu, e7Ga, 68Ga 86Y. The chemists for technetium, copper and gallium isotopes are selected for diaminodithiols, monoamine-monoamidethiols, triamide-monothiols, monoamide-diamide-monothiols, diaminadioximes and hydrazines. Chelators are generally tetradentate with donor atoms that are selected from nitrogen, oxygen and sulfur. Preferred reagents are made up of chelators having amine nitrogen or sulfur thiol donor atoms and hydrazine binding units. The thiol sulfur atoms and the hydrazines may have a protecting group which can be displaced either before using the reagent to synthesize a radiopharmaceutical substance or preferably in situ during the synthesis of the radiopharmaceutical. Exemplary thiol protecting groups include those included in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991), whose description is incorporated herein by reference. Any thiol protecting group known in the art can be used. Examples of thiol protecting groups include, but are not limited to the following: acetamidomethyl, benzamidomethyl, 1-ethoxyethyl, benzoyl and triphenylmethyl. Exemplary protecting groups for hydrazine binding units are hydrazones which may be aldehyde or ketone hydrazones having substituents that are selected from hydrogen, alkyl, aryl and heterocycle. Particularly preferred hydrazones are described in U.S.S.N. co-pending 08 / 476,296, the disclosure of which is hereby incorporated by reference in its entirety.
The hydrazine binding unit, when attached to a metal radionuclide is called a hydrazide, or a diazenide group and serves as the point of attachment of the radionuclide to the rest of the radiopharmaceutical. A diazenide group can be terminal (only one atom in the group binds to the radionuclide) or chelate. In order to have a diazenide chelating group, at least one additional atom of the group must also be attached to the radionuclide. The atoms attached to the metal are called donor atoms. Chelators for 11: LIn and for 86Y are selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, D03A, 2 -benzyl-DOTA, alpha- (2-phenethyl) 1,4,7, 10-tetraazazcyclododecane-1- acetic-4, 7,10-tris (methylacetic), 2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid, 2 -benzyl-6-methyl-DPTA and 6,6"-bis [N, N, N", N " -tetra (carboxymethyl) aminomethyl) -4 '- (3-amino-4-methoxyphenyl) -2,2': 6 ', 2"-t-erpyridine. Methods for synthesizing these chelators that are not commercially available can be found in Brechbiel, M. and Gansow, O., J. Chem. Soc. Perkin Trans. 1992, 1, 1175; Brechbiel, M. and Gansow, 0., Bioconjugate Chem. 1991, 2, 187; Deshpande, S., et. al., J. Nucí. Med. 1990, 31, 473; Kruper, J., U.S. Patent 5,064,956 and Toner, J., U.S. Patent 4,859,777, the disclosure of which is incorporated herein by reference in its entirety.
The coordination sphere of the metal ion includes all ligands or groups attached to the metal. For a transition metal radionuclide to be stable, it typically has a coordination number (number of donor atoms, consisting of an integer greater than or equal to 4 and less than or equal to 8, that is, there are 4 to 8 atoms attached to the metal and said to have a complete coordination sphere The coordination number required for a stable radionuclide complex is determined by the identity of the radionuclide, its oxidation state and the type of donor atoms. The binding sphere does not provide all the atoms necessary to stabilize the metallic radionuclide by completing its coordination sphere, the coordination sphere is completed by donor atoms of other ligands, called auxiliaries or cooligandos, which can also be terminal or chelating agents. of ligands can serve as auxiliaries or co-ligands, whose choice is determined by various considerations such as The ease of synthesis of the radiopharmaceutical, the chemical and physical properties of the auxiliary ligand, the rate of formation, yield and the number of isomeric forms of the resulting radiopharmaceuticals, the ability to administer such an adjuvant or to bind the patient without adverse physiological consequences to the patient, and the compatibility of the ligand in a formulation of lyophilized equipment. The loading and lipophilicity of the auxiliary ligand will affect the charge and lipophilicity of the radiopharmaceuticals. For example, the use of 4,5-dihydroxy-1,3-benzene disulfonate results in radiopharmaceuticals with two additional anionic groups because the sulfonate groups will be anionic under physiological conditions. The use of N-alkyl substituted 3,4-hydroxypyridinones results in radiopharmaceuticals with varying degrees of lipophilicity which depends on the size of the alkyl substituents. The preferred technetium radiopharmaceuticals of the present invention are composed of a hydrazide or diazenide linking unit and an auxiliary ligand, LI, OR a binding unit and two types of auxiliary AL1 and A ?, or a tetradentaled chelator consisting of two atoms of nitrogen and two of sulfur. The auxiliary ligands AL1 are constituted by two or more hard donor atoms such as oxygen and amine nitrogen (with sp3 hybridization). The donor atoms occupy at least two of the sites in the coordination sphere of the radionuclide metal; the auxiliary ligand AL1 serves as one of the three ligands in the ternary ligand system. Examples of auxiliary ligands AL1 include, but are not limited to, dioxygen ligands and functionalized aminocarboxylates. A large amount of such ligands are available for commercial sources. Auxiliary dioxygen ligands include ligands that coordinate with the metal ion through at least two oxygen donor atoms. Examples include but are not limited to: glucoheptonate, gluconate, 2-hydroxyisobutyrate, lactate, tartrate, mannitol, glucarate, maltol, kojic acid, 2,2-bis (hydroxymethyl) propionic acid, 4,5-dihydroxy-1-disulfonate. , 3-benzene or 1,2 or .3,4 hydroxypyridinones substituted or unsubstituted (the names for the ligands in these examples refer to either the protonated or non-protonated forms of the ligands). Functionalized aminocarboxylates include ligands that have a combination of amine nitrogen and oxygen donor atoms. Examples include, but are not limited to, iminodiacetic acid, 2,3-diaminopropionic acid, nitrilotriacetic acid, N, N'-ethylenediaminodiacetic acid, N, N, N'-ethylenediaminetriacetic acid, hydroxyethylenediaminetriacetic acid, and N, N'-ethylenediamine. -hydroxyphenylglycine. (The names for the ligands in these examples refer to the protonated or non-protonated forms of the ligands). A series of functionalized aminocarboxylates are described by Bri et. al in U.S. Patent 5,350,837, incorporated herein by reference, which result in improved rates of formation of technetium-labeled hydrazino-modified proteins. We have determined that some of these aminocarboxylates result in improved yields of the radiopharmaceuticals of the present invention. The aminocarboxylates with Au functionality of preferred auxiliary ligands that are glycine derivatives, the most preferred is tricine (tris (hydroxymethyl) methylglycine). The most preferred technetium radiopharmaceuticals of the present invention are comprised of a hydrazide or diazenide linking unit and two types of auxiliaries called AL1 or AL2, or a chelator diaminodithiol. The second type of auxiliary ligands AL2 are comprised of one or more soft donor atoms which are selected from the group: phosphine phosphorus, arsine arsenic, imine nitrogen (sp2 hybridized), sulfur (sp2 hybridized) and carbon (sp hybridized); atoms which have a p-acid character. The AL2 ligands can be monodentate, bidentate or tridentate, the dental condition is defined by the number of donor atoms in the ligand. One of the two donor atoms in a bidentate ligand and one of the three donor atoms in a tridentate ligand must be a soft donor atom. We have described in the document U.S.S.N. co-pending 08 / 415,908 and U.S.S.N. 60/013360 and 08 / 646,886, the disclosures of which are hereby incorporated by reference in their entirety, that radiopharmaceuticals comprised of one or more auxiliaries or associates AL2 are more stable in comparison with radiopharmaceuticals that are not comprised of one or more auxiliary ligands, AL2; that is, they have a minimum number of isomeric forms, whose relative relationships do not change significantly with time, and which remain substantially intact when diluted. Ligands A ^ which are comprised of phosphine or arsine donor atoms are trisubstituted phosphines, trisubstituted arsines, tetrasubstituted diphosphines and tetrasubstituted diarsines. Ligands that are comprised of nitrogenoimine are 5 or 6-membered nitrogen-containing, unsaturated or aromatic heterocycles. Ligands that consist of sulfur (with sp2 hybridization) as donor atoms are thiocarbonyls, comprised of the C = S portion. Ligands composed of carbon (with sp hybridization) as donor atoms are isonitriles, constituted of the CNR portion, where R is an organic radical. A large number of such ligands are available from commercial sources. The isonitriles can be synthesized as described in European Patent 0107734 and in U.S. Patent 4,988,827, incorporated herein by reference.
The preferred auxiliary ligands AL2 are trisubstituted phosphines and unsaturated or aromatic 5 to 6-membered heterocycles. The most preferred auxiliary AL2 ligands are trisubstituted phosphines and unsaturated 5-membered heterocycles. The auxiliary ligands AL2 may be substituted with alkyl, aryl, alkoxy, heterocycle, aralkyl, alkaryl and arylaryl groups and may or may not have functional groups consisting of heteroatoms such as oxygen, nitrogen, phosphorus or sulfur. Examples of such functional groups include, but are not limited to: hydroxyl, carboxyl, carboxamide, nitro, ether, ketone, amino, ammonium, sulfonate, sulfonamide, phosphonate and phosphonamide. The functional groups can be chosen to alter the lipophilicity and water solubility of the ligands which can affect the biological properties of the radiopharmaceuticals, for example altering the distribution in tissues, cells or fluids that are not the targets as well as the mechanism and speed of elimination of the body. Chelators or binding portions for therapeutic radiopharmaceuticals are selected to form stable complexes with radioisotopes having emissions of alpha particles, beta particles, Auger or Coster-Kronig electrons, such as 186Re, 188Re, 153Sm, 166Ho, 177Lu, 149Pm, 90Y, 212Bi, 103Pd, 109Pd, 159Gd, 10La, 198Au, 199Au, 169Yb, 175Yb, 165Dy, 166Dy, 16eDy, 67Cu, 105Rh, 113Ag and 109Ir. The chelators for the isotopes of rhenium, copper, palladium, platinum, iridium, rhodium, silver and gold are selected from diaminodithiols, monoamine-monoamidethiols, triamide-monothiols, monoamine-diamide-monothiols, diaminadioximes and hydrazines. Chelators for the isotopes of yttrium, bismuth and lanthanides are selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, D03A, 2 -benzyl-DOTA, alpha- (2-phenethyl) 1, 4, 7, 10- tetraazacyclododecane-l-acetic-4, 7, 10 -tris (methylacetic), 2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl-6-methyl-DPTA and 6, 6"-bis [N, N, N", N "-tetra (carboxymethyl) aminomethyl) -4 '- (3-amino-4-methoxyphenyl) -2, 2': 6 ', 2" -terpyridine. Chelators for contrast agents and magnetic resonance imaging agents are selected to form stable complexes with paramagnetic metal ions such as Gd (III), Dy (III), Fe (III) andMn (II), and are selected from cyclic polyaminocarboxylates. and acyclics such as DTPA, DOTA, D03A, 2 -benzyl-DOTA, alpha- (2-phenethyl) 1,4,7, 10-tetraazacyclododecane-1-acetic-4,7, 10-tris (methylacetic) acid, acid 2-benzyl-cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl-6-methyl-DPTA and 6,6T'-bis [NyN, N ", N" -tetra (carboxymethyl) aminomethyl) -4 '- (3-amino-4-) methoxyphenyl) -2,2 ': 6', 2"-terpyridine.
The technetium and rhenium radiopharmaceuticals of the present invention comprised of a hydrazide or diazenide linking unit can be easily prepared by mixing a salt of a radionuclide, a reagent of the present invention, an auxiliary ligand AL1, an auxiliary ligand A ^, and a reducing agent, in an aqueous solution at temperatures of 0 to 100 ° C. The technetium and rhenium radiopharmaceuticals of the present invention consisting of a tetradentate chelator having two nitrogen atoms and two sulfur atoms can be easily prepared by mixing a salt of a radionuclide, a reagent of the present invention and a reducing agent, in an aqueous solution at temperatures of 0 to 100 ° C. When the binding unit of the reagent of the present invention is present as a hydrazone group, then it must first be converted to a hydrazine, which may or may not be protonated, prior to the formation of the complex with the metal radionuclide. The conversion of the hydrazone group to the hydrazine can be carried out either before the reaction with the radionuclide, in which case the radionuclide and the auxiliary or ligand or ligands are combined not with the reagent but with the hydrolyzed form of the reagent that presents the chelator or the union unit, or in the presence of the radionuclide, in which case the reagent itself is combined with the radionuclide and the auxiliary or by binding or ligands. In the latter case, the pH of the reaction mixture must be neutral or acidic. Alternatively, the radiopharmaceuticals of the present invention comprised of a hydrazide or diazenide linking unit can be prepared by first mixing a salt of a radionuclide, an auxiliary ligand AL1, and a reducing agent in an aqueous solution at temperatures of 0 to 100 ° C to form an intermediate radionuclide complex with the auxiliary ligand AL1 and then add a reagent of the present invention and an auxiliary ligand and further react them at temperatures of 0 to 100 ° C. Technetium and rhenium radionuclides are preferably in the chemical form of pertechnetate or perrenate and a pharmaceutically acceptable cation. The pertechnetate salt form is preferably sodium pertechnetate such as that obtained from commercial Tc-99m generators. The amount of pertechnetate used to prepare the radiopharmaceuticals of the present invention can vary from 0.1 mCi to 1 Ci, or more preferably from 1 to 200 mCi. The amount of the reagent of the present invention used to prepare the technetium and rhenium radiopharmaceuticals of the present invention can vary from 0-01 μg to 10 mg, or more preferably from 0.5 μg to 200 μg. The amount used will be determined by the amounts of the other reagents and the identity of the radiopharmaceuticals of the present invention to be prepared. The amounts of the auxiliary ligands AL1 used can vary from 0.1 mg to 1 g, more preferably from 1 mg to 100 mg. The exact amount for a particular radiopharmaceutical is a function of the identity of the radiopharmaceuticals of the present invention to be prepared, the method used and the amounts of identities of the other reagents. A too large amount of AL1 will result in the formation of byproducts consisting of AL1-labeled technetium without a biologically active molecule or by-products consisting of biologically active molecules labeled with technetium with the auxiliary ligand AL1, but without the auxiliary ligand AL2. A too small amount of AL1 will result in other by-products such as technetium labeled biologically active molecules, with the auxiliary ligand AL2, but, but without the auxiliary ligand AL1, or reduced hydrolyzed technetium, or technetium colloid. The amounts of the auxiliary ligands AL2 used can vary from 0.001 mg to 1 g, more preferably from 0.01 mg to 10 mg. The exact amount for a particular radiopharmaceutical is a function of the identity of the radiopharmaceuticals of the present invention to be prepared, the method used and the amounts of identities of the other reagents. A too large amount of AL2 will result in the formation of byproducts made of AL2-labeled technetium without a biologically active molecule or by-products made up of biologically active molecules labeled with technetium, with the auxiliary ligand AL2, but without the auxiliary ligand AL1. If the reagent has one or more substituents that are constituted by a soft donor atom, as defined above, at least a 10-fold molar excess of the auxiliary ligand AL2 is required relative to the reagent of formula 2 to prevent the Substituent interferes with the coordination of the auxiliary ligand AL2 with the metallic radionuclide. Suitable reducing agents for the synthesis of the radiopharmaceuticals of the present invention include stannous salts, dithionite or bisulfite salts, borohydride salts and formamidinasulfinic acid, wherein the salts are in any pharmaceutically acceptable form. The preferred reducing agent is a stannous salt. The amount of a reducing agent used can vary from 0.001 mg to 10 mg, more preferably from 0.005 mg to 1 mg. The specific structure of a radiopharmaceutical of the present invention constituted by a hydrazide or diazenide linking unit will depend on the identity of the reagent of the present invention used, the identity of any auxiliary ligand AL1, the identity of any auxiliary ligand AL2, and the identity of the radionuclide. Radiopharmaceuticals consisting of a hydrazide or diazenide binding unit synthesized using the concentrations or reagents of <100 μg / ml, will consist of a hydrazido or diazenido group. Those synthesized using concentrations > 1 mg / ml will consist of two hydrazide or diazenide groups from two reagent molecules. For most applications, only a limited amount of the biologically active molecule can be injected without resulting in unwanted side effects, such as chemical toxicity, interference with a biological process or altered biodistribution of the radiopharmaceutical. Therefore, radiopharmaceuticals which require higher concentrations in the reagents constituted in part of the biologically active molecule, must be diluted or purified after the synthesis to avoid such side effects. The identities and quantities used of the auxiliary ligands AL1 and A ^ will determine the values of the variables y and z. The values of y and z can be independently an integer from 1 to 2. In combination, the values of y and z will result in a technetium coordination sphere that is made up of at least five and a maximum of seven donor atoms. For the monodentate auxiliary ligands ^, z can be an integer from 1 to 2; for bidentate or tridentate auxiliary ligands AL2, z is 1. The preferred combination for monodentate ligands is y equal to 1 or 2 and z equals 1. The preferred combination for bidentate or tridentate ligands is y equal to 1 and z equal to 1. Substances Indium, copper, gallium, silver, palladium, rhodium, gold, platinum, bismuth, yttrium and lanthanides radiopharmaceuticals of the present invention can be easily prepared by mixing a salt of a radionuclide and a reagent of the present invention in an aqueous solution of temperatures from 0 to 100 ° C. These radionuclides are typically obtained as an aqueous solution diluted in a mineral acid, such as hydrochloric, nitric or sulfuric acid. The radionuclides are combined from one to one thousand equivalents of the reagents of the present invention dissolved in aqueous solution. Typically a buffer is used to maintain the pH of the reaction mixture between 3 and 10. The gadolinium, dysprosium, iron and manganese metapharmaceutical substances of the present invention can be easily prepared by mixing a paramagnetic metal ion salt in a reagent the present invention in an aqueous solution at temperatures of 0 to 100 ° C. These paramagnetic metal ions are typically obtained as an aqueous solution diluted in a mineral acid, such as hydrochloric, nitric or sulfuric acid. The paramagnetic metal ions are combined with an amount of one to about one thousand equivalents of the reagents of the present invention dissolved in aqueous solution. Typically, a buffer is used to maintain the pH of the reaction mixture between 3 and 10. The total time of preparation will vary depending on the identity of the metal ion, the identities and amounts of the reagents and the process used for the preparation. The preparations can be complete, which results in > 80% yield of the radiopharmaceutical in 1 minute, or may require more time. If pharmaceutical substances in greater purity are needed or desired, the products can be purified by any of many techniques well known to those skilled in the art such as liquid chromatography, solid phase extraction, solvent extraction, dialysis or ultrafiltration. Buffers useful in the preparation of metapharmaceutical substances and in diagnostic equipment useful for the preparation of radiopharmaceuticals include but are not limited to phosphate, citrate, sulfosalicylate and acetate. A more complete list can be found at the United State Pharmacopeia.
Lyophilization aids useful in the preparation of diagnostic equipment useful for the preparation of radiopharmaceuticals include, but are not limited to mannitol, lactose, sorbitol, dextran, Ficoll and polyvinylpyrrolidine (PVP). Stabilization aids useful in the preparation of metapharmaceutical substances and in diagnostic equipment useful for the preparation of radiopharmaceuticals include but are not limited to ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic acid, and inositol. Solubilization aids useful in the preparation of metapharmaceutical substances and in diagnostic equipment useful for the preparation of radiopharmaceuticals include but are not limited to ethanol, glycerin, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monooleate, po 1 iso rb ates , block copolymers of poly (oxyethylene) poly (oxypropylene) poly (oxyethylene) (Pluronics) and lecithin. Preferred solubilization aids are polyethylene glycol and Pluronics. Bacteriostats useful in the preparation of metapharmaceutical substances and in diagnostic equipment useful for the preparation of radiopharmaceuticals include but are not limited to benzyl alcohol, benzalkonium chloride, chlorbutanol and methyl, propyl or butylparaben. A component in a diagnostic equipment can also have more than one function. A reducing agent can also serve as a stabilization aid, a buffer can also serve as a transfer ligand, a lyophilization aid can also serve as a transfer, auxiliary or binding and so on. Diagnostic radiopharmaceuticals are administered by intravenous injection, usually in saline, at a dose of 1 to 100 mCi per 70 kg of body weight, or preferably at a dose of 5 to 50 mCi. The image formation is carried out using known methods. The therapeutic radiopharmaceuticals are administered by intravenous injection, usually in saline, at a dose of 0.1 to 100 mCi per 70 kg of body weight, or preferably at a dose of 0.5 to 5 mCi per 70 kg of body weight. The contrast agents for magnetic resonance imaging of the present invention can be used in a manner similar to other MRI agents as described in U.S. Patent 5,155,215; U.S. Patent 5,087,440; Margerstadt et al., Magn. Reson. Med., 1986, 3, 808; Runge et al., Radiology, 1988, 166, 835; and Bousquet et al., Radiology, 1988, 166, 693. Generally, sterile aqueous solutions of the contrast agents are administered to a patient intravenously in dosages ranging from 0.01 to 1.0 mmol per kg of body weight. For use as X-ray contrast agents, the compositions of the present invention generally should have a heavy atom concentration of 1 mM to 5 M, preferably dosages of 0.1 M to 2 M, administered by intravenous injection, which typically vary from 0.5 mmoles / kg to 1.5 mmoles / kg, preferably from 0.8 mmoles / kg to 1.2 mmoles / kg. The imaging is performed using known techniques, preferably X-ray computed tomography. The ultrasound contrast agents of the present invention are administered by intravenous injection in an amount of 10 to 30 μl of the echogenic gas per kg body weight. or by infusion at a rate of approximately 3 μl / kg / min. Imaging is done using known sonography techniques. Other features of the invention will become apparent in the development of the following description of the exemplary embodiments which are provided for illustration of the invention and are not intended to be limiting thereof.
EXAMPLES Representative materials and methods that can be used to prepare the compounds of the invention are further described in the following. The l-methyl-4-oxo-7- (((1- (triphenylmethyl) imidazol-2-yl) amino) methyl) hydroquinoline-3-carboxylic acid is prepared, 7-bromo-4-oxohydroquinoline-3-ethyl carboxylate, 1- (triphenylmethyl) imidazol-2-ylamine and 3-amino-2- (((2,4,6-trimethylphenyl) sulfonyl) amino hydrochloride) methyl propanoate as described in PCT WO 98/23608. The Boc-L-cysteic acid, the N-hydroxyphenyl acid of Boc-L-cysteic acid and the latter p-nitrophenyl of p-Boc-L-cysteic acid are prepared as described in Liebigs Ann. Chem 1979, 776-783. Benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) is purchased from Novabiochem. Prepared (tert-butoxy) -N- (3-bromopropyl) formamide and 2- (2-aza-2- ((5- ((2,5-dioxopyrrolidinyl) carbonyl) (2-pyridyl)) amino) vinyl acid ) benzenesulfonic as described in PCT WO 96/40637. All other chemicals and solvents (Reactive grade) are used as supplied from the mentioned suppliers, without further purification. The t-butyloxycarbonyl (Boc) amino acids and other initial amino acids can be obtained commercially from Bachem Inc., Bachem Biosciences Inc. (Philadelphia, PA), Advanced ChemTech (Louisville, KY), Peninsula Laboratories (Belmont, CA), or Sigma (St. Louis, MO). 2- (1H-Benzotriazol-1-yl) -1, 1,3, 3-tetramethyluronium hexafluorophosphate (HBTU) and TBTU are purchased from Advanced ChemTech. The N-methylmorpholine (NMM), m-cresol, D-2-aminobutyric acid (.Abu), trimethylacetyl chloride, diisopropylethylamine (DIEA), 1,2,4-triazole, stannous chloride dihydrate, hydrochloride l- (3) -dimethylaminopropyl) -3-ethylcarbodiimide (EDC), triethylsilane (Et3SiH) and the trisodium salt of tris (3-sulfonatophenyl) phosphine (TPPTS) are purchased from Aldrich Chemical Company. The bis (3-sulfonatophenyl) phenylphosphine (TPPDS) clisodium salt is prepared by the published procedure (Kuntz, E., US Pat. No. 4,248,802). Monosodium salt of (3-sulfonatophenyl) diphenylphosphine (TPPMS) is purchased from TCI. American, Inc. Tricine is obtained from Research Organics, Inc. Technetium-99m- (99Tc04-) pertechnetate is obtained from a DuPont Pharma 99Mo generator / 99mTe Technelite. "In-111 (indichlor ^) chloride is obtained from Amersham Medi-Physics, Inc. Sm-153 chloride and Lutetium-177 chloride are obtained from the University of Missouri Research Reactor (MURR). Yttrium-90 chloride is obtained from Pacific Northwest Research Laboratories.Dimethylformamide (DMF), ethyl acetate, chloroform (CHC13), methanol (MeOH), pyridine and hydrochloric acid (HCl) are obtained from Baker. Acetonitrile, dichloromethane (DCM), acetic acid (HOAc), trifluoroacetic acid (TFA), ethyl ether, triethylamine, acetone and magnesium sulfate are commercially obtained Absolute ethanol is obtained from Quantum Chemical Corporation.
Synthesis of Boc-Glu- (OTFP) -OTFP To a solution of Boc-Glu-OH (28.9 g, 117 mmol) in 500 ml of DMF at room temperature and under nitrogen is added a solution of 2, 3, 5, 6-tetrafluorophenol (48.2 g, 290 mmol) in 50 g. ml of DMF. After stirring for 10 min, EDC (55.6 g 290 mmol) is added and the reaction mixture is stirred for approximately 96 h. The volatile fractions are removed in vacuo and the residue is triturated in 750 ml of 0.1 N HCl. 600 ml of ethyl acetate are added to this mixture, and the layers are separated. The aqueous layer is extracted with ethyl acetate (3 x -500 ml), and all the ethyl acetate fractions are combined, washed with 300 ml of water and 300 ml of brine, dried with (MgSO4), and concentrate to provide 62 g of a tan solid. The cinnamon solid is washed with acetonitrile to give the title compound (45.5 g, 73%) in purified form. ESEM: calculated for C22H17F8N06, 543.09; found, 566.0 [M + Na] +1.
Example 1 2- (((4- (4- (((3- (2- (2- (3- ((6- ((l-aza-2- (2-sulfophenyl) vinyl) amino) trifluoroacetate) (3-pyridyl)) carbonylamino) propoxy) ethoxy) ethoxy) propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl- 4-oxo (3-hydroquinolyl)) carbonylamino) propanoic 'P art A - N - (3 - (2 - (2 - (3-aminopropoxy) ethoxy) ethoxy) propyl) (phenylmethoxy) formamide A solution of 4, 7, 10-trioxa-l, 13-tridecanediamine (158 ml , 0.72 moles), TEA (16.7 ml, 0.12 moles) and 300 ml of MeOH in 1,000 ml of peroxide-free THF is placed in a 3-neck, 3-liter flask with a mechanical stirrer, a thermometer and an addition funnel with a nitrogen line. The addition funnel is charged with a solution of benzyl chloroformate (17.1 ml, 0.12 mol) in 1,000 ml of peroxide-free THF. The contents of the flask are cooled to below 5 ° C. The content of the addition funnel is added to the flask with rapid stirring for 4 h while maintaining the temperature below 5 ° C. The solution is stirred in an additional 30 min and concentrated to provide a thick syrup. This syrup is taken up in 1800 ml of saturated NaCl and 200 ml of 10% Na2C03 and extracted with ether (3 x 1, 000 ml). The combined ether extracts are washed with 500 ml of saturated NaCl, dried with MgSO 4 and concentrated to provide 36.74 g of a light yellow oil. Flash chromatography on a 7 x 29 cm silica gel column (DCM / MeOH / TEA, 20/15 / 0.5) gives the title compound as a colorless syrup (19.14 g, 45%). 1 H NMR (CDCl 3): 7.33-7.25 (m, 5H), 5.59 (s, 1H), 5.06 (s, 2H), 3.62-3.45 (m, 12H), 3.32-3.25 (m, 2H), 2.74 (t , J = 6.7 Hz, 2H), 1.75 (pente, J = 6.0 Hz, 2H), 1.67 (pente, J = 6.4 Hz, 2H), 1.33 (s, 2H); MS: m / e 355.4 [M + H]; High resolution MS: calculated for C18H31N205 [M + H]: 355.2233, found: 355.2222.
Part B - 3- ((tert-butoxy) carbonylamino) -2- (((4- (4- (((3 - (2 - (2 - (3 - ((phenylmethoxy) carbonylamino) propoxy) ethoxy) ethoxy) Methyl propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) propanoate. Biphenyl-4,4'-disulfonyl chloride (2.64 g 7.5 mmol, freshly recrystallized from CHC13) and 200 ml of DCM are placed in a flask. 3-necked 500 ml with a thermometer, an addition funnel and a nitrogen line. The addition funnel is charged with a solution of N- (3- (2- (2- (3-aminopropoxy) ethoxy) ethoxy) propyl) (phenylmethoxy) formamide (1.77 g, 5.0 mmol) and DIEA (0.87 ml, 5.0 mmoles) in 40 ml of DCM. The contents of the flask are cooled to below 5 ° C. The contents of the addition funnel are added to the flask with rapid stirring for 3 h while keeping the flask temperature below 5 ° C. The addition funnel is charged with a solution of N-ß-Boc-L-α, β, -diaminopropionic acid estermethyl hydrochloride (2.55 g, 10 mmol) and DIEA (3.8 ml, 22 mmol) in 25 ml of DCM. This solution is added to the flask with stirring at 5 ° C for 15 min, and stirred at room temperature for an additional 20 h. The reaction solution is washed consecutively with 100 ml of 0.1 N HCl and water (2 x 100 ml), dried with MgSO 4 and concentrated to give 5.79 g of a viscous oil. Column chromatography on a 5 x 21 cm silica gel column (85/15 EtOAc / hexanes, followed by 100% EtOAc) provides a colorless amorphous solid. Recrystallization from 85 ml of toluene gives the title compound as a colorless solid (2.52 g, 59%). p.f. 104.5-106.5 ° C; a H NMR (CDCl 3): 8.00-7.90 (m, 4H), 7.72-7.64 (m, 4H), 7.46-7.24 (m, 5H), 5.96-5.88 (m, 1H), 5.86-5.73 (m, 1H) , 5.41 (s, 1H), 5.16-5.00 (m, 3H), 4.15-4.02 (m, 1H), 3.68-3.39 (m, 17H), 3.34-3.22 (m, 2H), 3.13-3.03 (m, 2H), 1.80-1.62 (m, 4H), 1.39 (s, 9H); 13C NMR (CDC13): 170.2, 156.5, 156.1, 143.9, 143.0, 140.4, 139.4, 136.7, 128.4, 128.1, 128.0, 127.9, 127.9, 127.8, 127.3, 80.1, 70.6, 70.5, 70.2, 70.1, 70.0, 69.6, 66.5, 56.1, 52.9, 43.2, 42.4, 39.3, 29.4, 28.5, 28.2, MS: m / e 868.3 [M + NH4]; High resolution MS: calculated for C3gHS5N4013S2 [M + H]: 851.3207, found: 851.3226.
Part C - 3 - ((1 -me t i 1 - 4 - oxo - 7 - (((1 (triphenylmethyl) imidazol-2-yl) amino) methyl) (3-hydroquinolyl)) carbonylamino) -2- (((4- (4- (((3- (2- (2- (3 ((f-enylmethoxy)) carbonylamino ) methyl propoxy) ethoxy) ethoxy) propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) propanoate The product of part B above (748 mg, 0.88 mmol) is dissolved in 15 ml of TFA / DCM 25/75 and allowed to stand at a temperature under nitrogen for 15 min. The TFA is removed under vacuum and the resulting amber oil is taken up in 50 ml of ACN / 50/50 water and treated in portions with Bio-Rad AG-3-X4A resin, hydroxide form, to increase the pH from 2 to 6. The resin is removed by filtration and the filtrate is lyophilized to give a light yellow sticky foam. In a separate flask, 1-methyl-4-oxo-7- (((1- (trifluoryl-1)) imidazol-2-yl) amino) methyl) idroquinoline-3-carboxylic acid (432 mg, 0.80 mmol) are dissolved. , 0.33 ml of TEA and HBTU (364 mg, 0.96 mmoles) in 25 ml of anhydrous DMF. The resulting solution is stirred at room temperature under a nitrogen atmosphere for 10 min and combined with a solution of the yellow foam in 15 ml of anhydrous DMF. The DMF is removed under vacuum after 18 h to provide a viscous yellow oil. This oil is taken up in 175 ml of EtOAc, washed consecutively with 25 ml of water, 50 ml of saturated NaHCO 3 and 25 ml of saturated NaCl, dried with MgSO 4 and concentrated to give a yellow viscous oil. Purification by flash chromatography on a 7 x 25 cm silica gel column using a step gradient of CHCl3 / EtOAc / MeOH (47/47/6, 46/46/8, 60/30/10) affords the compound of the title as a light yellow solid (510 mg, 50%). p.f. 136-140C; MS: m / e 1273.4 [M + NH 4]; High resolution MS: calculated for C68H73N8013S2 [M + H]: 1273.4738, found: 1273.4730.
Part D -3- ((1-met i 1-4-oxo-7 - (((1- (triflumethyl) imidazol-2-yl) amino) methyl) (3-hydroquinolyl)) carbonylamino) -2- ( ((4- (4- (((3- (2- (2- (3 - ((phenylmethoxy) carbonylamino) propoxy) ethoxy) ethoxy) propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) propanoic The product from part C above (295 mg, 0.232 mmol) is dissolved in a mixture of 12 ml of peroxide-free THF, 1.8 ml of water and 1.2 ml of 3 N LiOH, and stirred at room temperature under a nitrogen atmosphere for 30 min. The THF is removed under vacuum and the resulting mixture is dissolved in 75 ml of CHC13 and 50 ml of water. The aqueous layer is adjusted to pH 3 with 0.5 N HCl and the layers are mixed thoroughly. The aqueous layer is extracted with additional CHC13 (2 x 25 ml). The combined extracts of CHC13 are washed with 50 ml of saturated NaCl, dried with MgSO 4 and concentrated to give the title compound as a light yellow solid (291 mg, 100%). MS: m / e 1259.3 [M + H] High resolution MS: calculated for C67H71N8013S2 [M + H]: 1259.4582, found: 1259.4610.
Part E - 2- (((4- (4- (((3- (2- (2- (3-aminopropoxy) ethoxy) ethoxy) propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino acid - ((7- ((imidazol-2-yl) methyl) -1-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic The product from part D above (279 mg, 0.222 mmol) is dissolved in 30 ml. ml of degassed TFA and treated with Et3SiH (0.424 ml, 2.66 mmol). The solution is heated to 70 ° C under a nitrogen atmosphere for 1 h and concentrated to a viscous oil. This oil is dissolved in 20 ml of water and washed with ether (2 x 20 ml). The combined ethereal washes are back-extracted with 10 ml of water. The combined aqueous extracts are diluted with an equal volume of ACN and treated with Bio-Rad AG-3-X4A resin, hydroxide form, to increase the pH from 4 to 6. The resin is removed by filtration and the filtrate is lyophilized to provide the title compound as 200 mg of a colorless solid. MS: m / e 883.4 [M + H], 442.5 [M + 2H]; High resolution MS: calculated for C40H51N8O11S2 [M + H]: 833.3118, found: 833.3118.
Part F - 2- (((4- (4- (((3- (2- (2- (3- ((6- ((l-aza-2- (2-sulfophenyl)) vinyl trifluoroacetate amino) (3-pyridyl)) carbonylamino) propoxy) ethoxy) ethoxy) propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l -methyl-4-oxo O-hydroxyquinolyl)) carbonylamino) propanoic A solution of the product from part F above (15 mg, 0.0135 mmol) 0.007 ml of TEA and 2- (2-aza-2- ((5- ( (2,5-dioxopyrrolidinyl) carbonyl) (2-pyridyl)) amino) vinyl) benzenesulfonic acid (9.0 mg, 0.0204 mmol) in 2.5 ml of anhydrous DMF is allowed to stand at room temperature under a nitrogen atmosphere for 22 h. The DMF is removed under vacuum and the glassy solid is dissolved in a 20% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using 0.1% TFA in water for 5 min followed by a gradient of 2.52% / min of ACN from 0 to 63% containing 0.1% TFA at a flow rate of 20 ml / min. The main product peak elutes at 21.2 min and is collected and lyophilized to provide the title compound as a colorless powder (3.5 mg, 20%). MS: m / e 1186.7 [M + H]; High resolution MS: calculated for CS3H60N11OlsSa [M + H]: 1186.3442, found: 1186.3410.
• TFA Example 2 Salt of 3 - ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino acid bis (trifluoroacetate) -2- (((4- (4- (((3- (2- (2- (3- (2- (1, 4, 7, 1, 0-tetraaza-4, 7, 1 -tris (carboxymethyl) cyclododecyl) acetylamino) propoxy) ethoxy) ethoxy) propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) propanoic Part A - 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxycarbonyl) methyl) cyclododecyl) acetate of phenylmethyl A solution of 1, 4, 7, 10-tetraaza-4, 7-bis (((tertbutyl) oxycarbonyl) methyl) cyclododecyl) tert-butyl acetate (0.922 g1.79 mmole), 1.8 ml of TEA and benzyl bromoacetate (0.86 ml, 5.73 mmol) in 24 ml of anhydrous DMF is stirred at room temperature under a nitrogen atmosphere for 24 h. The DMF is removed under vacuum and the resulting oil is dissolved in 300 ml of EtOAc. This solution is washed consecutively with water (2 x 50 ml) and 50 ml of saturated NaCl, dried over MgSO4 and concentrated to give the title compound as 1.26 g of an amorphous solid. MS: m / e 663.5 [M + H].
Part B - 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxycarbonyl) methyl) cyclododecyl) acetic acid The product of part A above (165 mg, 0.25 mmoles) is hydrogenated on 50 ml of 10% Pd mg in carbon in 15 ml of EtOH at 414 kPa (60 psi) for 24 h. The catalyst is removed by filtration through a filter aid and washed with EtOH. The filtrates are concentrated to provide the title compound as an amorphous solid (134 mg, 94%). MS: m / e 573.5 [M + H].
Part C - Pentakis (trifluoroacetate) salt of 3- ((7- ((imidazol-2-ylamino) methyl) -l-raethyl-4-oxo (3-hydroquinolyl)) carbonylamino) -2- (((4- (4- (((3- (2- (2- (3- (2- (1,4,7,10-tetraaza-4,7,1-tris (((tert-butyl) oxycarbonyl) methyl) cyclododecyl ) methyl acetylamino) propoxy) ethoxy) ethoxy) propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) propanoate A solution of the product of example 1, part C (68 mg, 0.534 mmol) and Et3SiH (0.051 mL, 0.32 mmol) in 5.0 mL of degassed TFA is stirred at 70 ° C under a nitrogen atmosphere for 1 h and concentrated to dryness. The resulting amber oil is dissolved in 2 ml of anhydrous DMF and treated with TEA until it becomes basic when determining the pH with paper. A solution of the product of part B above (46 mg, 0.080 mmol) in 1.0 ml of anhydrous DMF is added, followed by HBTU (24 mg, 0.064 mmol), and the solution is stirred at room temperature under a nitrogen atmosphere for 3 h. The DMF is removed under vacuum and the residue is dissolved in 50% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 2.1% / min of ACN from 0 to 63% which contains 0.1% TFA at a flow rate of 20 ml / min. The main product peak elutes at 23.8 min and is harvested and leophilized to provide the title compound as a colorless powder (16 mg, 15%). MS: m / e 1451.7 [M + H]; High resolution MS: calculated for C69H103N12O18S2 [M + H]: 1451.6954, found: 1451.698.
TFA Part D - 3- ((7- ((Imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino bis (trifluoroacetate) salt. 4- (4- (((3- (2- (2- (3- (2- (1,4,7,10-tetraaza-4,7,1-tris (carboxylmethyl) cyclododecyl) acetylamino) propoxy) ethoxy ) ethoxy) propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) propanoic The product of part C above (16 mg, 0.0102 mmole) is dissolved in a mixture of 1 ml of peroxide-free THF, 0.115 ml of water and 0.075 ml of 3 N LiOH, and stirring at room temperature under a nitrogen atmosphere for 24 h. The reaction is concentrated to provide an oily solid. This solid dissolves in 50% ACN and is purified by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 2.52% / min of ACN, from 0 to 63%, containing 0.1% TFA, at a flow rate of 20 ml / min. The main product peak eluting at 24.0 min is collected and leofilized to provide 6.0 mg of colorless powder. This solid is dissolved in 2.0 ml of degassed TFA and 0.050 ml of Et3SiH, stirred at 70 ° C under a nitrogen atmosphere for 4.5 h and concentrated to dryness. The resulting oil is dissolved in 25% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 1.5% / min of 0 to 45% ACN containing 0.1% TFA. a flow rate of 20 ml / min. The peak of the main product eluting at 19.0 min is collected and leophilized to provide the title compound as a colorless powder (2.0 mg, 17%). MS: m / e 1269.5 [M + H], 635.5 [M + 2H], 424.3 [M + 3H]; High resolution MS: calculated for C56H77N12018S2 [M + H]: 1269.4920, found: 1269.4950. 2 TFA Example 3 2- (((4- (3- (N- (3- (2- (2- (3- ((6- ((l-aza-2- (2-sulfophenyl) vinyl) amino) trifluoroacetate ) (3-pyridyl)) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-yl am i no)) me useful) - l - methyl - 4 - oxo (3 - hydroquinolyl)) carbonylamino) propanoic Part A - ethyl 4- (3,5-dimethylphenoxy) butanoate. Metallic sodium (17.12 g, 0.744 mole) is added to 350 ml of anhydrous EtOH and stirred until dissolved, 3, 5-dimethylphenol is added and the solution stir at 15 min at room temperature. Ethyl 4-bromoacetate (58.7 ml 0.41 mol) is added and the solution is stirred at room temperature under a nitrogen atmosphere for 28 h. EtOH is removed under vacuum and the oily solid is partitioned between 1 liter of water and 500 ml EtOAc. The aqueous layer is extracted with 500 ml of additional EtOAc. The combined EtOAc extracts are washed consecutively with 300 mL of saturated NaHCO 3 and 300 mL of saturated NaCl, dried with MgSO 4 and concentrated to give an amber liquid. This liquid is fractionally distilled under vacuum through a 15 cm Vigreu column. The main fraction is collected at 91-117 ° C / 6 mmHg to provide the title compound as a colorless liquid (77.77 g, 89%). X H NMR (CDC13): 6.59 (s, 1 H), 6.52 (s, 2 H), 4.16 (c, J - 7.16 Hz 2 H): 5.59 (s, 1 H), 6.52 (s, 2 H), 4.16 (c, J - 7.16 Hz, 2H), 3.98 (t, J = 6.14 Hz, 2H) -, 2.49 (t, J = 7.34 Hz, 2H), 2.28 (s, 6H), 2.11-2.07 (m, 2H), 1.26 ( t, J = 7.16 Hz, 3H); Analysis calculated for C 14 H 20 O 3: C, 71.16; H, 8.53, found: C, 71.35; H, 8.59.
Part B - 4- (3,5-dimethylphenoxy) butanoic acid The product of part A above (75.52 g, 0.320 mol) and KOH shot (38.5 g, 0.584 mol) is dissolved in 1.50 ml of absolute EtOH and heated reflux for 3 h. The solution is concentrated to a colorless solid, which is taken up in 2.0 l of water and washed with ether (2 x 750 ml). The aqueous layer is adjusted to pH 1 with 55 ml of concentrated HCl and the resulting oily precipitate is extracted into EtOAc (2 x 500 ml). The combined EtOAc extracts are washed consecutively with 300 mL of water and saturated NaCl, dried over MgSO4 and concentrated to give a 64.13 g of colorless solid. Recrystallization from 500 ml of hexanes gives the title compound as a colorless solid (59.51 g, 89%). p.f. 66-68.5 ° C; XH NMR (CDC13): 11.70 (s broad, 1H), 6.59 (s, 1H), 6.52 (s, 2H), 3.99 (t, J = 6.06 Hz, 2H), 2.57 (t, J = 7.29 Hz, 2H), 2.28 (s, 6H) ), 2.12-2.08 (m, 2H); Analysis calculated for C12H1603: C, 69. twenty-one; H, 7 74, found: C, 69. 2. 3; H, 7.40.
Part C - 4- (4- (Chlorosulfonyl) -3,5-dimethylphenoxy) butanoic acid A solution of the product of part B above (20.8 g, 0.100 mol) in 100 ml of CHC13 is cooled to 0 ° C and treated with chlorosulfonic acid (36 ml, 0.54 moles) dropwise, and with rapid stirring while maintaining the reaction temperature at 0 ° C. The resulting gelatinous mixture is stirred an additional 10 min and poured into 600 ml of an ice / water mixture. The resulting solid precipitate is collected by filtration, washed with water (3 x 75 ml) and dried under vacuum to provide 12.52 g of a colorless solid, mp .: 114-115 ° C (with decomposition); XH NMR (CDC13): 13.84 (broad s, 1H), 6.50 (s, 2H), 3.91 (t, J = 6.48 Hz, 2H), 2.48 (s, 6H), 2.32 (t, J = 7.23 Hz, 2H ), 1.89-1.84 (m, 2H), IR (KBr cm'1): 1705 (s), 1370 (s), 1175 (s); MS: m / e 305.1 [M-H].
For example, 4 - (4 - (((2 - ((tert-butoxy) carbonylamino) -1- (methoxycarbonyl) ethyl) amino) sulfonyl) 3, 5-dimethyl-enoxy) butanoic A solution of the hydrochloride of the This N-ß-Boc-La, ß, -diaminopropionic acid methyl ester (568 mg, 2.10 mmol) and DIEA (0.73 mL, 4.2 mmol) in 5 mL of DCM is cooled to 0 ° C and treated with a suspension of product of part C above (656 mg, 2.10 mmol) in 20 ml of DCM, in small portions over a period of 15 min. The reaction is stirred at room temperature under a nitrogen atmosphere for 18 h. The reaction is diluted with 100 ml of DCM and washed with water (3 x 75 ml). The organic phase is dried with MgSO 4 and concentrated to provide 698 mg of crude product, which is purified by preparative CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.96% / min from 18 to 58.5 % ACN containing 0.1% TFA at a flow rate of 80 ml / min. The main product fraction elutes at 23.8 min and is collected and adjusted to pH 3partially concentrated to remove ACN and extracted with DCM (2 x 100 ml). The DCM extracts are dried (MgSO4) and concentrated to provide the title compound as a colorless solid (297 mg, 29%). tH NMR (CDC13): d 6 61 (s, 2H), 5.66 (d, J = 7. 2 Hz, 1H), 4.90 (s, 1H), 4.03 (broad s, 2H), 3.86 (broad s, 1H), 3.59 (s, 3H), 3.49 (s broad, 2H), 2.62 (s, 6H) , 2.58-2.51 (m, 2H), 2.18-2.07 (m, 2H), 1.41 (s, 9H); MS: m / e 489.4 [M + H]; High resolution MS: calculated for C21H33N203S [M + Na]: 511.1726, found: 511.1747; Analysis calculated for C21H32N209S: C, 51.62; H, 6.61; N, 5.74, found: C, 51.47; H, 6.27; N, 5.48.
Part E-3- ((tert-butoxy) carbonylamino) -2- (((2,6-dimethyl-4 - (3 - (N - (3 - (2 - (2 - (3 - ((phenylmethoxy)) carbonylamino ) methyl propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) phenyl) sulfonyl) amino) propanoate A solution of the product from part D above (233 mg, 0.477 mmol), the product of example 1, part A (190 mg, 0.536 mmol), TEA (0.2 mL, 1.43 mmol) and HBTU (226 mg, 0.701 mmol) in 8 mL of anhydrous DMF is stirred at room temperature under a nitrogen atmosphere for 1 hour. The DMF is removed under vacuum and the oily residue is taken up in 50 ml of EtOAc and washed consecutively with 35 ml of 0.1 N HCl, 35 ml of water and 35 ml of saturated NaCl, dried with MgSO 4 and concentrated to provide the Crude product as a yellow viscous oil. Flash chromatography on a 3 x 18 cm silica gel column (EtOAc / MeOH, 95/5) gives the title compound as a colorless viscous oil (393 mg, 100%). ? NMR (CDC13): d 7.34-7.28 (m, 5H), 6.60 (s, 2H), 6.26 (broad s, 1H), 5.67 (broad s, 1H), 5.29 (s broad, 1H), 5.08 (s, 2H), 4.88 (broad s, 1H), 3.99 (t, J = 6.1 Hz, 2H), 3.88-3.84 (m, 1H), 3.62-3.40 (m, 17H), 3.37-3.26 (m, 4H), 2.62 (s, 6H), 2.32 (t, J = 7.2 Hz, 2H), 2.08 (t, J = "6.3 Hz, 2H), 1.79-1.70 (m, 4H), 1.41 (s, 9H); EM: m / e 825.5 [M + H]; High resolution MS: calculated for C39H61N4013S [M + H]: 825.3955, found: 825.3940.
Part F - 3-amino-2- (((2,6-dimethyl-4- (3- (N- (3- (2- (2- (3- ((phenylmethoxy) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) phenyl) sulfonyl) amino) propanoate The product of part E above (750 mg, 0.91 mmol) is dissolved in 25 ml of 4M HCl / dioxane and stirred at room temperature for 1 h. The solution is diluted with 500 ml of ether and the resulting gummy precipitate is triturated with fresh ether (2 x 250 ml). The gummy solid is dissolved in 100 ml of water and adjusted to pH 9 with NaHCO 3, which causes an oily precipitate to form. This precipitate was extra in DCM (2 x 75 ml). DCM extracts dry (MgSO4) and concentrate to give the title compound as a colorless oil (386 mg, 56%). EM: m / e 7.25.5 [M + H] Part G - 2- (((2,6-dimethyl-4- (3 - (N - (3 - (2- (2- (3- ((phenylmethoxy) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) phenyl) sulfonyl) amino) -3- ((1-methyl-4-oxo-7- (((1- (triphenylmethyl) imidazol-2-yl) amino) methyl) (3-hydroquinolyl)) carbonylamino) propanoate of methyl A solution of l-methyl-4-oxo-7- (((1- (triphenylmethyl) imidazol-2-yl (amino) methyl) hydroquinoline-3-carboxylic acid (274 mg, 0.51 mmol), TEA (0.22) ml, 1.52 mmole) 'and HBTU (192 mg, 0.51 mmol) in 3 ml of anhydrous DMF is stirred at room temperature for 5 min. A solution of the product from part F above (367 mg, 0.51 mmol) in 7 ml of anhydrous DMF is added, and the resulting solution is stirred at room temperature under a nitrogen atmosphere for 2 h. The DMF is removed under vacuum and the resulting oily solid is dissolved in 150 ml of EtOAc. The EtOAc solution Wash consecutively with 50 ml of water, 25 ml of saturated NaHCO 3 and 25 ml of saturated NaCl, and dry with MgSO 4, and concentrate to give a yellow solid. Purification by flash chromatography on a silica gel column using a EtOAc / MeOH step gradient (95/5, 92.5 / 7.5) gives the title compound as a light yellow solid (254 mg, 43%). MS: m / e 1247.7 [M + H], 624.6 [M + 2H].
; Part H - 2- (((2,6-dimethyl-4- (3- (N- (3- (2- (2- (3- ((phenylmethoxy) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl ) propoxy) phenyl) sulfonyl) amino) -3- ((1-methyl-4-oxo-7- (((1- (triphenylmethyl) imidazol-2-yl) amino) methyl) (3-hydroquinolyl)) carbonylamino) propanoic The product of the previous G part is dissolved (60.0 mg, 0.048 mmol) in a mixture of 2.5 ml of peroxide-free THF, 0.37 ml of water and 0.244 ml of 3 N LiOH, and stirred at room temperature under a nitrogen atmosphere for 30 min. The THF is removed under vacuum and the resulting mixture is dissolved in 25 ml of CHC13 and 20 ml of water. The aqueous layer is adjusted to pH 3 with 0.1 N HCl and the layers are mixed thoroughly. The aqueous layer is extracted with additional CHC13 (2 x 20 ml). The combined extracts of CHC13 are washed with 30 ml of saturated NaCl, dried with MgSO 4 and concentrated to give the title compound as a light yellow solid (44.0 mg, 74%). MS: m / e 1233.7 [M + H]; High resolution MS: calculated for C67H77N8013S [M + H]: 1233.5330, found: 1233.5330. - Part I - 2- (((4- (3- (N- (3- (2- (2- (3-aminopropoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((imidazol-2-ylamino) methyl) -1-methyl-4-oxo- (3-hydroquinolyl)) carbonylamino) propanoic The product of part H above (42.1 mg, 0.0341 mmol) and Et3SiH ( 0.033 ml, 0.205 mmoles) is dissolved in 3.5 ml of degassed TFA, heated at 70 ° C under a nitrogen atmosphere for 1 h and concentrated to give a viscous amber oil. This oil is dissolved in 20 ml of water and washed with ether (2 x 20 ml). The combined ethereal washes are back-extracted with 10 ml of water, the combined aqueous extracts are diluted with an equal volume of ACN and treated with Bio-Rad AG-3-X4A resin, hydroxide form to increase the pH from 4 to 6. The resin is removed by filtration and the filtrate is lyophilized to provide the title compound as 34 mg of a colorless solid. MS: m / e 857.5 [M + H], 429.4 [M + 2H].
Part J - Salt of trifluoroacetate of 2 - (((4- (3- (N- (3- (2- (2- (3- ((6- ((1-aza-2- (2-sulfophenyl)] vinyl) amino) (3-pyridyl)) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-yl) no) useful) - l - me tyl - 4 - oxo - (3 - hydroquinolyl)) carbonylamino) propanoic A solution of the product of part I, above (30 mg, 0.035 mmol), DIEA (0.018 ml, 0.105 mmol) and 2- (2-aza-2- ((5- ((2,5-dioxopyrrolidinyl) carbonyl) - (2-pyridyl)) amino) vinyl) benzenesulfonic acid (18.5 mg, 0.042 mmol) in 1.5 ml of anhydrous DMF it is allowed to stand at room temperature under a nitrogen atmosphere for 20 h. The DMF is removed under vacuum and the amber oil is dissolved in 50% ACN and purified by preparative CLAP on a Zorbac C-18 RX column (21.2 x 250 mm) using a gradient of 1.5% / min of ACN from 0 to 45. % containing 0.1% TFA at a flow rate of 20 ml / min. The main product peak eluting at 21.0 min is collected and lyophilized to provide the title compound as a colorless powder (8.9 mg, 20%). MS: m / e 1160.6 [M + H], 581.0 [M + 2H] Example 4 Salt of trifluoroacetate of 3- ((1- (3- ((6- ((1-az a - 2 - (2-sulfo f) l) vi ni l) ami) (3-pyridyl)) carbonylamino ) propyl) -7- ((imidazol-2-ylamino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic Part A - ethyl 1- (3- ((tert-butoxy) carbonylamino) propyl) -7-bromo-4-oxohydroquinoline-3-carboxylate A mixture of ethyl 7-bromo-4-oxohydroquinoline-3-carboxylate (6.28 , g, 0.0212 moles), tert-butoxy-N-3-bromopropyl formamide (30.3 g, 0.127 moles) and anhydrous K2C03 (12.5 g, 0.904 moles) in 200 ml of anhydrous DMF is stirred at 60 ° C under a nitrogen atmosphere for 4 h and then at room temperature for 72 h. The DMF is removed under vacuum and the resulting oily solid is dissolved in 500 ml of EtOAc. The EtOAc solution is washed sequentially with 500 ml of water, 500 ml of saturated NaHCO 3 and 500 ml of saturated NaCl, dried with MgSO 4 and concentrated to give a red oil. This oil is taken up in 250 ml of EtOAc and cooled, which causes a solid precipitate to form. This precipitate is collected by filtration, washed with cold EtOAc and dried to provide the title compound as a colorless solid (6.25 g, 65%). p.f. 140,142 ° C; X H NMR (CDCl 3): 8.49 (s, 1 H), 8.39 (d, J = 8.6 Hz, 1 H), 7.58 (s, 1 H), (d, J = 8.6 Hz, 1 H), 4.72 (broad s, 1 H) , 4.39 (c, J = 7.1 Hz, 2H), 4.20 (t, J = 7.6 Hz, 2H), 3.28-3.24 (m, 2H), 2.10-2.06 (m, 2H), 1.46 (s, 9H), 1.40 (t, J = Hz, 3H); MS: m / e 455.2. [M + H]; High resolution MS: calculated for C2J) H26BrN0s [M + H]: 453.1025, found: 453.1028.
-Part B - ethyl 1- (3- ((tert-butoxy) carbonylamino) propyl) -4-oxo-7-vinylhydroquinoline-3-carboxylate The product of part A above (2.98 mg, 6.60 mmol) is dissolved in 50 ml of toluene at a temperature of 0 ° C and treated with tetrakis (triphenylphosphine) palladium (0) (152 mg, 0.132 mmol). After 5 min, the mixture is treated with tributyl (vinyl) tin (1.93 ml, 6.60 mmol) and stirred for 4.5 h at 100 ° C under a nitrogen atmosphere and at 18 h at room temperature. Additional tributyl (vinyl) tin (0.386 ml) and 152 mg of tetrakis (triphenylphosphine) palladium (0) are added and the mixture is heated at 100 ° C for an additional 17 h. The toluene is removed under vacuum and the solid residue is triturated with ether to give the title compound as a light green solid (1.67 g, 63%). p.f. 133-135 ° C; ? NMR (CDC13): 8.52 (d, J = 8.4 Hz, 1H), 8.51 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 6.88-6.82 (m, 1H ), 5.97 (d, J = 17.4 Hz, 1H), 5.51 (d, J = 10.8 Hz, 1H), 4.75 (s broad, 1H), 4.42 (c, J = 7.2 Hz, 2H), 4.27 (t, J = 7.8 Hz, 2H), 3.6-3.25 (m, 2H), 2.16-2.11 (m, 2H), 1.49 (s, 9H), 1.45 (t, J = 7.2 Hz, 3H); MS: m / e 401.3 [M + H]; High resolution MS: calculated for C22H29N205 [M + H]: 401.2076, found: 401.2075.
P ar te C - 1 - (3 - ((tert -butoxy) carbonylamino) propyl) -7-formyl-4-oxohydroquinoline-3-carboxylic acid ethyl A solution of the product from Part B, above (1.50 mg, 3.75 mmol) ) in 119 ml of dioxane and 39 ml of water is treated with a solution of osmium tetroxide (19.6 mg, 0.077 mmol) in 0.600 ml of dioxane and stirred at room temperature under a nitrogen atmosphere for 5 min. Sodium periodate (2.40 g, 11.2 mmol) is added and stirred at room temperature for 2 h. The dioxane is removed under vacuum and the residue is taken up in 500 ml of DCM. The DCM solution is. wash consecutively with 500 ml of water and 500 ml of saturated NaCl, dry with MgSO 4 and concentrate to provide the title compound as an orange oil solid (1.52 g, 100%). H NMR (CDC13): 10.17 (s, 1H), 8.68 (d, J = 8.2 Hz, 1H), 8.64 (s, 1H), 8.01 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H) , 4.82 (s broad, 1H), 4.41-4.35 (m, 4H), 3.28 (s, 2H), 2.15-2.07 (m, 2H), 1.45 (s, 9H), 1.41 (t, J = 7.1 Hz, 3H); MS: m / e 403.3 [M + H]; High resolution MS: calculated for C21H27N206 [M + H]: 403.1870, found: 403.1875.
Part D-1- (3- ((tert-butoxy) carbonylamino) propyl) -4-OXO-7 - (((1 - (t-ri-f-enyl-methyl-yl) -imide-z-2-yl) -amino) -methyl) -hydroquinoline -3-ethylcarboxylate A solution of the product from part C above (544 mg, 1.35 mmol) and 1-triphenylmethyl) imidazole -2-amine (456 mg, 1.35 mmol) in 60 ml of toluene is heated to reflux under a nitrogen atmosphere with water removal for 5 h. The solution is cooled, treated with Na (OAc) 3BH (1.14 g, 5.38 mmol) and stirred at room temperature for 18 h. The mixture is diluted with 400 ml of EtOAc, washed consecutively with 500 ml of water and 500 ml of saturated NaCl, dried with MgSO 4 and concentrated to give an orange solid. This solid dissolves in 50% ACN and is purified by preparative CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.60% / min of ACN 18 to 52% containing 0.1% TFA at a rate of flow of 49 ml / min. The main product peak elutes at 30.8 min and is collected and lyophilized to provide the title compound as a light yellow solid (407 mg, 60%). EM: m / e 712. 4 [M + H]; High resolution MS: calculated for C43H46Ns05 [M + H]: 712.3499, found: 712.3485.
Part E - acid 1 - (3 - ((tert-but-oxy) carbonylamino) propyl) -4-oxo-7- (((1- (triphenylmethyl) imidazol-2-yl) amino) methyl) hydroquinoline-3- carboxylic A mixture of the product of part D above (997 mg, 1.40 mmol), 7.3 ml of water, 3.5 ml of 3 N LiOH and 50 ml of THF is stirred at room temperature under a nitrogen atmosphere for 3 h. The THF is removed under vacuum and the resulting mixture is dissolved in 500 ml of CHC13 and 100 ml of water. The aqueous layer is adjusted to pH 3 with 1.0 N HCl and the layers are mixed thoroughly. The organic layer is washed consecutively with 500 ml of water and 500 ml of saturated NaCl, dried with MgSO 4 and concentrated to provide 958 mg of the title compound as a light yellow solid, mp 153-160 ° C; 1 H NMR (CDCl 3): d 14.83 (s, 1 H), 8.76 (s, 1H), 8.68 (s, 1H), 8.24 (d, J = 6 Hz, 1H), 7.49-7.35 (m, 9), 7.12-7.10 (m, 6H), 6.82 (s, 1H), 6.52 (s, 1H), 6.24 (d, J = 6 Hz, 1H), 5.75 (broad s, 1H), 4.87-4.83 (m, 2H), 4.77 (broad s, 1H), 4.51 (t, J = 9 Hz, 2H), 3.38 (s, 2H), 2.23 (s, 2H), 1.42 (s, 9H); MS: m / e 684.3 [M + H]; High resolution MS: calcd for C41H42N505 [M + H]: 684.3186, found: 684.3181.
P art F-3 - ((1 - (3 - ((ter -but oxy) carbonylamino) propyl) -4-oxo- 7- (((1- (triflumethyl) imidazol-2-yl) amino) methyl) (3-Hydroquinolyl) carbonylamino) -2 - (((2,4,6-trimethylf-enyl) sulfonyl) amino) propanoate methyl A solution of the product of part E above (300 mg, 0.437 mmol), TFA ( 0.243 ml, 1.75 mmoles) and HBTU (230 mg, 0.606 mmoles) in 4 ml of anhydrous DMF is stirred at room temperature for 5 min. A solution of 3-amino-2 - ((2, 4) hydrochloride is added. Methyl 6-trimethylphenyl) sulfonyl) amino) propanoate (184 mg, 0.637 mmol) in 3 ml of anhydrous DMF and the solution is stirred at room temperature under a nitrogen atmosphere for 2 h.The solution is diluted with 200 ml of EtOAc and washed consecutively with water (2 x 50 ml), 50 ml of saturated NaHCO 3 and 50 ml of saturated NaCl, dried over MgSO 4 and concentrated to give a viscous amber oil. in a column of 2.5 x 24 cm silica gel using a step gradient of EtOAc / MeOH (98/2, 95/5, 75/25) gives the title compound as a light yellow oil (330 mg, 78 mg). %). MS: m / e 966.6 [M + H]; High resolution MS: calculated for C54H60N7O8S [M + H]: 966.4224, found: 966.4224.
Part G - 3 - ((1 - (3 - ((tert-butoxy) carbonylamino) propyl) -4-oxo-7- (((1 (triphenylmethyl) imidazol-2-yl) amino) methyl) (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic A solution of the product from part F above (51 mg , 0.052 mmole), 0.27 ml of water and 0.13 ml of 3 N LiOH in 2 ml of MeOH are allowed to stand at room temperature for 3.5 h and concentrated in vacuo. The resulting solid is dissolved in 10 ml of water and adjusted to pH 3 with 1.0 N HCl. The aqueous mixture is extracted with DCM (2 x 30 ml). The combined DCM extracts are washed with 30 ml of saturated NaCl, dried with MgSO 4, and concentrated to give the title compound as 72 mg of a colorless solid. MS: m / e 952.5 [M + H]; High resolution MS: calculated for C53H58N708S [M + H]: 952.4067, found: 952.4056.
Part H - 3- ((1- (3-Aminopropyl) -7- (imidazol-2-ylamino) methyl) -4 -oxo (3-hydroquinolyl)) carbonylamino acid bis (trifluoroacetate) salt -2- ( ((2,4-, 6-trimethylphenyl) sulfonyl) amino) propanoic The product of part I above (0.052 mmol) and Et3SiH (0-042 ml, 0.26 mmol) is dissolved in 2 ml of degassed TFA, heated to 70 C for 2.5 h and concentrated to provide an amber oil. This oil is dissolved in 25 ml of water and washed with ether (2 x 15 ml). The combined ethereal washes are back-extracted with 15 ml of water. The combined aqueous extracts are lyophilized to provide the title compound as a colorless powder (34 mg, 78%). MS: m / e 610.4 [M + H]; High resolution MS: calculated for C29H36N706S [M + H]: 610-2448, found: 610.2462.
Part I - 3 - ((l- (3- ((6- ((1-aza-2- (2-sulf of enyl (vinyl) amino) (3-pyridyl)) carbonylamino) propyl trifluoroacetate ) -7- ((imidazol-2-ylamino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic A solution of the product from part H above (13.7 mg, 0.0163 mmol), TEA (0.015 ml, "0.108 mmol) and 2- (2-aza-2- ((5- ((2,5-dioxopyrrolidinyl) carbonyl) acid ( 2-pyridyl)) amino) vinyl) benzenesulfonic acid (8.2 mg, 0.0186 mmole) in 2.0 ml of anhydrous DMF is allowed to stand at room temperature under a nitrogen atmosphere for 24 hrs. DMF is removed under reduced pressure and amber oil dissolves in ACN 50% and is purified by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using 0.1% TFA in water for 5 min followed by a gradient of 2.52% / min from 0 to 63% ACN containing 0.1% TFA at a flow rate of 20 ml / min. pal elute at 21.4 min and collect and lyophilize to give the title compound as a colorless powder (12.5 mg 75%), MS: m / e 913.3 [M + H]; High resolution MS: calculated for C42H45N10O10S2 [M + H]: 913.2761, found: 913.2751.
• TFA Example 5 3 - ((1- (3 - ((6 - ((l-az a - 2 - (2-sulfo-fyl) (vinyl) amino) (3-pyridyl)) carbonylamino) propyl trifluoroacetate salt ) -7- (((1-hydroxymidazol-2-yl) amino) methyl) -4 -oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic Part A - 3- ({(1- (3-Aminopropyl -7- ((imidazol-2-ylamino) methyl) -4 -oxo (3-hydroquinolyl)) carbonylamino bis (trifluoroacetate) salt (Methyl ((2,4,6-trimethylphenyl) sulfonyl) amino) propanoate A solution of the product of example 4, part F (120 mg, 0.124 mmol) and Et3SiH (0.99 mL, 6.20 mmol) in 10 mL of TFA is heated at 70 C for 1 h and concentrated to provide an amber oil. This oil is dissolved in 50 ml of water and washed with ether (2 x 30 ml). The combined ether washes are back-extracted with 20 ml of water. The combined aqueous extracts are leophilized to provide the title compound as a colorless powder (105 mg, 100%). MS: m / e 624.4 [M + H]; High resolution MS: calculated for C30H38N7O6S [M + H]: 624.2604, found: 624.2608.
Part B - 3 - ((l- (3- (aminopropyl) -7- (((l-hydroxymidazol-2-yl) amino) methyl) -4-oxo (3-hydroquinolyl) (carbonylamino) acid trifluoroacetate salt -2- (((2, 4, 6-trimethylphenyl) sulfonyl) amino) propanoic A mixture of the product of part A above (105 mg, 0.126 mmol), "3.0 ml of water and 1.82 ml of 3 N LiOH in 4 ml of THF containing peroxide is allowed to stand at room temperature for 1 hr. The resulting solid is dissolved in 10 ml of water and adjusted to pH 5 with 1.0 N HCl. The insoluble impurities are removed by filtration and the filtrate is lyophilized to give a colorless solid. purify by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using 0.1% TFA in water for 5 min, followed by a gradient of 2.52% / min of ACN, 0 to 63% of 0.1% TFA at a flow rate of 20 ml / min The main product peak elutes at 19.5 min and is collected and lyophilized to give the title compound as a colorless powder (10.0 mg, 11%) MS: m / e 314.0 [M + 2H].
Part C - 3 - ((1- (3- ((6- ((1-aza-2- (2-sulf of enyl (vinyl) amino) (3-pyridyl)) carbonylamino) propyl) trifluoroacetate -7- (((l-hydroximidazol-2-yl) amino) methyl) -4 -oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) ammon) propanoic A solution of the product from part B above (10.0 mg, 0.0135 mmol) TEA (0.018 ml, 0.129 mmol) and acid 2- (2-aza-2- ((5- (2,5-dioxopyrrolidinyl) carbonyl) (2-pyridyl)) amino) vinyl) benzenesulfonic (7.2 mg, 0.0163 mmol) in 4 ml of Anhydrous DMF is allowed to stand at room temperature under a nitrogen atmosphere for 20 h. The DMF is removed under vacuum and the amber oil is dissolved in 30% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using 0.1% TFA in water for 5 min followed by a gradient of 2.52. % / min of ACN 0 to 63% containing 0.1% TFA at a flow rate of 20 ml / min. The main product peak eluting at 21.5 min is collected and leofylated to provide the title compound as a colorless powder (3.5 mg., 25%). MS: m / e 929.4 [M + H]; High resolution MS: calculated for C42H45N10O?; LS2 [M + H]: 929.2710, found: 929.2698.
• TFA Example 6 3 - ((1- (3 - (3 - (N- (3- (2- (2- (3 - ((6 - ((l-aza-2- (2-sulfophenyl)) vinyl trifluoroacetate salt amino) (3-pyridyl)) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propanoylamino) propyl) -7- ((imidazol-2-ylamino) methyl) -4 -oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-Trimethylphenyl) sulfonyl) amino) propanoic Part A - 3- (N- (3- (2- (2- (3- ((tert-butoxy) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propanoic A solution of N- (3- (2- (2- (3-aminopropoxy) ethoxy) ethoxy) propyl) (tert-butoxy) formamide (as described by DS Ilbur et al. in Bioconjugate Chem. 1998, 9, 322-330) (2.00 g, 6.24 mmol), TEA (1.0 mL, 7.49 mmol) and succinic anhydride (624, g, 6.24 mmol) in 5 mL of anhydrous DMF is stirred at room temperature under a nitrogen atmosphere for 4 h-. The DMF is removed under reduced pressure to provide the title compound as 2.80 g of a light yellow oil. MS: m / e 839.5 [2M-H], 419.4 [M + H].
Part B - 3- ((l - '(3- (3- (N- (3- (2- (2- (3- ((tert-butoxy) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propanoylamino ) propyl-4-oxo-7- (((1- (triphenylmethyl) imidazol-2-yl) amino) methyl) (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) ) amino) methyl propanoate The product of Example 4, part F (46.1 mg, 0.477 mmol) is dissolved in 2.0 ml of 50% TFA / DCM for 15 min at room temperature and concentrated to give a yellow oil. Dissolve in 1.0 ml of anhydrous DMF and become basic until pH detected by paper with ASD In a separate flask, dissolve the product from part A above (26.1 mg, 0.062 mmol), TEA (0.014 ml, 0.099 mmol) and HBTU ~ (27.7 mg, 0.074 mmol) in 1.0 ml of anhydrous DMF The resulting solution is allowed to react for 5 min and is combined with the DMF solution from the TFA deprotection reaction. rest to tempera The atmosphere is heated under a nitrogen atmosphere for 20 min and concentrated under vacuum. The resulting oil is dissolved in 50% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 260 mm) using a gradient of 1.8% / min of ACN from 18 to 72% containing 0.1% TFA at a flow rate of 20 ml / min. The main product peak elutes at 26.8 min and is collected and lyophilized to provide the title compound as a colorless powder (44.5 mg, 68%). MS: m / e 1268.6 [M + H]; High resolution MS: calcd for C68H86N9013S [M + H]: 1268.6065, found: 1268.6070.
Part C - 3- ((1- (3- (3- (N- (3- (2- (2- (3- ((tert-butoxy) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propanoylamino ) propyl-4-oxo-7- ((((triphenylmethyl) imidazol-2-yl) amino) methyl) (3-hydroquinolyl)) carbonylamino) -2 - (((2,4,6-trimethylphenyl) sulfonyl) amino) ) propanoic A solution of the product from part B above (31.1 mg, 0.0227 mmoles) in 0.091 ml of 3 N LiOH and 0.117 ml of water in 1.30 ml of MeOH is stirred at room temperature for 8.5 h. The MeOH is removed under vacuum and the aqueous mixture is diluted with 30 ml of water and adjusted to pH 4 with 1 N HCl. The resulting aqueous mixture is extracted with DCM (2 x 50 ml). The DCM and combined extracts are washed with 50 ml of saturated NaCl, dried with MgSO 4 and concentrated to provide the title compound as a colorless solid. (24.6 mg, 86%).
Part D - 3- ((1- (3- (3- (N- (3- (2- (2- (3-aminopropoxy) ethoxy) ethoxy) propyl) carbamo bis (trifluoroacetate) salt propanoi lamino) rop i 1) -7- ((imidazol-2-ylamino) methyl) -4 -oxo (3-hydroquinolyl)) carbonylamino) -2 - (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic A solution of the product from part C above (24.6 mg, 0.0194 mmole) and Et3SiH (0.016 ml, 0.097 mmole) in 2.0 ml of TFA is heated at 70 ° C under a nitrogen atmosphere for 3 h and concentrated to give a yellow solid. This solid is dissolved in 50 ml of water and washed with ether (2 x 25 ml). The aqueous layer is leophilized to give the title compound as a light yellow solid (20.7 mg, 93%). MS: m / e 912.5 [M + H]. 2TFA Part E - Trifluoroacetate salt of 3 - ((1- (3 - (3 - (N- (3 - (2 - (2 - (3 - ((6 - ((1-aza-2 - (2 - sulfophenyl) vinyl) amino) (3-pyridyl)) carbonylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propanoylamino) propyl) -7- ((imidazol-2-ylamino) methyl) -4-oxo (3-hydroquinolyl) ) carbonylamino) -2- (((2,4,6-Trimethylphenyl) sulfonyl) amino) propanoic 1 A solution of the product from Part D above (15.5 mg, 0.0136 mmol), TEA (0.010 ml, 0.0746 mmol) and 2- (2-aza-2- ((5- ((2,5-dioxopyrrolidinyl) carbonyl) (2-pyridyl)) amino) vinyl acid ) benzensulfonic (8.0 mg, 0.0182 mmol) in 2.0 ml of anhydrous DMF is allowed to stand at room temperature under a nitrogen atmosphere for 24 h. The DMF is removed under vacuum and the resulting yellow oil is dissolved in 50% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using 0.1% TFA in water for 5 min, followed by a gradient. 2.52% / min of ACN from 0 to 63% containing 0.1% TFA, at a flow rate of 20 ml / min. The main product peak eluting at 21.7 min is collected and leofylated to provide the title compound as a colorless powder (7.2 mg, 40%). MS: m / e 1215.5 [M + H]; High resolution MS: calculated for C56H71N12015S2 [M + H]: 1215.4603, found: 1215.4580.
Example 7 Salt of trifluoroacetate of 2- (2-aza-2- (5- (N- (1,3- bis (3- (2- (3- (3- (N- (3- (3- N- (3-carboxy-2- (((2,4,6-trimethylf-enyl) sulfonyl) amino) ethyl) carbamoyl) -7- (imidazol-2-ylamino) methyl) 4-oxo-hydroquinone propyl) carbamoyl) -propane and lamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) (2-pyridyl)) amino) vinyl) -benzenesulfonic Part A '- N, N' -bis (3- (2- (2- (3-- (3- (N- (3- (3- (N- (3-carboxymethoxy-2 - (((2, 4, d-t rime ti lf eni l) -sulphonyl) amino) ethyl) carbamoyl) -4 -oxo- 7 - (((1- (triflumethyl) imidazol-2-yl) amino) methyl) -hydroquinolyl) propyl ) carbamoyl) propanoylamino) propoxy) ethoxy) propyl-2- ((tert-butoxy) carbonylamino) pentan-1,5-diamide A solution of the product of Example 6, Part B (50.5 mg, 0.0398 mmol) in 2 ml of TFA / DCM 50/50 is allowed to react for 20 min at room temperature and concentrated to a viscous oil.This oil is taken up in anhydrous DMF and becomes basic up to pH determined by paper with TEA.This solution is treated with Boc-L -Glu-OH (4.5 mg, 0.0181 mmol) and HBTU (16.6 mg, 0.0438 mmol) and allowed to stand at room temperature for 2 hrs. DMF is removed under vacuum and the resulting oil is dissolved in 60% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using a 1.8% gradient / min of ACN 18 to 72% containing 0.1% TFA at a flow rate of 20 ml / min. The main product peak elutes at 21.5 min and is collected and lyophilized to provide the title compound as a colorless powder (38.8 mg, 0.84%). MS: m / e 2306.5 [M + H-Tr], 2064.4, [M + H-2Tr], 1275.0 [M + 2H]; High resolution MS: calculated for C117H154N19OS2 [M + H-Tr]: 2305.0753, Found: 2305.0770.
Part B - Tris (trifluoroacetate) salt of 2-amino-N, N'-bis (3- (2- (2- (3- (3- (N- (3- (3- (N- (3 - carboxy-2- (((2,4,6-trimethylphenyl) -sulfonyl) amino) ethyl) carbamoyl) -7- ((imidazol-2-ylamino) methyl) 4-oxohydroquinolyl) propyl) carbamoyl) propanoylamino) propoxy) eto xi) ethoxy) propyl) pentane-1,5-diamide A solution of the product of part A, above (38.8 mg, 0.0152 mmol), 0.075 ml of 3 N LiOH and 0.156 ml of water in 2.0 ml of MeOH is stirred at room temperature for 18 h. The mixture is removed under vacuum MeOH and the aqueous mixture is diluted with 50 ml of water and adjusted to pH 3 using 0.5 N HCl. The mixture is extracted with DCM (2 x 50 ml). The combined DCM extracts are washed with 50 ml of saturated NaCl, dried with MgSO 4 and concentrated to provide a colorless solid. This solid is dissolved in 3.0 ml of TFA together with Et3SiH (0.031 ml, 0.178 moles), is heated at 70 ° C under a nitrogen atmosphere for 11 h and concentrated to give a yellow oil. This oil is dissolved in 25 ml of water and washed with ether (2 x 50 ml). The aqueous solution is lyophilized to give a light yellow solid. This solid is dissolved in water and purified by preparative CLAP on a Vydac C-18 column (22 x 250 ml) using 0.1% n TFA in water for 5 min followed by a gradient of 2.52% / min of ACN 0 to 63% containing 0.1% TFA at a flow rate of 20 ml / min. The peak of the main product elutes at 22.4 min and is collected and lyophilized to provide the title compound as a colorless powder (5.1 mg, 18%). MS: m / e 968.2 [M + 2H], 646.0 [M + 3H].
Part C - 2- (2-aza-2- (5- (N- (1, 3-bis (3- (2- (2- (3- (3- (N-) N-bis (trifluoroacetate) acid salt - (3- (3- (N- (3-carboxy-2 - (((2,4,6-trimethylphenyl) sulf pnyl) amino) ethyl) carbamoyl) -7- ((imidazol-2-ylamino) -ethyl 4-Oxohydroquinolyl) propyl) carbamoyl) -propanoylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) (2-pyridyl)) amino) vinyl) benzenesulfonic acid - A solution of the product from Part B above (5.1 mg, 0.00224 mmol), TEA (0.002 mL, 0.0115 mmol) and acid 2- (2-aza-2- ((5- ((2,5-dioxopyrrolidinyl) carbonyl) (2-pyridyl)) -amino) vinyl) benzenesulfonic acid (1.2 mg, 0.00272 mmol) in 2.0 ml of anhydrous DMF is allowed that it rests at room temperature under nitrogen for 72 h. DMF is removed under vacuum and the resulting oil is dissolved in 50% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 250-mm) using 0.1% TFA in water for 5 min followed by a 2.52 gradient. % / min of ACN 0 to 63% containing 0.1% TFA at a flow rate of 20 ml / min. The main product peak elutes at 23.5 min and is collected and lyophilized to provide the title compound as a colorless powder (0.5 mg, 9.0%). MS: m / e 1120.0 [M + 2H]; High Resolution MS: Calculated for 4Hi37N22 ° 28S3 [+]: 2237.9055, Found: 2237.9120.
DOTA Conjugate of the bis (trifluoroacetate) salt of 3- ((1- (3- (3- (N- (3- (2- (2- (N- (L-Asp-L-Asp) 3 - aminopropoxy) ethoxy) ethoxy) propyl) carbamoyl) -propanoylamino) propyl-7- ((imidazol-2-ylamino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4, 6- trimethylphenyl) sulfonyl) amino) propanoic Part A - Carbobenzyloxy-L-Asp (O-t-Bu) -L-Asp (O-t-Bu) -OMe , A solution of Cbz-Asp (O-t-Bu) -OH) 1.54 g, 4.76 mmole), H-Asp (O-t-Bu) -OMe. HCl (1.14 g, 4.76 mmole), DIEA (1.85 ml, 10.5 mmol) and HBTU (1.99 g, 5.24 mmol) in 20 ml of DMF are stirred at room temperature for 18 h. Add to 100 ml of water and 50 ml of EtOAc and the layers are separated. The layer Aqueous is extracted with EtOAc (2 x 50 ml). The combined EtOAc extracts are washed consecutively with 50 ml of water, 10% KHS04 (2 x 50 ml) and 50 ml of 10% NaHCO3. The organic phase is dried with MgSO 4 and concentrated to give an oily solid. This material is triturated with ether to provide the title compound as a colorless solid (2.14 g, 89%). MS: m / e 1017.6 [2M + H], 509.4 [M + H].
Part B - Carbobenzyloxy-L-Asp (O-t-Bu) -L-Asp (O-t-Bu) -OH A mixture of the product from part A above (200 mg, 0.393 mmol), LiOH (28 mg, 0.865 mmol), 40 ml of water and 200 ml of THF is stirred at room temperature for 28 h and concentrated to remove THF. The aqueous mixture is diluted with 20 ml of additional water and washed with 20 ml of EtOAc. The aqueous phase is adjusted to pH 4 with 1.0 N HCl and extracted with 20 ml of EtOAc. The EtOAc extract is washed with 15 ml of saturated NaCl, dried with MgSO 4 and concentrated to give a colorless solid. This solid dissolves in 60% ACN and is purified by preparative CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 2.4% / min from 18 to 90% ACN containing 0.1% TFA at a speed flow rate of 20 ml / min. The main product peak eluting at 19.0 min is collected and lyophilized to provide the title compound as a colorless powder (95 mg, 49%).
Part C - 3- ((1- (3- (3- (N- (3- (2- (2- (N- (benzyloxycarbonyl-LA sp (O - t - B u) - L - A sp (O - t - B u)) 3-aminopropoxy) ethoxy) ethoxy) propyl) carbamoyl) -propanoylamino) propyl-4-oxo-7- (((1- (triphenylmethyl) -imidazol-2-yl) amino) methyl) ( 3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoate methyl The product of Example 6, part B is allowed (44.0 mg, 0.0894 mmoles) in 1.5 ml of TFA, stand at room temperature for 45 min and concentrate to a yellow oil. This oil is dissolved in 2.0 ml of anhydrous DMF and becomes basic until pH determined by paper with TEA. In a separate flask, the product of part B above (69.3 mg, 0.0547 mmol) is dissolved in 2.0 ml of anhydrous DMF and pre-activated by treatment with TEA (0.015 ml, 0.104 mmol) and HBTU (32.6 mg, 0.0859 mmol). After 10 min, this solution is added to the DMF solution from the deprotection reaction of TFA and the combined solutions are stirred at room temperature for 30 min. The DMF is removed under vacuum and the resulting oil is dissolved in 60% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 250 ml) using a gradient of 1.54% / min of ACN 18 at 72%. contains 0.1% TFA at a flow rate of 20 ml / min. The peak of the main product elutes at 29.9 min and is adjusted to pH 8"with saturated NaHCO 3 and concentrated to remove the ACN The remaining aqueous mixture is extracted with EtOAc (2 x 40 ml) The combined EtOAc extracts are washed with 40 ml of saturated NaCl, dried over MgSO4 and concentrated to give the title compound as a colorless solid (56.4 mg, 63%) MS: m / e 1644.8 [M + H]; High resolution MS: Calculated for CBTHUQNUO ^ S [M + H]: 1644.7700, Found: 1644.771.
Part D - 3- ((1- (3- (3- (N- (3- (2- (2- (N- (L-As (Ot-Bu) -L-Asp (Ot-Bu)) 3 -aminopropoxi) ethoxy) ethoxy) propyl) carbamoyl) propanoylamino) propyl -4 -oxo - 7 - (((1- (trif enylmethyl) imidazol-2-yl) amino) methyl) (3 -hidroquinolil)) carbonylamino) -2 - (Methyl ((2,4,6-trimethylphenyl) sulfonyl) amino) propanoate The product of part E above (55.0 mg, 0.0335 mmol) is subjected to hydrogenolysis on 25 mg of 10% Pd / C in 15 ml of MeOH at 276 kPa (40 psi) for 3.5 h. The catalyst is removed by filtration through a filter aid and the filtrate is concentrated to give the title compound as a light yellow oil (41.8 mg, 83%). MS: m / e 1510.8 [M + H].
Part E - Conjugate of the DOTA-tri-t-butyl ester of 3 - ((l- (3- (3- (N- (3- (2- (2- (N- (L-Asp (Ot-Bu ) -L-Asp (Ot-Bu)) 3 -aminopropoxi) ethoxy) ethoxy) propyl) carbamoi 1) propanoylamino) propyl - 4 -oxo- 7 - (((1- (trif enylmethyl) imidazol-2-yl) amino methyl) (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfyl) amino) propanoate methyl A solution of the product of part D above (41.8 mg, 0.277 mmol), the product of example 2, part B (39.9 mg, 0.0436 mmol), TEA (0.023 ml, 0.166 mmol) and HBTU (15.6 mg, 0.0411 mmoles) in 3.0 ml of anhydrous DMF is allowed to stand at room temperature under a nitrogen atmosphere for 20 h. The DMF is removed under vacuum and the resulting oil is dissolved in 60% ACN and purified by preparative CLAP on a Vydac C-18 column (22 x 250 ml) using a gradient of 2.4% / min of ACN 18 at 90% which contains 0.1% TFA at a flow rate of 20 ml / min. The main product peak elutes at 21.2 min and is collected and lyophilized to provide the title compound - as a colorless powder (24.8 mg, 43%). MS: m / e 2066.3 [M + H], 1033.6 [M + 2H]; High resolution MS: Calculated for C107H154N15O24S [M + H]: 2065.1011. Found: 2065.1030.
Part F - DOTA conjugate of the bis (trifluoroacetate) salt of 3- ((1- (3- (3- (N- (3- (2- (2- (N- (L-Asp-L -Asp)) 3-aminopropoxy) ethoxy) ethoxy) propyl) carbamoyl) propanoil- "amino) propyl-7- ((imidazol-2-ylamino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) - 2 - (((2, 4, 6 -trimethylphenyl) sulfonyl) amino) propanoic A mixture of the product of part G above (18.8 mg, 0.0091 mmol), 0.150 ml of water, 0.015 ml of 3 N LiOH and 1.5 ml of peroxide-free THF is stirred at room temperature for 3 h. The THF is removed under vacuum and the aqueous mixture is diluted with 40 ml of water and adjusted to pH 7 with 0.1 N HCl. The mixture is extracted with DCM (2 x 30 ml) and the combined extracts are concentrated to give an oil. yellow. This oil is dissolved in 1.0 ml of TFA together with Et3SiH (0.030 ml, 0.184 mmol) and heated at 40 ° C under a nitrogen atmosphere for 48 h. The solution is concentrated and the resulting oil is dissolved in water and purified by preparative CLAP on a Vydac C-18 column (22 x 250 ml) using 0.1% TFA in water for 5 min, followed by a gradient of 2.52% / min. of ACN from 0 to 63% containing 0.1% TFA at a flow rate of 20 ml / min. The peak of the main product elutes at 19.9 min and is collected and lyophilized to provide the title compound as a colorless powder. (1.5 mg, 9.4%). ^ MS: m / e 1528.9 [M + 2H], 765.1 [M + 2H], 510.7 [M + 3H].
Illustrated 8 The 9 DOTA / Tris (trifluoroacetate) salt conjugate of 2-amino- N, N'-bis (3- (2- (2- (3- (3- (N- (3- (3- (N- (3 -carboxy-2- (((2,4,6-trimethylphenyl) sulfonyl) amino) ethyl) carbamoyl) -7- ((imidazole-2-ylamino) methyl) 4-oxohidroquinolil) - propyl) carbamoyl) propanoylamino) propoxy ) ethoxy) ethoxy) propyl) -pentane-1,5-diamide Part A - DOTA-tri-t-butyl ester conjugate / hexakis (trifluoroacetate) salt of 2-amino-N, N '-bis (3- (2- (2- (3- (3- (N- ( 3- (3- (N- (3-carboxy-2- (((2,4,6-trimethylphenyl) sulfonyl) amino) -ethyl) carbamoyl) -7- ((_imidazol-2-ylamino) methyl) 4 -oxohydroquinolyl) propyl) carbamoyl) propanoylamino) propoxy) -ethoxy) ethoxy) propyl) pentane-1,5-diamide A solution of the product from example 2, part B, HBTU and DIEA in anhydrous DMF is stirred at room temperature under nitrogen for 15 min and treated with the product of example 7, part B. The resulting solution is stirred at an additional 18 h and The DMF is removed under vacuum. The resulting residue is purified by preparative CLAP on a C-18 column using a water gradient: ACN: 0.1% TFA. The product fraction is lyophilized to provide the title compound.
Part B - DOTA Conjugate / Tris (trifluoroacetate) salt of 2-amino-N, N'-bis (3- (2- (2- (3- (3- (N- (3- (3- (N)) - (3-carboxy -2 - ((. {2,4, 6-trimethylphenyl) sulfonyl) amino) ethyl) carbamoyl) -1 - ((imidazol-2-ylamino) methyl) 4 -oxohydroquinolyl) propyl) -carbamoyl propanoylamino) propoxy) ethoxy) ethoxy) propyl) pentane-1,5-diamide The product from part B above is dissolved in degassed TFA, treated with triethylsilane and heated at 50 ° C under nitrogen for 1 h. The solution is concentrated under vacuum and the resulting residue is purified by preparative CLAP on a C18 column using a water gradient: ACN: 0.1% TFA. The product fraction is lyophilized to provide the title compound.
Example 10 DOTA Conjugate / 2 - (((4- (3- (N- (3- (2- (2- (3- (2-amino-3-sulfopropyl) propoxy) ethoxy) ethoxy) propyl trifluoroacetate salt ) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -1-methyl-4 -oxo (3-hydroquinolyl)) carbonylamino) propanoic Part A - 2- (((4- (3- (N- (3- (2- (2- (3- (2- ((tert-butoxy) -carbonylamino) -3-sulfopropyl) propoxy) ethoxy) ethoxy) propyl) -carbamoyl) propoxy -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) -carbonylamino) propanoic.
The product of Example 3, Part I is dissolved in anhydrous DMF and treated with the N-hydroxysuccinimido ester of boc-cysteic acid (as described in Liebigs Ann. Chem. 1979, 776-783) and DIEA. The solution is stirred at room temperature under nitrogen for 18 h, and the DMF is removed under vacuum. The resulting residue is purified by preparative CLAP on a C18 column using a water gradient: ACN: 0.1% TFA. The product fraction is lyophilized to provide the title compound.
Part B - DOTA-tri-t-butyl ester conjugate / 2- (((4- (3- (2- (3- (2-amino-3-sulfopropyl)) tetrakis (trifluoroacetate) salt propoxy) ethoxy) ethoxy) propyl) carbamoyl) -propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo ( 3-hydroquinolyl)) carbonylamino) -propanoic acid The product of part A above is dissolved in degassed TFA and stirred at room temperature for 15 min. The solution is concentrated under vacuum and the resulting residue is dissolved in 50% ACN and lyophilized to remove the last traces of TFA. In a separate flask, a solution of the product of Example 2, part B and DIEA in anhydrous DMF is treated with HBTU and allowed to react 15 min at room temperature under nitrogen. The product deprotected from the above is added to this solution and stirring is continued at room temperature under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative CLAP on a C18 column using a water gradient: ACN: 0.1% TFA. The product fraction is lyophilized to provide the title compound.
Part C - DOTA Conjugate / 2- (((4- (3- (2- (2- (3- (2-amino-3-sulfopropyl) propoxy) ethoxy) -, ethoxy) propyl) trifluoroacetate acid carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) -amino) -3- ((7- ((imidazol-2-ylamino) methyl) -1-methyl-4 -oxo (3-hydroquinolyl)) carbonylamino) propanoic The product from part B above and Et3SiH are dissolved in degassed TFA and heated at 50 ° C under nitrogen for 1 h. This solution is concentrated and the resulting residue is purified by preparative CLAP on a C18 column using a gradient of water: CN: TFA 0.1%. The product fraction is lyophilized to provide the title compound.
Example 11 - DOTA Conjugate / 2- (((4- (3- (N- (3- (2- (2- (3- (2-amino-3- (4- (phosphonooxy)) phenyl) trifluoroacetate propandylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2, 6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroxyquinolyl)) carbonylamino) propanoic The title compound is prepared by the same procedure described for Example 10 by substituting Boc-Cys (0H) -OSu for Boc-Tyr (P03H2) -Osu Example 12 DOTA Conjugate / 2 - (((4- (3- (N- (3- (2- (2- (3- (2-amino-3- (4- (sulfooxi) phenyl)) trifluoroacetate propanoylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-sylamino) methyl) -l-methyl-4 -oxo (3-hydroxyquinolyl)) carbonylamino) propanoic The title compound is prepared by the same procedure described for Example 10 by substituting Boc-Cys (03H) -OSu for Boc-Tyr (S03H) -Osu.
Example 13 DOTA / acid conjugate 2- (((4- (3 - (N- (3- (2- (2- (3- (2-amino-4- (N- (ethyl-3, 6-0-disulfo -β-D-galactopyranosyl) carbamoyl) butanoylamino) propoxy) -ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic Part A - Preparation of Boc-Glu (aminoethyl-3,6-O-disulfo-β-D-galactopyranosyl) -OSu ** "A solution of Boc-Glu-OMe, aminoethyl-3, 6, 0-disulfo-β -D-galactopyranoside (as described in Tet.Lett., 1997, 53, 11937-11952), DIEA and HBTU in anhydrous DMF are stirred at room temperature under nitrogen for 18 h.The DMF is removed under vacuum and the resulting residue hydrolyze using aqueous NaOH, adjust the reaction solution to pH 7, purify by preparative anion exchange chromatography using a resin such as DEAE cellulose and a gradient of Et3NH2C03.The product fraction is treated with a cation exchange resin, form of sodium, to provide the intermediate carboxylic acid as a sodium salt The above compound, N-hydroxysucmimide and DCC are dissolved in anhydrous DMF and stirred at room temperature under nitrogen for 18 hrs. The DMF is removed under vacuum and the resulting residue it is purified by gas chromatography preparative anionic change as in the above to provide the title compound as the triethylammonium salt.
Part B - DOTA / acid conjugate 2- (((4- (3- (N- (3- (2- (2- (3- (2-amino-4 - (N- (ethyl-3,6- O-disulfo-ß-D-ga lac top i rano sil) -carbamoyl) butanoylamino) propoxy) ethoxy) ethoxy) ropil) • carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- (( 7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic The title compound is prepared by the same procedure described for Example 10 by substituting Boc-Glu ( aminoethyl-3,6-O-disulfo-β-D-galactopyranosyl) -OSu by Boc-Cys (03H) -OSu.
Example 14 DOTAS / bis (trifluoroacetate) salt conjugate of 2- (((4- (3- (N- (3- (2- (2- (3- (2-amino-4- (N- (6- deoxy-β-D-cyclodextryl) carbamoyl) butanoylamino) propoxy) ethoxy) -ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazole-2- " ilamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) - carbonylamino) propanoic Part A - Preparation of Boc-Glu (6-amino-6-deoxy-β-D-cyclodextril) -OMe A solution of Boc-Glu-OMe, 6-amino-6-deoxy-β-cyclic extrine (as described in J. Org Chem, 1996, 61, 903-908), DIEA and HBTU in anhydrous DMF is stirred at room temperature under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative CLAP on a C18 column using a water gradient: ACN: 0.1% TFA. The product fraction is lyophilized to provide the title compound.
Part B Preparation of Boc-Glu (6-amino-6-deoxy-β-cyclodextril) -OSu The product from part A above is hydrolyzed by stirring in a mixture of LiOH, THF and water at room temperature under nitrogen for 4 h. The THF is removed under vacuum and the resulting mixture is diluted with water and adjusted to pH 3 using 0.1 N HCl. The mixture is extracted with EtOAc, and the combined extracts are dried with MgSO 4 and concentrated. The resulting material is dissolved in anhydrous DMF with N-hydroxysuccinimide and DCC, and stirred at room temperature under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative CLAP on a C18 column using a water gradient: CN: 0.1% TFA. The product fraction is lyophilized to provide the title compound.
Part C - DOTA / bis (trifluoroacetate) salt conjugate of 2- (((4- (3- (N- (3- (2- (2- (3- (2-amino-4- (N - (6-deoxy-β-cyclodextril) carbamoyl) butanoylamino) propoxy) ethoxy) -ethoxy) propyl) ca rbyloyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazole -2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) -carbonylamino) propanoic acid The title compound is prepared by the same procedure described by Example 10 by substituting Boc-Cys (03H) -Osu for Boc-Glu (6-amino-6-deoxy-β-cyclodextrile) -Osu.
Example 15 DOTA / Bis (trifluoroacetate) acid 2- (((4- (3- (N- (3- (2- (2- (3- (2-amino-4- (N- (? methoxypolyethylene (5,000) glycoxyethyl) carbamoyl) butanoylamino) -propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((? ilamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic Part A - Preparation of Boc-Glu (amino -? - methoxypoliethylene glycol) - Orne.
A solution of Boc-Glu-OMe, amino-α-methoxypolyethylene glycol, (MW = 5,000), DIEA and HBTU in anhydrous DMF is stirred at room temperature under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative CLAP on a C18 column using a water gradient: ACN: 0.1% TFA. The product fraction is lyophilized to provide the title compound.
Part B - Preparation of Boc-Glu (amino-O'-methoxypolyethylene glycol) -OSu The product of part A above is hydrolysed by stirring in a mixture of LiOH, THF and water at room temperature under nitrogen for 4 h. The THF is removed under vacuum and the resulting solution is adjusted to pH 7 using 0.1 N HCl. The solution is desalted using a Sephadex PD-10 desalting column and the eluent of the product is lyophilized. The resulting material is dissolved in anhydrous DMF together with N-hydroxysuccinimide and DCC, and stirred at room temperature under nitrogen for 18 h. It is removed under vacuum and the DMF and the resulting residue is purified by preparative CLAP on a C18 column using a water gradient: ACN: 0.1% TFA. The product fraction is lyophilized to provide the title compound.
Part C - DOTA / bis (trifluoroacetate) salt conjugate of 2- (((4 - (3 - (N- (3 - (2- (2- (3 - (2-amino-4- (N- (? -methoxypoliethylene (5,000) glycoxyethyl) carbamoyl) butanoylamino) -propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethyl-yl) sulfonyl) amino) -3- ((7- ((imidazole) 2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic acid The title compound is prepared by the same procedure described for example 10 by substituting Boc-Cys (03H) -Osu for Boc-Glu (amino-β-methoxypolyethylene glycol) -Osu p Example 16 Tris (trifluoroacetate) salt of 2- (((4- (3-N- (3- (2- (2- (3- (2- (1,4,7, 10-tetraaza-4, 7, 10-tris (carboxymethyl) - (cyclododecylacetylamino) -6- t-aminohexanoylamino) propoxy) ethoxy) ethoxy) propyl) carbamoyl) prop oxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazole -2- ylamino) methyl) -1-methyl-4-oxo (3-hydroejuinolyl)) carbonylamino) propanoic The title compound is prepared by the same procedure described for Example 10 by substituting Boc-Cys (03H) -Osu for Boc-Lys (Cbz) -Osu Example 17 2- (((4- (3-N- (3- (2- (2- (3- (2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (carboxymethyl) cyclododecylacetylamino) -6- (2- (bis (phosphonomethyl) amino) acetylamino) hexanoylamino) -propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7 - ((imidazol-2-ylamino) methyl) -1-methyl-4 -oxo (3-hydroquinolyl)) - carbonylamino) propanoic A solution of bis (phosphonomethyl) glycine, DIEA and HBTU in anhydrous DMF is stirred at room temperature under nitrogen for 15 min and treated with the product of example 16. Stirring is continued for 18 h and DMF is removed under vacuum.
The resulting residue is purified by ion exchange chromatography.
Example 18 2- (((4- (3- (N- (3- (2- (2- (3- (2- (2- (22- ((2- (bis (carboxymethyl) amino) ethyl) (carboxymethyl) amino) ethyl) - (carboxymethio) amino) acetylamino) -3- sulfopropyl) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) 2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ( (imidazol-2-imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic The product from example 10, part A is dissolved in degassed TFA and stirred at room temperature for 15 min. The solution is concentrated under vacuum and the resulting residue is dissolved in 50% ACN and lyophilized to remove the last traces of TFA. The material is dissolved in anhydrous DMF together with DIEA and diethylenetriaminepentaacetic dihydride. The resulting solution is stirred at room temperature under nitrogen for 18 h. The DMF is removed under vacuum and the resulting residue is purified by preparative CLAP on a C18 column using a water gradient: ACN: 0.1% TFA. The product fraction is lyophilized to provide the title compound.
The following procedure describes the synthesis of radiopharmaceuticals of the present invention of the formula 99mTc (VnA) (tricine) (phosphine), in which (VnA) represents a vitronectin receptor antagonist compound of the present invention attached to the Te through a diazenido portion (-N = N) or hydrazido (= N-NH-). The diazenido or hydrazido portion results from the reaction of a hydrazinonicotinamido group, present either as free or protected hydrazine as a hydrazone, with Tc-99m. The other two ligands in the coordination sphere of Te are tricine and a phosphine.
Examples 19 to 23 Synthesis of complexes of [39mTc (HYNIC-VnA) (tricine) (TPPTS)].
To a lyophilized flask containing 4.84 mg of TPPTS, 6.3 mg of tricine, 40 mg of mannitol, succinic acid buffer, pH 4.8, and surfactant Pluronic F-64 0.1%, 1.1 ml of sterile water for injection, 0.2 ml is added (20 μg) of the appropriate HYNIC-conjugated vitronectin antagonist (VnA) in deionized water or 50% aqueous ethanol and 0.2 ml of 99mTc04 ~ (50 + 5 mCi) in saline. The reconstituted equipment is heated in a water bath at 100 ° C for 15 minutes, and allowed to cool 10 minutes at room temperature. A sample of the reaction mixture is analyzed by CLAP. The results of CPR are included in table 1.
CLAP method Column: Zorbacx C18, 25 cm x 4.6 mm Flow rate: 1.10 ml / min Solvent A: 10 mM sodium phosphate buffer, pH 6.0 Solvent B: 100% CH3CN Gradient A (Examples 19, 20, 21) t (min ) 0 20 21 30 31 40 % of solvent B 0 25 75 75 0 0 Gradient B (Example 22) t (min) 0 20 30 31 40% solvent B 0 50 50 0 0 Gradient C (Example 23) t (min) 0 20 21 30 31 40 % of solvent B 10 30 75 75 0 0 Table 1. Analytical and performance data for 99raTc (VnA) complexes (tricine) (TPPTS) Example No. Reactive Time of% of No. Retention (min) Performance 19 8.8 73 20 17.2 81 21 4 17.6 68 22 6 11.7 79 23 7 16.4 52 Example 24 Synthesis of 3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino complex In-111 complex (-2 (((4- ( 4- (((3- (2- (2- (3- (2- (1,4,7,10-tetraaza-4,7,1-tris (carboxymethyl) cyclododecyl) acetylamino) propoxy) ethoxy) -ethoxy propyl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) -propanoic acid A 35 μg conjugate of Example 2 and 1.0 mg of the sodium salt of gentisic acid dissolved in 70 μl of ammonium acetate buffer (0.4 M, pH 4.7) are added to a self-priming flask with lead and folded, followed by the addition of 2 mCi, 20 μl of In-111 in 0.05 N HCl (specific activity: 17 μg / mCi). The reaction mixture is heated at 70-80 ° C for 60 min and analyzed by CLAP and by CCDI. A complex is formed with 93% yield and has a retention time of 19.6 min.
CLAP method Column: Zorbacx Rx C18, 25 cm x 4.6 mm Column temperature: ambient Flow: 1.0 ml / min Solvent A: 10% acetonitrile / 0.1% TFA / H2O Solvent B: acetonitrile Detector: Radiometric sodium iodide probe ( Nal) Gradient t min 0 25 26 35 36 45 % B 10 20 60 60 10 10 Examples 25 to 26 Synthesis of 177Lu and 90Y complex of 3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) -2- (((4- ( 4- (((3-2- (2 - (3- (2- (1,4,7,10-tetraaza-4,7,1-tris (carboxymethyl) (cyclododecyl) acetylamino) propoxy) ethoxy) -ethoxy pro-yl) amino) sulfonyl) phenyl) phenyl) sulfonyl) amino) -propanoic acid To a sealed and clean 5 ml bottle is added 0.3 ml of a solution of the conjugate of example 2 (200 μg / ml in 0.5 M ammonium acetate buffer, pH 6.9) followed by 0.5 M of a solution of gentic acid. (sodium salt, 10 mg / ml in 0.5 M ammonium acetate buffer, pH 6.9), 0.3 ml of 0.5 M ammonium acetate buffer (pH 6.9) and 0.010 ml of a 177LuCl3 or 90YC13 solution (1000 mCi / ml for 177LuCl3 and 500 mCi / ml for 90YC13) in 0.05 N HCl. The resulting mixture is heated at 100 ° C for 30 min. After cooling to room temperature, a sample of the resulting solution is analyzed by radio-CLAP and by CCDI. Radiolabeled yields are = 90% (after correction for a small amount of colloid) for both complexes, and the retention time is 19.2 min.
CLAP method Column: Zorbax C18, 25 cm x 4.6 mm Flow rate: 1.0 ml / min Solvent A: aqueous solution of TFA 0.1% Solvent B: 100% CH3CN t (min) 0 20 25 30 31 40 % of the solvent B 10 25 60 60 10 10 The present instant thin layer chromatography (CCDI) method used silica gel strips from Gelman Sciences in a 1: 1 mixture of acetone and saline as eluent.
Example 27 Synthesis of the complex of 177Lu of the DOTA conjugate of 3- ((1- (3- (3- (N- (3- (2- (2- (N- (L-Asp-L-Asp) 3-aminopropoxy ) - ethoxy) ethoxy) propyl) carbamoyl) propanoylamino) propyl-7 - ((imidazol-2-ylamino) methyl) -4-oxo (3-idroquinolyl) -carbonylamino) -2 - (((2,4,6 - trimethylphenyl) sulfonyl) amino) -propanoic acid To a sealed and clean 5 ml flask is added 0.5 ml of a solution of the conjugate of example 8 (200 μg / ml in 0.5 M ammonium acetate buffer, pH 6.9), followed by 0.05 ml of a gentic acid solution (sodium salt, 10 mg / ml in 0.5 M ammonium acetate buffer, pH 6.9), 0.25 ml of a 0.5 M ammonium acetate buffer (pH 6.9) and 0.05 ml of a 177LuCl3 solution (200 mCi / ml ) in 0.05 N HCl. The resulting mixture is heated at 100 ° C for 30 min.-After cooling to room temperature, a sample of the resulting solution is analyzed by radio-CLAP and CCDI. The radiolabeled yield is 75% (after correction for the colloid) and the retention time is 20 min.
CLAP method Column: Zorbax C18, 25 cm x 4.6 mm Flow rate: 1.0 ml / min Solvent A: 10 mM phosphate buffer, pH = 6 Solvent B: 100% CH3CN t (min) 0 20 25 30 31 40% of solvent B 0 20 50 50 Example 28 Synthesis of the gadolinium complex of 2- (((4- (3- (N- (3- (2- (2- (3- (2- (2- ((2- (bis (carboxymethyl) amino) ethyl) - (carboxymethyl) amino) ethyl) (carboxymethyl) amino) acetylamino) -3-sulfopropyl) propoxy) ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3 - ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic The gadolinium complex of the conjugate of Example 18 is prepared according to the following procedure. 3-3.5 mg of the conjugate are dissolved in 2 ml of 1 M ammonium acetate buffer at pH 7.0, and one equivalent of a solution of Gd (N03) 3 (0.02 M in water) is added thereto. The reaction mixture is allowed to stand at room temperature for 3-5 hours and the product is isolated by CLAP. The fraction containing the complex is lyophilized and dissolved in 1 ml of H20. The identity of the complex is confirmed by mass spectroscopy.
Example 29 Synthesis of the salt of trifluoroacetate of (2S) -2- [(. {2,6-dimethyl-4- [3- (N-. {2- [3-sulfo-2- (3-sulfo- 2- {1 2- [1, 4, 7, 10-tetraaza-4, 7, 10-tris (carboxymethyl) cyclododecyl] -acetylamino.}. Propyl) propyl] ethyl) carbamoyl) propoxy] phenyl] • sulfonyl) amino) -3- ( { 7- [(imidazol-2-ylamino) methyl] -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic Part A - Preparation of (2S) -3- [(tert-butoxy) carbonylamino] -2- [(. {2,6-dimethyl-4- [3- (N-. {2- [(phenylmethoxy)] carbonylamino] ethyl) -carbamoyl) propoxy] phenyl} methyl sulfonyl) amino] propanoate A solution of the product of example 3, part D (369 mg, 0.756 mmol), DIEA (0.52 ml, 3.0 mmol) and HBTU (315 mg, 0.832 mmol) in 14 ml of anhydrous DMF is stirred at room temperature under nitrogen for 5 hours. min. and treated with benzyl N- (2-aminoethyl) carbamate hydrochloride (192 mg, 0.832 mmol) and stirred for an additional 1 h. The DMF is removed under vacuum and the oily residue is taken up in 150 ml of EtOAc, washed consecutively with 40 ml of 0.1 N HCl, 40 ml of water and 40 ml of saturated NaCl, dried with MgSO 4 and concentrated to give a viscous oil colorless. Flash chromatography on a 3 x 16 cm silica gel column (EtOAc) gives the title compound as a colorless viscous oil (450 mg, 89.6%). X H NMR (CDCl 3): d 7.34-7.27 (m, 5H), 6.58 (s, 2H), 6.31 (broad s, 1H), 5.86 (s broad, 1H), 5.36 (broad s, 1H), 5.14-5.03 (m, 3H), 3.96 (t, J = 6.0 Hz, 2H), 3.88-3.83 (m, 1H), 3.56 (s, 3H), 3.47-3.25 (m, 6H), 2.59 (s, 6H), 2.31 (t, J = 6.9 Hz, 2H), 2.05 (p, J = 6.6 Hz, 2H), 1.39 (s, 9H); 13C NMR (CDCl3): d 172.9, 170.5, 160.6, 157.3, 155.9, 141.8, 136.3, 128.5, 128.2, 128.0, 116.6, 79.9, 66.9, 55.5, 52.8, 43.1, 40.9, 40.3, 32.4, 28.2, 24.9, 23.3; MS: m / e 665.4 [M + H]; 687.3 [M + Na]; High resolution MS: Calculated for C31H45N4O10S [M + H]: 665.2856, Found: 665.2883.
Part B - Preparation of the trifluoroacetate salt of (2S) -3-am inp-2 - [(. {2, 6-di me til-4 - [3 - (N -. {2 - [(f methyl enymetoxy) carboni lamino] and il.}. carbamoyl) propoxy] -phenyl) sulfonyl) amino] propanoate The product of Part A, above (420 mg, 0.632 mmol) is dissolved in 20 ml of DCM / TFA 25/75 and allowed to stand at room temperature under nitrogen for 10 min. The solution is concentrated and the resulting viscous oil is dissolved in 50% ACN and lyophilized to give the title compound as a colorless solid (437 mg, 102%). MS: m / e 565.3 [M + H].
Part C - Preparation of (2S) -2- [( {2,6-dimethyl-4- [3- (N-. {2- 2- [(phenylmethoxy) carbonylamino] ethyl} carbamoyl) propoxy] phenyl .}. -sulfonyl) amino] -3-. { [L-methyl-4-oxo-7- ( { [1- (triphenylmethyl) -imidazol-2-yl] amino) methyl) (3-hydroquinolyl)] carbonylamino) • methyl propanoate A solution of l-methyl-4-oxo-7- (((1- (triphenylmethyl) imidazol-2-yl) amino) methyl) hydroquinoline-3-carboxylic acid (702 mg, 1.30 mmol), DIEA (0.678 mol, 3.90 mmole) and HBTU (542 mg, 1.43 mmole) in 60 ml of anhydrous DMF is stirred at room temperature under nitrogen for min, and it is treated with the product of stage B above (881 mg, 1.30 mmol). After 75 min, the DMF is removed under vacuum and the resulting oil is purified by CLAP on a Vydac C18 column (50 x 250 mm) using a gradient of 1.24% / min of ACN 18 at 67.5% containing 0.1% TFA a flow rate of 80 ml / min. A peak that is eluted at 18.9 min is lyophilized to provide 308 mg of l-methyl-4-oxo-7- (((1- (triphenylmethyl) im-dazol-2-yl) amino) methyl) hydroquinoline-3-acid. carboxylic that has not reacted. The peak of the main product elutes at 23.7 min and is lyophilized to provide the title compound as a colorless solid (800 mg, 63.0%). XR NMR (CDC13 / D20): d 8.50 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), 7.51-7.25 (m, 15H "), 7.25-7.12 (m , 5H), 6.97 (s, 1H), 6.58 (d, J = 2.3 Hz, 1H), 6.34 (s, 2H), 6.32 (d, J = 8.5 Hz, 1H), 5.09 (s, 2H), 4.65 (s, 2H), 4.29-4.23 (m, 1H), 3.88 (s, 3H), 3.80-3.50 (m, 7H), 3.41-3.28 (m, 4H), 2.61 (s, 6H), 2.26-2.11 (m, 2H), 1.92-1.76 (m, 2H); MS: m / e 1087.4 [M + H]; 845.3 [M + H-Tr]; High resolution EM: Calculated for C60H63N8O10S [M + H]: 1087.4388; found: 1087,440.
Part D - Preparation of (2S) -2-. { [(4 - { 3 - [N- (2-aminoethyl) carbamoyl] propoxy] -2-, 6-dimethyl-phenyl) sulfonyl] amino} -3 - . { [methyl l-methyl-4-oxo-7- ( { [1- (trif.-enylmethyl) imidazol-2-yl] amino} methyl} (3-hydroquinolyl)] carbonylamino) propanoate The hydrogenolysis of the product of part C above (468 mg 0.431 mmol) is carried out in 100 ml of MeOH over 95 mg of 10% Pd / C at 414 kPa (60 psi) for 1 h. The catalyst is removed by filtration through Celite and the filtrate is concentrated to give the title compound as a light amber oil (405 mg, 98.7%). MS: m / e 953.3 [M + H], 711.3 [M + H-trityl].
Part E - Preparation of the acid (2R) -N-. { 2- [4- (4-. {[[((SS) -1- (methoxycarbonyl) -2-. {- [l-methyl-4-oxo-7 - ( { [1 - (trifluoromethyl ) imidazol-2-yl) amino.} methyl) (3-hydroquinolyl)] carbonylamino, yl) yl) amino] sulfonyl] -3,5-dimethylphenoxy) butanoylamino] ethyl} - 2 - [(terbutoxy) carbonylamino] propansulfonic A solution of the product from Part E above (405 mg, 0.425 mmol), the p-nitrophenyl ester of Boc-L-cysteic acid (425 mg, 1.03 mmol) and DIEA (0.435 mL, 2.55 mmol) in 20 mL of DMF Anhydrous is stirred at room temperature under nitrogen for 3 h. 1 DMF is removed under vacuum and the resulting oil is purified by CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 1.12% / min of ACN 9 to 54% containing 0.1% TFA at a rate of flow of 80 ml / min. The peak of the main product eluting at 37.3 min is lyophilized to afford the title compound as a colorless solid (410 mg, 80.2%). MS: m / e 1204.4 [M + H], 962.3 [M + H-Trt].
Part F - Preparation of the acid (2R) -N-. { 2- [4- (4- { [(SS) -1- (methoxycarbonyl) -2-. {[[L-methyl-4-oxo-7- ( { [1 - (trif.-enylmethyl) imidazole] -2-yl] amino.} Methyl) (3-hydroquinolyl)] carbonylamino, ethyl) amino] sulfonyl} -3,5-dimethylphenoxy) butanoylamino] ethyl} -2-aminopropanesulfonic The product of part E above (410 mg, 0.341 mmol) is dissolved in 20 ml of 50/50 TFA / DCM and allowed to react at room temperature for 10 min. The solution is concentrated and the resulting amber oil is dissolved in 50 ml of 50% ACN and lyophilized to give the title compound as a colorless solid (371 mg, 98.6%). MS: m / e 1104.4 [M + H], 862.3 [M + H-Trt]; High resolution MS: Calculated for C55H62N9012S2 [M + H]: 1104.3959; Found: 1104,393.
Part G - Preparation of the acid (2R) -N- [(IR) -1- (N- { 2- [4- (4- { [((ÍS) -1- (methoxycarbonyl) -2- {[[l-methyl-4-oxo-7- ( { [1- (trif.-enylmethyl) imidazol-2-yl] amino} methyl) (3-hydroquinolyl)] carbonylamino} ethyl) amino ] sulphonyl] -3,5-dimethyl-yl-enoxy) -butanoyl-amino] -ethyl} -carbamoyl) -2-sulf-o-ethyl] -2- [(tert-butoxy) carbonylamino] -propansulfonic acid.
A solution of the product of part F above (110 mg, 0.100 mmol), the p-nitrophenyl ester of Boc-L-cysteic acid (82.4 mg, 0.200 mmol) and DIEA (0.104 ml, 0.600 mmol) in 5.0 ml of DMF Anhydrous is stirred at room temperature under nitrogen for 48 h. The DMF is removed under vacuum and the resulting amber oil is purified by CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 1.12% / min of ACN 9 to 54% containing 0.1% TFA at a speed flow rate of 80 ml / min. The main product peak elutes at 37.0 min. Is lyophilized to provide the title compound as a colorless solid (96.0 mg, 70.9%). MS: m / e 1355.3 [M + H], 113.3 [M-Trt + H], 1013.2 m-Trt-Boc + H].
Part H - Preparation of the acid (2R) -N- [(IR) -1-. { 2- [4- (4- { [((1S) -1- (methoxycarbonyl) -2-. {[[L-methyl-4-oxo-7- ( { [1- (trif.-enylmethyl)] imidazol-2-yl] amino.} methyl) (3-hydroquinolyl) J carbonylamino) ethyl) amino] sulfonyl} 3, 5-dimethyl-enoxy) utanoylamino] ethyl} carbamoyl) -2-sulphonoethyl] -2-aminopropansul phonic The product of part G above (21 mg, 0.0155 mmol) is dissolved in 5.0 ml of 50/50 TFA / DCM and allowed to react at room temperature for 10 min. The solution is concentrated and the residue is taken up in 15 ml of 50% ACN and lyophilized to give the title compound as a colorless solid (18.7 mg, 96.2%). MS: m / e 1255.3 [M + H], 1013.2 [M + H-Trityl]; High resolution MS: Calculated for C 58 H 67 N 10 O 16 S 3 [M + H]: 1255.3899; Found: 1255,391.
Part I - Preparation of the acid (2R) -N- [(IR) -1- (N- { 2- [4- (4- { [((ÍS) -1- (methoxycarbonyl) -2- {. [1 -me t il-4-oxo-7 - ( { [1- (trifluoryl) imidazol-2-yl] amino} methyl) (3-hydroquinolyl)] carbonylamino) ethyl) amino ] sulfonyl] -3,5-dimethyl-yl-enoxy) -butanoylamino] -ethyl} carbamoyl) -2-sulfoethyl] -2- (2- { 1, 4, 7, 1 0 - tet raaz a-4, 7, 1 0 - t ri s [(t-butoxycarbonyl) methyl] cyclododecyl} acetylamino) propanesulfonic.
A solution of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxycarbonyl) methyl) cyclododecyl) acetic acid (30.0 mg, 0.0327 mmol) (as described in DM-7003), DIEA (0.034 ml, 0.196 mmol) and HBTU (9.3 mg, 0.0245 mmol) in 1.5 ml of anhydrous DMF is stirred under nitrogen at room temperature for 15 min and treated with the product from part H above ( 18.7 mg, 0.0137 mmol). The DMF is removed under vacuum after 75 min and the resulting amber oil is purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 0.9% / min of ACN 22.5 to 58.5% containing TFA 0.1 % at a flow rate of 20 ml / min. The peak of the main product elutes at 26.1 min and is lyophilized to provide the title compound as a fluffy solid without color (7.5 mg, 53%). MS: m / e 1809.7 [M + H].
Part J - Preparation of the trifluoroacetate salt of (2S) -2 - [(. {2,6-dimethyl-4- [3- (N-. {2- [3-sulfon-2- (3)} -sulfo-2 - {2 - [1,4,7,10-tetraaza-4,7,10-tris (carboxymethyl) cyclododecyl] -acetylamino) propyl) propyl] ethyl} carbamoyl) propoxy] phenyl} sulphonyl) amino] -3- ( { 1 - [(imidazol-2-ylamino) methyl] -l-methyl-4-oxo (3-hydroquinolyl).}. carbonylamino) propanoic The product from step I above (7.5 mg, 0.0039 mmol) is dissolved in a solution of 1.40 ml of peroxide-free THF and 0.21 ml of water, and treated with 0.14 ml of 3 N LiOH. The mixture is stirred at room temperature under nitrogen for 1 h and concentrated to dryness under vacuum. The resulting solid residue is dissolved in 2.0 ml of TFA / Et3SiH 95/5 and heated at 70 ° C under nitrogen for 1 h. The solution is concentrated under vacuum and the resulting solid residue is purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 0.90% / min of ACN from 0 to 27% containing 0.1% TFA at a flow rate of 20 ml / min. The peak of the main product elutes at 20.5 min and is lyophilized to provide the title compound as a colorless fluffy solid (4.2 mg, 71.9%). MS: m / e 1385.3 [M + H]; High resolution MS: Calculated for C54H77N14023S3 [M + H]: 1385.4448; found: 1385,446.
Example 30 Synthesis of the bis (trifluoroacetate) salt of the conjugate of DOTA / acid (2S) -2-. { [(4- { 3- [N- (2- { 2- [(4S) -4- (N- (1- [N- (2- { 4- [4- (. { . ((SS) -1-carboxy-2- ( { 7- [(imidazol-2-ylamino) methyl] -1- methyl-4-oxo (3-hydroquinolyl).] Carbonylamino) ethyl] amino} sulfonyl) -3,5-dimethylphenoxy] butanoylamino} ethyl) carbamoyl] -2-sulfoethyl) carbamoyl) -4-aminobutanoylamino] -3-sulfopropyl) ethyl) carbamoyl] propoxy. - dimethylphenyl) sulfonyl] amino} -3- ( { 7- [(imidazol-2-ylamino) methyl] -l-methyl-4-oxo (3-hydroquinolyl).] - carbonylamino) propanoic Part A - Preparation of (2S) -2- [(terbutoxy) carbonylamino] pentane-1,5-dioatium Di-2, 3,5,6-tetraf luorofenyl To a solution of Boc-L-Glu-OH (28.9 g, 117 mmol) in 500 ml of DMF at room temperature and under nitrogen is added a solution of 2, 3, 5, 6-tetrafluorophenol (48.2 g, 290 mmol. ) in 50 ml of DMF. After stirring for 10 min, EDC (55.6 g, 290 mmol) is added and the mixture is stirred for 96 h. The volatile fractions are removed under vacuum and the residue is triturated with 750 ml of 0.1 N HCl. 600 ml of EtOAc are added to this mixture and the layers are separated. The aqueous layer is extracted with EtOAc (3 x 500 ml) and all the EtOAc extracts are combined, washed consecutively with 300 ml of water and 300 ml of saturated NaCl, dried with MgSO 3 and concentrated to provide 62 g of a solid cinnamon. The cinnamon solid is washed with ACN to provide the title compound (45.5 g, 73.0%) in purified form. MS: m / e 566.0 [M + Na].
Part B - Preparation of the acid (2R) -2- [4- (N- { (IR) -1- [N- (2- { 4- [4- ( { [(ÍS) - 2- ( { [1- (triphenylmethyl) imidazol-2-yl] amino) methyl] -1-methyl-4-oxo (3 -hidroquinolil).}. carbonylamino) -1- (methoxycarbonyl) ethyl] amino sulfonyl) -3,5-dimethylphenoxy] butanoylamino, ethyl) -carbamoyl] -2-sulfoethyl) carbamoyl) (4S) -4- [(tert-butoxy) -carbonylamino] butanoylamino] -N- (2 - { 4- [4- ( { [(ÍS) -2- ( { 7- [(imidazol-2-ylamino) methyl] -l-methyl-4 -oxo (3-hydroquinolyl)} -carbonylamino) -1- (methoxycarbonyl) ethyl]] amino.}. sulfonyl) -3,5-dimethylphenoxy] butanoylamino) ethyl) propanesulfonic A solution of the product of Example 29, part F (130 mg, 0.118 mmol), the product of Part A above (27.2 mg, 0.050 mmol) and DIEA (0.070 ml, 0.40 mmol) in 0.0 mL anhydrous DMF is stirred at room temperature under nitrogen for 29 h. The DMF is removed under vacuum and the resulting amber oil is purified by CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.90% / min of ACN from 22.5 to 58.5% ACN containing 0.1% TFA at a flow rate of 80 ml / min. The peak of the main product eluting at 35.7 min is lyophilized to afford the title compound as a colorless fluffy solid (108 mg, 89.3%). MS: m / e 2419.6 [M + H], 1210.4 [M + 2H].
Part C - Preparation of the acid (2R) -2- [4- (N- { (IR) -1- [N- (2- { 4- [4- ( { [(ÍS) - 2- ( { 7- [ { [1- (triphenylmethyl) imidazol-2-yl] amino) methyl] -l-methyl-4-oxo (3 -hidroquinolil).}. carbonylamino) • 1- ( methoxycarbonyl) ethyl] amino.}. sulfonyl) -3,5-dimethylphenoxy] butanoylamino.} ethyl) carbamoyl] -2-sulphonyl) carbamoyl) (4S) -4-aminobutanoi lamino] -N- (2-. { 4- [4- ( { [(LS) -2- ( { 7- [(imidazol-2-ylamino) methyl] -l-methyl-4-oxo (3-hydroquinolyl).} - carbonylamino) -1- (methoxycarbonyl) ethyl] -amino.}. sulfonyl) -3,5-dimethyl-yl-enoxy] -butoyl-lamino-yl) -propansulfonic acid The product of part B above (107 mg, 0.0442 mmol) is dissolved in 5.0 ml of TFA / DCM 50/50 and allowed to react at room temperature under nitrogen for 10 min. The solution is concentrated and the resulting amber oil is dissolved in 25 ml of 50% ACN and lyophilized to give the title compound as a light yellow solid (105 mg, 98.0%). MS: m / e 1159.9 [M + 2H]; 1039.4 [M + 2H-Trt].
Part D - Preparation of the conjugate of the tri-t-butyl ester of DOTA / acid / (2R) -2- [4- (N- { (IR) -1- [N- (2-. {4- [4- ( { [(ÍS) -2- ( { 7- [ { [1- (triphenylmethyl) imidazol-2-yl] amino) methyl] -l-methyl-4-oxo (3 -hydroquinolyl).) carbonylamino) -1- (methoxycarbonyl) ethyl] amino.}. - sulfonyl) -3,5-dimethylphenoxy] butanoylamino.} ethyl) carbamoyl] -2-sulfoethyl) carbamoyl) (4S) -4 -aminobutanoylamino] -N- (2- { 4- [4 - ( { [(ÍS) -2- ( { 7- [(imidazol-2-ylamino) methyl] -l-methyl-4 -oxo (3-hydroquinolyl).] .carbonylamino) -1- (methoxycarbonyl) ethyl] -amino.] sulfonyl) -3,5-dimethyl-phenoxy] butanoylamino) yl) -propanesulfonic acid A solution of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxocarbonyl) methyl) cyclododecyl) acetic acid (31.6 mg, 0.0346 mmol) (as described in DM-7003), DIEA (0.072 ml, 0.416 mmol) and HBTU (9.8 mg, 0.026 mmol) in 1. 8 ml of anhydrous DM is stirred under nitrogen at room temperature for 15 min and treated with the product of part C above (40.0 mg, 0.173 mmol). The DMF is removed under vacuum after 90 min and the clear yellow oil resulting on HPLC purified on a Vydac C-18 (50 x 250 mm) column using a gradient of 1.01% / min of ACN of 22.5 to 63.0% containing TFA 0.1% at a flow rate of 80 ml / min. The peak of the main product elutes at 27.6 min and is lyophilized to provide the title compound as a colorless solid (29.0 mg, 62.4%). MS: m / e 1437.6 [M + 2H], 1316.6 [M + 2H-Trt].
Part E - Preparation of the bis (trifluoroacetate) salt of the DOTA / acid (2S) -2- conjugate. { [(4- { 3- [N- (2- { 2- [(4S) -4- (N- { L- [N- (2 - { - [4- ( { [(iS) -l-carboxy-2- ( { 7- [(imidazol-2-ylamino) methyl] -l-methyl-4-oxo (3 -hidroquinolil).}. carbonylamino) -ethyl] amino.}., .sulfonyl) -3,5-dimethyl-phenoxy] -butaoylamino.} - ethyl) carbamoyl] -2-sulfoethyl) carbamoyl) -4-aminobutanoylamino] -3-sulfopropyl-ketoyl) carbamoyl] propoxy} -2, 6 -dimethylphenyl) sulfonyl] amino} -3- ( { 7- [(imidazol-2-ylamino) methyl] -l-methyl-4-oxo (3-hydroquinolyl).] Carbonylamino) propanoic A mixture of the product from part D above (30.0 mg, 0.0104 mmol), 3.2 ml of peroxide-free THF, 0.485 ml of water and 3 N LiOH (0.320 ml, 0.96 mmol) are stirred at room temperature under nitrogen for 2 h. The solution is concentrated under vacuum and the resulting solid residue is dissolved in 5.0 ml of TFA / Et3SiH 95/5. The solution is heated at 70 ° C under nitrogen for 1 h and concentrated under vacuum. The resulting oily solid is purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 0.90% / min of ACN 0 to 27% as it contains 0.1% TFA and at a flow rate of 20 ml / min . The main product peak elutes at 27.8 min and is lyophilized to provide the title compound as a colorless fluffy solid (12.8 mg, 48.5%). MS: m / e 1096.8 [M + 2H], 731.8 [M + 3H]; High resolution MS: Calculated for C91R122l22023Yes [M + H]: 2192.7458; Found: 2192,741.
Example 31 Synthesis of the salt of trifluoroacetate of 2- [(. {4- [3- (N- [(2R) -2- ((2R) -3-sulfo-2-. {2- [1, 4 , 7, 10-tetraaza-4, 7, 10-tris (carboxymethyl) - (cyclododecyl] acetylamino,} propyl) -3-sulfopropyl] ethyl} carbamoyl) propoxy] -2,6-dimethylphenyl) sulfonyl) amino ] (2S) -3- ( { 7- [(imidazol-2-ylamino) methyl] -l-methyl-4-oxo (3-hydroquinolyl).} Carbon] lamino) propanoic Part A - Preparation of the acid 2- ( { [4- (3 { N- [2- ((2R) -2-amino-3-sulfopropyl) ethyl] carbamoyl} propoxy) -2, 6-dimethyl phenyl] sulfonyl. Amino) (2S) -3-. { [L-methyl-4-oxo-7- ( { [1- (trif.-enylmethyl) imidazol-2-yl] amino) methyl) (3-hydroquinolyl)] carbonylamino) propanoic A mixture of the product of example 29, part F (125 mg, 0.113 mmol), 3.8 ml of peroxide-free THF, 0. 57 ml of water and 3 N LiOH (0.38 ml, -1.13 mmol) are stirred at room temperature under nitrogen for 1 h. The mixture is adjusted to pH 1 using 0.70 ml of 1 N HCl and concentrated to dryness under vacuum. The resulting solid is purified by CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.90% / min of ACN from 18 to 54% containing 0.1% TFA at a flow rate of 80 ml / min. . The main product peak eluting at 21.0 min is lyophilized to provide the title compound as a colorless solid (96.0 mg, 77.9%). EM; m / e 1090.3 [M + H], 848.2 [M + H-Trt]; High resolution MS: Calculated for C54H60N9O12S2 [M + H]: 1090.3808; Found: 1090.381.
Part B - Preparation of the acid 2- ( { [4- (3- { N- [2- ((2R) -2- { (2R) -2- [(tert-butoxy) carbonylamino] -3-sulfopropyl) -3 • sulphopropyl) and il] carbamoyl-J-propoxy) -2,6-dimyl-tyl-enyl] -sulfonyl) amino) (2S) -3-. { [L-methyl-4-oxo-7- ( { [1- (trif.-enylmethyl) imidazol-2-yl] amino) methyl) (3 • hydroquinolyl)] carbonylamino) propanoic A solution of Boc-L-cysteic acid (37.0 mg, 0.128 mmol), DIEA (0.040 ml, 0.228 mmol) and PyBOP (53.0 mg, 0.102 mmol) in 1.0 ml of anhydrous DMF is stirred at room temperature under nitrogen for 15 min. , and it is added to a solution of the product of part A above (93.0 mg, 0.0854 mmol) and DIEA (0.045 ml, 0.256 mmol) in 3.0 ml of anhydrous DMF. The resulting solution is stirred at room temperature under nitrogen for 1.5 h and concentrated to a viscous amber oil. Purification by CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.68% / min of ACN from 18 to 45% "containing 0.1% DFA at a flow rate of 8D ml / min. Peak of the main product eluted at 36.4 min and lyophilized to give the title compound as a colorless solid (94.0 mg, 82.1%) MS: m / e 1341.2 [M + H], 1099.1 [M + H + Trt], 999.1 [M + H-Trt-Boc].
Part C - Preparation of the acid 2-. { [(4- { 3- [N- (2- { (2R) -2- [(2R) -3-sulfo-2- (2- { L, 4,7,10-tetraaza 4,7,10-tris [(tert-butoxycarbonyl) methyl] cyclododecyl}. Cetylamino) propyl] -3-sulfopropyl-Jetyl) carbamoyl] propoxy] -2,6-dimethyl enyl) sulfonyl] amino} (2S) -3-. { [L-methyl-4-oxo-7- ( { [1- (trif.-enylmethyl) imidazol-2-yl] amino} methyl) (3-hielro? uinolyl)] carbonylamino) propanoic A solution of the product from part B above (90.0 mg, 0.0672 mmol) in 10.0 ml of TFA / DCM 50/50 is allowed to react at room temperature under nitrogen for 10 min and concentrated under vacuum to provide the intermediate amine as a amber oil MS: m / e 1241.3 [M + H], 999.3 [M + H-Trt]; High resolution EM: Calculated for C57H65N10O16S3 [M + H]: 1241.3742; Found: 1241,375. A solution of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxycarbonyl) methyl) cyclododecyl) acetic acid (123 mg, 0.134 mmol) (as described in DM-7003), DIEA (0.092 ml, 0.538 mmol) and PyBOP (52.4 mg, 0.101 mmol) in 1.5 ml of anhydrous DMF is stirred under nitrogen at room temperature for 15 min and added to a solution of the free amine produced before (90.0 mg, 0.0672 mmol) and DIEA (0.046 ml, 0.269 mmoles) in 1.5 ml of anhydrous DMF. The DMF is removed under vacuum after 1 h and the resulting amber oil is purified by CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.288% / min of ACN from 30.6 to 45% containing TFA 0.1 % at a flow rate of 80 ml / min. The peak of the main product elutes at 25.8 min and is lyophilized to provide the title compound as a colorless solid. (92.0 mg, 76.3%). MS: 1795.6 [M + H], 1553.5 [M + H-trt]; High resolution MS: Calculated for CasH ^ N ^ O ^ Sa [M + H]; 1795.7422; Found: 1795,744.
Part D - Preparation of the trifluoroacetate salt of 2- [[(. {4- [3- (N-. {2- [(2R) -2- ((2R) -3-sulfo-2- (2- {, 1, 4, 7, 10-tetraaza-4, 7, 10-tris (carboxymethyl) cyclododecyl] acetylamino) propyl) -3-sulfo-ropolyl] ethyl} carbamoyl) propoxy] -2, 6 -dime tilf eni l) s ul f oni l) am i no]) 2 S) - 3-hydroquinolyl)} carbonylamino) propanoic A solution of the product from part C above (89.0 mg, 0.0496 mmoles) in 10. O ml of TFA / Et3SiH 97/3 is heated at 70 ° C under nitrogen for 30 min and concentrated in vacuo. The resulting oily solid is purified by CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.45% / min of ACN from 4.5 to 22.5% containing 0.1% TFA at a flow rate of 80 ml / min. The main product peak elutes at 19.5 min and is lyophilized to provide the stoichiometrically pure title compound as a colorless fluffy solid (65.0 mg, 87.5%). MS: m / e 1385.4 [M + H].
Example 32 Alternative Synthesis of the Intermediate Acid 2- ( { [4- (3- { N- [2- ((2R) -2-amino-3-sulfopropyl) ethyl] carbamoyl) propoxy) -2,6-dimethylphenyl ] sulfonyl} amino) (2S) -3-. { [L-methyl-4-oxo-7- ( { [1- (triphenylmethyl) imidazol-2-yl] amino.} methyl) (3-hydroquinolyl)] carbonylamino} propanoic Part A - Preparation of the acid (2S) -2-. { [(4-. {3- [N- (2-aminoethyl) carbamoyl] propoxy) -2,6-dimethylphenyl) sulfonyl] amino} - 3-. { [L-methyl-4-oxo-7- ( { [1- (trif.-enylmethyl) imidazol-2-yl] amino.} methyl) (3-hydroquinolyl)] carbonylamino} propanoic A mixture of the product of example 29, part D (956 mg, 1004 mmol), 35 ml of peroxide-free THF, 5.3 ml of water and 3 N LiOH (3.53 ml, 10.6 mmol) is stirred at room temperature "under nitrogen for 1 h and adjusted to pH 5-6 using 10 ml of 1 N HCl The THF is removed under vacuum which causes a gummy yellow solid to precipitate, the water layer is removed by decanting and the solid is washed with water. 15 ml of water The solid is dried under vacuum to provide the title compound as a dry yellow solid.
Part B - Preparation of the acid 2-. { [(4- { 3- [N- (2- [(2R) -2- [(tert-butoxy) carbonylamino] -3-sulfopropyl) ethyl) carbamoyl] propoxy} -2, 6 -dimethylphenyl) sulfonyl] amino. { (2S) -3-. { [L-methyl-4-oxo-7- ( { [1- (triphenylmethyl) imidazol-2-yl] amino.} methyl) (3-hydroquinolyl)] carbonylamino} propanoic A solution of Boc-L-cysteic acid (175 mg, 0. 60 mmol), DIEA (0.208 ml, 1.20 mmol) and PyBOP (250 mg, 0.480 mmol) in 5.0 ml of anhydrous DMF are stirred at room temperature under nitrogen for 17 min, and added to a solution of the product from part A previous (375 mg0.400 mmole) and DIEA (0.070 ml, 0.400 mmole) in 4.0 ml of anhydrous DMF. The resulting solution is stirred at room temperature under nitrogen for 45 min and concentrated under vacuum to provide an amber oil. Purification by PLC on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.292% / min of ACN from 31.5 to 43.2% containing 0.1% TFA at a flow rate of 80 ml / min. The main product peak elutes at 22.0 min and is lyophilized to provide the title compound as a colorless solid (430 mg, 90.4%). MS: m / e 1190.3 [M + H], 948.3 [M + H-Trt].
Part C - Preparation of 2- ( { [4- (3- { N- [2- ((2R) -2-amino-3-sulfopropyl) ethyl] carbamoyl}. Propoxy) -2, 6-dimethylphenyl] sulfonyl, amino) (2S) -3-. { [L-methyl-4 -oxo-7- ( { [1- (trifluoromethyl) imidazol-2-yl] amino) methyl) (3-hydroquinolyl)] carbonylamino} propanoic A solution of the product of part B, above (430 mg, 0.362 mmol) in 15 ml of TFA / DCM 50/50 is allowed to react at room temperature under nitrogen for 10 min and concentrated under vacuum. The resulting amber oil is taken up in 50 ml of 50% ACN and lyophilized to give the title compound as a light yellow solid (398 mg, 100%). MS: m / e 1090.3 [M + H], 842.2 [M + H-Trt].
Example 33 Synthesis of the DOTA / 2-acid conjugate. { [(4- { 3 - [N- (2- { (2R) - 2 - [(2R) -2- (4- { N- [(IR) -1- (N- { (IR) -1- [N- (2- { 4- [4- ( { [(1S) -1- carboxy-2- ( { 7- [(imidazol-2-ylamino ) methyl] -l-methyl-4 -oxo (3-hydroquinolyl).] carbonylamino) -1-carboxyethyl] amino.} sulfonyl) 3, 5-dimethylphenoxy] butanoylamino) ethyl) carbamoyl] -2-sulfoethyl. carbamoyl) -2-sulfoethyl] carbamoyl { (2S) -2-aminobutanoylamino) -3-sulfopropyl] -3-sulfopropyl} ethyl) carbamoyl] propoxy) -2,6-di ethylphenyl) sulfonyl] amino. { (2S) -3- ( { 7- [(imidazol-2-ylamino) methyl] -l-methyl-4-oxo (3-hydroquinolyl).}. Carbonylamino) propanoic Part A - Preparation of the acid 2-. { [(4- { 3- [N- (2- { (2R) -2- [(2R) -2- (4- { N- [(lR) -l- (N- { (1R) -1- [N- (2- { 4- [4- ( { [(ÍS) -l-carboxi-2- ( { 7- [( { L- (triphenylmethyl) imidazol-2-yl) amino) methyl] -l-methyl-4-oxo (3-hydroquinolyl).] carbonylamino) -1-carboxyethyl] amino} sulfonyl) -3,5-dimethylphenoxy] butanoylamino ) ethyl) carbamoyl] -2-sulphonylcarbamoyl) -2-sulfoethyl] carbamoyl. {(2S) -2- [(tert-butoxy) carbonylamino] butanoylamino) -3-sulfopropyl] -3-sulf opropyl j ethyl) carbamoyl] propoxy) -2,6-dimethylphenyl) sulfonyl] amino. { (2 S) -3 - ( { 7 - [( { 1 -trifenylmethyl) imidazol-2-yl}. Amino) methyl] -1-methyl--oxo (3-hydroquinolyl). { carbonylamino) propanoic A solution of the product of the first half of example 31, part C (136 mg, 0.110 mmol), DIEA (0.076 ml, 0.44 mmol) and the product of example 30, part A (26.2 mg, 0.050 mmol) in 3.0 ml of Anhydrous DMF is stirred at room temperature under nitrogen for 7 h. The DMF is removed under vacuum and the viscous amber oil is purified by CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.45% / min of ACN from 27 to 45%, followed by a gradient of 0.72. % ACN 45-63% containing 0.1% TFA at a flow rate of 80 ml / min. The main product peak eluting at 75.2 min is lyophilized to afford the title compound as a colorless solid (129 mg, 47.9%). MS: m / e 1347.3 [M + 2H].
Part B - Preparation of the conjugate of the tri-t-butyl ester DOTA / acid 2-. { [(4- { 3- [N- (2- { (2R) -2- [(2R) -2- (4- { N- [(IR) -1- (N- { (IR) -1- [N- (2- { 4- [4- [ { [(ÍS) - 1 - carboxy - 2 - (. {7- 7- ( { (trifluoromethyl) imidazol-2-yl.} amino) methyl] -l-methyl-4-oxo (3-hydroquinolyl).] carbonylamino) -1-carboxyethyl] amino.} sulfonyl) - 3, 5 -dimethyl-enoxy] -butanoylamino-} ethyl) carbamoyl] -2-sulfoethyl-} carbamoyl) -2-sulfoethyl] carbamoyl} - (2S) -2-aminobutyl-yl-amino) -3-sulphopropyl] - 3-sulfopropyl] ethyl) carbamoyl] propoxy} - 2,6-dimethylphenyl) sulfonyl] amino) (2S) -3- (. {7- [(. {L- (triflumethyl) imidazol-2-yl] amino) methyl] -l-methyl -4 -oxo (3-hydroquinolyl).}. Carbonylamino) propanoic,. The product of part A above (34.0 mg, 0.0? 26 mmol) is dissolved in 12 ml of TFA / DCM 50/50 and allowed to react at room temperature under nitrogen for 10 min. ^ The solution is concentrated and the oil The resulting amber is dried under vacuum. A solution of 2- (1, -4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxycarbonyl) methyl) cyclododecyl) acetic acid (23.1 mg, 0.0253 ^ mmoles), DIEA ( 0.020 ml, 0.115 mmoles) and PyBOP (9.8 mg, 0.019 mmoles) in 2.0 ml of anhydrous DMF are stirred under nitrogen at room temperature for 15 min., and add to a solution of the deprotection reaction product, above and DIEA (0.020 ml, 0.115 mmole) in 2.0 ml of anhydrous DMF. The DMF is removed under vacuum after 2 h and the resulting residue is purified by CLAP on a Vydac C-18 column (50 x 250 mm) using a gradient of 0.45% / min of ACN 27 to 49.5% containing 0.1% TFA a flow rate of -80 ml / min. The main product peak elutes at 43.8 min and is lyophilized to give the title compound as a dry colorless (16.0 mg, 40.4%). MS: m / e 1574.8 [M + 2H], 1453.7 [M + 2H-Trt], 1332.2 [M + 2H-2Trt].
Part C - Preparation of the DOTA / acid conjugate 2-. { [(4- { 3- [N- (2- { (2R) -2- [(2R) -2- (4- (N- [(IR) -1- (N- { (IR) -1- [N- (2- { 4- [4- ( { [(ÍS) -l-carboxy-2- ( { 7- [(imidazol-2-ylamino) methyl ] -l-methyl-4-oxo (3-hydroquinolyl).] carbonylamino) -1-carboxyethyl] amino.} - - sulfonyl) - 3,5-dimethylphenoxy] butanoylamino) ethyl) carbamoyl] -2-sulfoethyl} carbamoyl) -2-sulfoethyl] carbamoyl} - (2S) -2-amino-butanoylamino) -3-sulfopropyl] -3-sulfopropyl) ethyl) carbamoyl] -propoxy} -2, 6-dimethylphenyl) sulfonyl] amino) (2S) -3- (. {7- [(imidazol-2-ylamino) methyl] -l-methyl-4-oxo (3-hydroquinolyl).] Carbonylamino ) -propanoic The product of part B above (14.0 mg, 0.00445 mmol) is dissolved in 8.0 ml of TFA / Et3SiH 95/5 and heated at 70 ° C under nitrogen for 1 h. The solution is concentrated under vacuum and the resulting yellow solid is purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 0.9% / min of ACN 0 to 27% containing 0.1% TFA at a speed flow rate of 20 ml / min. The main product peak elutes at 24.5 min and is lyophilized to provide the title compound as a colorless solid (8.2 mg, 73.9%). MS: m / e 1247 * .7 [M + 2H].
Example 34 Synthesis of the salt of trifluoacetate of (2S) -3- acid. { [7- [(imidazol-2-ylamino) methyl] -4-oxo-l- (3- {2- [1, 4,7, 10-tetraaza-4, 7, 10-tris (carboxymethyl) cyclododecyl] acetylamino.} - propyl) (3-hydroquinolyl)] carbonylamino} -2-. { [(2,4,6-trimethylphenyl) sulfonyl] amino} propanoic Part A - Preparation of the tris (trifluoroacetate) salt of (2S) -3- (~ { L - [(imidazol-2-ylamino) methyl] -4-oxo-l- [3- (2- (2- (2- .1, 4, 7, 10-tetraaza-4, 7, 10-tris [(tert-butoxycarbonyl) methyl] -cyclo odecyl) acetylamino) propyl] (3-hydroquinol i)} -carbonylamino) -2 -. { [(2,4,6-Trimethylphenyl) sulfonyl] amino) -propanoic acid A solution of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) dicarcarbonyl) methyl) cyclododecyl) acetic acid (89 mg, 0.0974 mmol) (as described in DM-7003), DIEA (0.103 ml, 0.607 mmol) and HBTU (28.0 mg, 0.0735 mmol) in 1.0 ml of anhydrous DMF is stirred under nitrogen at room temperature for 15 min and treated with a solution of the product of example 4, Part H (30.0 mg, 0.049 mmol) in 1.0 of anhydrous DMF. The DMF is removed under vacuum after 3 h and the residue is purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 1.08% / min of ACN 18 at 72% containing 0.1% TFA at a flow rate of 20 ml / min. The peak in the main product elutes at 17.5 min and is lyophilized to provide the title compound as a colorless solid (48.0 mg, 65.0%). MS: m / e 1164.7 [M + H].
Part B - Preparation of the salt tris ((2S) -3- (. {7- [(imidazol-2-ylamino) methyl] -4-oxo-l- [3- (2- { 1, 4,7,10-tetraaza-4, 7, 10-tris (carboxymethyl) cyclododecyl) -acetylamino) propyl] (3-hydroquinolyl).] carbonylamino) -2-. { [(2,4,6-trimethylphenyl) sulfonyl] amino) propanoic A solution of the product of part A above (48.0 mg, 0.0375 mmole) in 2.1 ml of TFA / Et3SiH 95/5 is stirred at 50 ° C under nitrogen for 2 h. The solution is concentrated under vacuum and the oily residue is purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient 1.2% / min ACN from 0 to 36% containing 0.1% TFA at a reflux rate of 20 ml / min. The peak of the main product elutes at 18.6 min. Is lyophilized to provide the title compound as a colorless solid (25.7 mg, 51.2%). MS: m / e 996.5 [M + H], Em high resolution: Calculated for C45H62N11013S [M + H] 996. 4249; Found: 996 .4278.
Example 35 Synthesis of the bis (trifluoroacetate) salt of 3- ( { L- [3- (2R) -3-sulfo-2-. {2- [1, 4, 7, 10-tetraaza-4, 7 , 10-tris (carboxymethyl) cyclododecyl] acetylamino.}. Propyl) propyl] -7 - [(imidazol-2-ylamino) methyl] -4 -oxo (3-hydroquinolyl)] carbonylamino) (2S) -2-. { [(2,4,6-trimethylphenyl) sulfonyl] amino} propanoic Part A - Preparation of the acid 3-. { [1- (3- { [1- (3- { (2R) -2- [(tert-butoxy) carbonylamino] -3-sulfopropyl}. Propyl) -7- [(imidazole-2- ilamino) methyl] -4-oxo (3-hydroquinolyl)] carbonylamino. (2S) -2- { [(2,4,6-trimethylphenyl) sulfonylamino.} propanoic A solution of the product of example 4, part H (105 mg, 0.125 mmol) and the N-hydroxysuccinimide ester of Boc-cysteic acid as described eti-Liebigs Ann. Chem. 1979, 776-783) (146 mg, 0.467 mmol) and DIEA (0.120 ml, 0.69 mmol) in 1.5 ral of anhydrous DMF is stirred at room temperature under nitrogen for 24 h. The DMF is removed under vacuum and the resulting solid residue is purified by CLAP on a column Vydac C-18 (22 x 250 mm) using a gradient of 0.68% / min of ACN 9 to 36% containing 0.1% TFA at a flow rate - 3Ó6 - of 20 ml / min. The peak of the main product elutes at 30.3 min and is lyophilized to provide the title compound as a colorless solid (73.0 mg, 67.9%). MS: m / e 861.3 [M + H].
Part B - Preparation of the trifluoroacetate salt of 3- acid. { [1- (3- ((2R) -2-amino-3-sulfopropyl] propyl) -7- [(imidazol-2-ylamino) methyl] -4-oxo (3-hydroquinolyl).] Carbonylamino} (2S) -2- { [(2,4,6-trimethylphenyl) sulfonylamino.} Propanoic The product of part B above is dissolved, (70.0 mg, 0.0814 mmoles) in 1.5 ml of DCM / TFA 2: 1 and allowed to react at room temperature under nitrogen during min. The solution is concentrated under vacuum and the amber oil is dissolved in 25 ml of 50% ACN and lyophilized to give the title compound as a colorless solid (70.8 mg, 99.5%). MS: m / e 761.2 [M + H]; High resolution MS: Calculated for C32H41N801DS2 [M + H]: 761.2387; Found: 761.2393.
Part C - Preparation of the bis (trifluoroacetate acid 3- [(1 -. {3 - 3 [(2R) - 3 - sulfo - 2- (2-. {1, 4, 7, 10- tetraaza-4, 7, 10-tris [(tert-butoxycarbonyl) methyl] cyclododecyl) acetylamino) -propyl] propyl.} - 7 - [(imidazol-2-ylamino) methyl) -4 -oxo (3-) hydroquinolyl)) carbonylamino] (2S) -2-. { [(2,4,6-Trimethylphenyl) sulfonyl] amino} propanoic A solution of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxycarbonyl) methyl) cyclododecyl) acetic acid (20.8 mg, 0.0228 mmol) (as described in DM-7003), DIEA (0.006 ml, 0.034 mmol) and HBTU (6.5 mg, 0.0171 mmol) in 0.5 ml of anhydrous DMF are stirred under nitrogen at room temperature for 5 min and treated with a solution of the product from part B previous (10.0 mg, 0.0114 mmol) and DIEA (0.006 ml, 0.034 mmole) in 0.5 ml of anhydrous DMF. Stirring is continued at room temperature for 24 h and the reaction is diluted with 3.0 ml of water, treated with 0.003 ml of concentrated ammonium hydroxide and stirred an additional 10 min. The solution is adjusted to pH 3 using 6.0 ml of 0.1 N HCl and further diluted with 5.5 ml of 10% ACN. This Be solution is directly purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 0.68% / min of ACN from 9 to 36% containing 0.1% TFA at a flow rate of 20 ml / min. . The peak of the main product elutes at 36.0 min and is lyophilized to provide the title compound as a colorless solid (12.0 mg, 68.3%). MS: m / e 1315.6 [M + H].
Part D - Preparation of the bis (trifluoroacetate) salt of 3- [(1- (3- (2R) -3-sulfo-2- (2- {747,7,10-tetraaza- 4, 7, 10-tris (carboxymethyl) cyclododecyl] acetylamino.] Propyl] propyl.] - 7 - [ { Imidazol-2-ylamino) met il] -4-oxo (3-hydroquinolyl)) - carbonylamino] (2S) -2-. { [(2,4,6-trimethylphenyl) sulfonyl] -amino} Propanoic A solution of the product of part C above (12.0 mg, 0.00778 mmol) in 1.0 ml of TFA / Et3SiH 95/5 is stirred at room temperature under nitrogen for 18 h. The solution is concentrated under vacuum and the oily residue is purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 1.2% / min of ACN 0 to 36% containing 0.1% TFA at a rate of flow of 20 ml / min. The peak of the main product eluting at 21.1 min is lyophilized to provide the title compound as a colorless solid (8.1 mg, 75.7%). MS: m / e 1147.3 [M + H]; High resolution MS: Calculated for C4ßH67N12017S2 [M + H]: 1147.4189; Found: 1147,418.
Example 36 Synthesis of acid 3-. { [1- (3 - { 2- [(6- { [(1E) -l-aza-2- (2-sulfophenyl) vinyl] amino) (3-pyridyl)) carbonylamino] (2R) - 3- sulfopropyl} propyl) -7- [(imidazol-2-ylamino) methyl] -4-oxo (3- 'hydroquinolyl)] carbonylamino) (2S) -2-. { [(2,4,6-trimethylphenyl) sulfonyl] amino} propanoic A solution of the product of example 35, part B (10.0 mg, 0.0101 mmol), DIEA (0.007 ml, 0.040 mmol), 2 - (2 - aza - 2 - ((5 - ((2,5 - dioxopyrrole idinyl) carbonyl) ) (2-pyridyl)) amino) vinyl) benzenesulfonic acid (5.3 mg, 0.0120 mmole) in 0.5 ml of anhydrous DMF is allowed to stand at room temperature under a nitrogen atmosphere for 48 h. Additional 2- (2-aza-2- ((5- ((5- (. {2, 5-dioxopyrrolidinyl) -carbonyl) (2-pyridyl)) amino) vinyl) benzenesulfonic acid (2.0 mg, 0.00455) mmoles) and stirring is continued for an additional 48 h.The DMF is removed under vacuum and the residue is purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 0.9% / min of ACN 0 to 36. % containing 0.1% TFA at a flow rate of 20 ml / min.The peak of the main product elutes at 30.0 min and freeze-dried to give the title compound as a colorless solid (2.5 mg, 23.3%). 1064.3 [M + H]; High resolution MS: calculated for C45H50N1; LO14S3 [M + H]: 1064.27005; Found: 1064-272 *.
Example 37 Synthesis of the bis (trifluoroacetate) salt of 3- acid. { [l- (3- { (2R) -2- [4- (N- { (IR) -1- [N- (3- (3- [N- ((2S) -2-carboxy -2- { [(2,4,6-Trimethylphenyl) sulfonyl] amino.} Ethyl) carbamoyl] -7 - [(imidazol-2-ylamino) methyl] -4-oxohydroquinolyl}. Propyl) carbamoyl] -2- sulfoethyl.} Carbamoyl) (2S) -2-. {2- 2- [1,4,7,10-tetraaza-4,7,1- tris (carboxymethyl) cyclododecyl] acetylamino.} Butanoylamino] - 3- sulfopropyl.] Propyl) -7- [(imidazol-2-ylamino) methyl] -4-oxo (3-hydroquinolyl)] carbonylamino. (2S) -2- { [(2, 4, 6- trimethylphenyl) sulfonyl] amino.} Propanoic Part A - Preparation of the acid 3-. { [1- (3- { (2R) -2- [4- (N- { (IR) -1- [N - (3 - { 3 - [N - ((2 S) - 2-c arb-sxy-2 -. {[[(2,4,6-trimethylphenyl) sulfonyl] amino} ethyl) carbamoyl] -7- [(imidazol-2-ylamino) met il] - 4 -oxohydroquinolyl Jpropil) carbamoyl] -2-sulf oethyl.}. Carbamoyl) (2S) -2- [(tert-butoxy) carbonylamino] -butanoylamino] -3-sulphopropyl.] Propyl) -7- [( imidazol-2-ylamino) methyl] -4 -oxo (3-hydroquinolyl)] carbonylamino. (2S) -2- { [(2,4,6-trimethylphenyl) sulfonyl] amino) propanoic A solution of the product of example 35, part B (38.0 mg, 0.0434 mmol), DIEA (0.015 ml, 0.0869 mmol) and the product of example 30, part A (10.9 mg, 0.0202 mmol) in 1. 0 ml of anhydrous DMF is stirred at room temperature under nitrogen for 48 h. The DMF is removed under vacuum and the amber oil is purified by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 0.68% / min of ACN from 9 to 36% containing 0.1% TFA at a speed flow rate of 20 ml / min. The peak of the main product elutes at 36.1 min and is lyophilized to provide the title compound as a colorless solid (13.5 mg, 38.6%). MS: m / e 1732.4 [M + H], 1632.2 [M + H-Boc].
Part B - Preparation of the trifluoroacetate salt of 3- acid. { [1- (3- { (2R) -2- [4- (N- { (IR) -1- [N- (3- { 3- [N- ((2S) -2 -carboxy-2- { [(2,4,6-trimethylphenyl) sulfonyl] amino.} ethyl) carbamoyl] -7 - [(imidazol-2-ylamino) methyl] -4-oxohydroquinolyl} propyl) carbamoyl] -2-sulfoethyl.} carbamoyl) (2S) -2-aminobutanoylamino] -3-sulfopropyl}. propyl) -7- [(imidazol-2-ylamino) methyl] -4-oxo (3-hydroquinolyl) carbonylamino) (2S) -2-. { [(2,4,6-trimethylphenyl) sulfonyl] amino} propanoic The product of part A above, (13.5 mg, 0. 00779 mmoles) is dissolved in 1.0 ml of 50/50 TFA / DCM and allowed to react at room temperature under nitrogen for 45 min. The solution is concentrated under vacuum to provide the title compound as a light amber oil. MS: m / e 1633.3 [M + H].
Part C - Preparation of the bis (trifluoroacetate) salt of 3- acid. { [1- (3- { (2R) -2- [4- (N- { (IR) -1- [N- (3- { 3- [N- ((2S) -2 -carboxi -2- { [(2, 4, 6-trimethylphenyl) sulfonyl] amino} ethyl) -carbamoyl] -7 - [(imidazol-2-ylamino) methyl] -4 -oxohydroquinolyl} propyl) carbamoyl] -2-sulfoethyl} carbamoyl) (2S) -2 -. { 2 - [1, 4, 7, 10-tetraaza-4, 7, 10-tri s [(tert-butoxycarbonyl) methyl] cyclododecyl] acetylamino} butanoylamino] -3-sulfopropyl} propyl) -7- [(imidazol-2-ylamino) methyl] -4 -oxo (3-hydroquinolyl) carbonylamino) (2S) -2-. { [(2,4,6-Trimethylphenyl) sulfonyl] amino} propanoic A solution of 2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (((tert-butyl) oxycarbonyl) methyl) cyclododecyl) acetic acid (15.0 mg, 0.0164 mmol) (as described in DM-7003) DIEA (0.004 ml) and HBTU (4.7 mg, 0.0124 mmol) in 0.5 ml of anhydrous DMF is stirred under nitrogen at room temperature for 8 min and treated with 0.00779 mmoles of the product solution from part B above and 0.004 ml of DIEA in 0.5 ml of anhydrous DMF. The solution is stirred at room temperature for 24 h, treated with 0.33 ml of 0.1 N NaOH, stirred for an additional 5 min and adjusted to pH 3 with 0.60 ml of 0.1 N HCl. The solution is diluted with 4.5 ml of water and purified directly by CLAP on a Vydac C-18 column (22 x 250 mm) using a gradient of 1.01% / min of ACN 9 to 49.5% containing 0.1% TFA at a flow rate of 20 ml / min. The peak of the main product eluting at 26.7 min is lyophilized to afford the title compound as a colorless solid (7.0 mg, 37.2%). MS: m / e 1094.4 [M + 2H]; High resolution MS: Calculated for C97H13SN2102gS4 [M + H]: 2186.8696; Found: 2186.867.
Part D - Preparation of the bis (trifluoroacetate) salt of 3- acid. { [1- (3- { (2R) -2- [4- (N- { (IR) -1- [N- (3- [3- [N- ((2S) -2-carboxy] -2 - { [(2,4,6-Trimethylphenyl) sulfonyl) amino) ethyl) -carbamoyl] -7 - [(imidazol-2-ylamino) methyl] -4-oxohydroquinolyl) -propyl) carbamoyl] -2 -sulfoethyl} carbamo? l) (2S) -2-. { 2- [1, 4,7, 10-tetraaza-4, 7, 10-tris (carboxymethyl) cyclododecyl] acetylamino} -butanoylamino] -3-sulfopropyl} propyl) -7- [(imidazol-2-ylamino) -methyl] -4 -oxo (3-hydroquinolyl)] carbonylamino} (2S) -2-yl (2,4,6-trimethylphenyl) sulfonyl] amino} propanoic A solution of the product of step C above (7.0 mg, 0.00290 mmol) in 1.0 ml of TFA / Et3SiH 95/5 is heated to reflux under nitrogen for 3 .. The solution is concentrated under vacuum and the oily residue is purified by CLAP in a Vydac C-18 column (22 x 250 mm) using a gradient of 1.2% / min of ACN from 0 to 36% containing 0.1% TFA at a flow rate of 20 ml / min. The peak of the main product elutes at 26.5 min and is lyophilized to provide the title compound as a colorless solid (4.5 mg, 66.1%). High resolution MS: Calculated for C85H112N21029S4 [M + H]; 2018.6818; Found: 2018.683.
Example 38 Synthesis of the In-111 complex of the conjugate of Example 29 A 70 μg conjugate of example 29 dissolved in 140 μl of 0.5 M ammonium acetate buffer (pH 4.8) followed by the addition of 2 mg of the sodium salt of the acid is added to a self-shielded flask of 2 μs shielded and folded. Genetic and 2.6 mCi (7 μl) of In-111 in 0.5 M HCl. The reaction mixture (specific activity is heated at 85 ° C for 20 minutes and analyzed by CLAP) Yield: 87.9% (total for the two isomers) Retention time: 12.5, 13.1 min.
CLAP method Column: Zorbax Rx C18, 25 cm x 4.6 mm Column temperature: ambient Flow: 1.0 ml / min Solvent A: 10 mM ammonium acetate Solvent B: acetonitrile Detector: IN-US ß-ram and UV to 220 nm wavelength Gradient t (min) 0 25 26 35 36 45% B 7 7 60 60 7 7 Example 39 Synthesis of the In-111 complex of the conjugate of Example 30 A 120 μg conjugate of Example 30 dissolved in 240 μl of 0.5 M ammonium acetate buffer (pH 4.7) followed by the addition of -2 mg of gentic acid is added to a 2-lead flask, shielded with lead and folded. (sodium salt) dissolved in 20 μl of H20 and 10 μl, 2.3 mCi of In-111 (NEN) in 0.5 N HCl (specific activity: 52 μg / mCi). The reaction mixture is heated at 100 ° C for 20 minutes and analyzed by CLAP. Yield: 94.7% (total for the two isomers); Retention time: 16.6 and 17.3 min.
CLAP method Column: Zorbax Rx C18, 25 cm x 4.6 mm Column temperature: ambient Flow: 1.0 ml / min Solvent A: 10 mM ammonium acetate Solvent B: acetonitrile Detector: IN-US ß-ram and UV to 220 nm wavelength Gradient t (min) 0 25 26 35 36 45 % B 10 15 60 60 10 10 Example 40 Synthesis of the In-111 complex of the conjugate of Example 31 A 70 μg conjugate of example 31 dissolved in 140 μl of 0.5 M ammonium acetate buffer (pH 4.8) followed by the addition of 2 mg of the sodium salt of the same is added to a 2 μm shielded and folded autosampler flask. gentic acid and 2.6 mCi (7 μl) of In-111 in 0.5 M HCl The reaction mixture (specific activity is heated to 85% for 20 minutes and analyzed by CLAP Yield: 92.2%, retention time: 12.9 min .
CLAP method Column: Zorbax Rx C18, 25 cm x 4.6 mm Column temperature: ambient Flow: 1.0 ml / min Solvent A: 10 mM ammonium acetate Solvent B: acetonitrile Detector: IN-US ß-ram and UV to 220 nm wavelength Gradient t (min) 0 25 26 35 36 45 % B 7 7 60 60 7 7 Example 41 Synthesis of the In-111 complex of the conjugate of example 33 A 107 μg of the conjugate of Example 33 dissolved in 140 μl of 0.5 M ammonium acetate buffer is added to a 2-fold shielded self-sampling flask. (pH 4.8) followed by the addition of 2 mg of the sodium salt of gentic acid and 2.6 mCi (7 μl) of In-111 in 0.5 M HCl. The reaction mixture (specific activity) is heated to 85 ° C during 20 minutes and analyzed by CLAP. Yield: 77.9%; Retention time: 17.8 min.
CLAP method Column: Zorbax Rx C18, 25 cm x 4.6 mm Column temperature: ambient Flow: 1.0 ml / min Solvent A: 10 mM ammonium acetate Solvent B: acetonitrile Detector: IN-US ß-ram and UV to 220 nm wavelength Gradient t (min) 0 25 26 35 36 45% B 9 11 60 60 9 9 Example 42 Synthesis of the In-111 complex of the conjugate of Example 34 A 25 μg conjugate of Example 34 and 1.0 mg of sodium salt of gentic acid dissolved in 50 μl of ammonium acetate buffer (0.4 M, pH 4.7) followed by the addition are added to a self-shielded flask with lead and fold. 1.2 mCi (5 μl) of In-111 in 0.05 M HCl (specific activity: 21 μg / mCi). The reaction mixture is heated at 80 ° C for 45 minutes and analyzed by CLAP and CCDI. Performance of 93.5% by CLAP, retention time; 16.7 min.
CLAP method Column: Zorba Rx C18, 25 cm x 4.6 mm Column temperature: environment Flow rate: 1.0 ml / min Solvent A: 25 mM sodium phosphate buffer at pH 6 Solvent B: acetonitrile Detector: radiometric iodide probe sodium (Nal) and UV at 220 nm wavelength Gradient t (min) 0 25 26 35 36 45 % B 10 20 60 60 10 10 Example 43 Synthesis of the In-111 complex of the conjugate of example 35 To a 1 cc autosampler flask covered with lead and folded, 40-50 μg of the conjugate of example 35 dissolved in 100 μl of ammonium citrate buffer (0.4 M, pH 4.7) is added followed by the addition of 2 mCi (5 μCi). μl) In-111 in 0.05 N HCl (specific activity: 25 μg / mCi). The reaction mixture is heated at 90-100 ° C for 30 minutes and analyzed by CLAP. 95% yield, retention time; 12.5 min.
CLAP method Column: Zorbax Rx C18, 25 cm x 4.6 mm Column temperature: ambient Flow: 1.0 ml / min Solvent A: 25 mM sodium phosphate buffer at pH 6 Solvent B: acetonitrile Detector: radiometric iodide probe sodium (Nal) and UV at 220 nm wavelength Gradient t (min) 0 25 26 35 36 45 % B 10 20 60 60 10 10 Example 44 Synthesis of the In-111 complex of the conjugate of example 37 A 150 μg of the conjugate of Example 37 dissolved in 300 μl of ammonium citrate buffer (0.3 M, pH 4.8) followed by the addition of 4.5 mCi (25 μl) is added to a 2 cc autosampler flask covered with lead and folded. of In-111 (NEN) in HCl 0.05 N (specific activity: 33 μg / mCi). The reaction mixture is heated at 100 ° C for 20 minutes and analyzed by CLAP. RCP: 80%, Retention time: 21 min.
CLAP method Column: Zorbax Rx C18, 25 cm x 4.6 mm Column temperature: ambient Flow: 1.0 ml / min Solvent A: 25 mM sodium phosphate buffer at pH 6 Solvent B: acetonitrile Detector: radiometric iodide probe sodium (Nal) and UV at 220 nm wavelength Gradient t (min) 0 25 26 35 36 45 % B 17 19 60 60 17 17 Examples 45-51 Synthesis of complexes of Y-90 and Lu-177 of the conjugates of examples 30, 31, 34, 35 and 37.
To a sealed and clean 5 ml bottle is added 0.5-1.0 ml of the appropriate conjugate solution (200 μg / ml in 0.5 M ammonium acetate buffer, pH 7.0-8.0) followed by 0.05 ml gentisate solution of sodium (10 mg / ml in 0.5 M ammonium acetate buffer, pH 7.0-8.0) and 10-40 μl of a solution of 90YC13 or 177LuCl3 (10-20 mCi) in 0.05N HCl. The reaction mixture is heated at 100 ° C for 5-10 minutes. After cooling to room temperature, a sample of the resulting solution is analyzed by CLAP and by ICCD.
CLAP Method A: The CLAP method using a C 18 column Reverse phase zorbax (4.6 mm x 25 cm, 80 A pore size) at a flow rate of 1.0 ml / min with a mobile phase gradient of 85% A (25 mM, pH 6.0 phosphate buffer) and 15% B (acetonitrile) at 75% A and 25% B at 20 min.
CLAP Method B: The CLAP method using a C 18 column Reverse phase zorbax (4.6 mm x 25 cm, 80 A pore size) at a flow rate of 1.0 ml / min with a mobile phase gradient of 90% A (25 mM, pH 6.0 phosphate buffer) and 10% B (acetonitrile) up to 80% A and 20% B at 20 min.
CLAP Method D: The CLAP method using a reverse phase C18 Zorbax column (4.6 mm x 25 cm, 80 A pore size) at a flow rate of 1.0 ml / min with a mobile phase gradient of 87% A (25 mM, pH 6.0 phosphate buffer) and 13% B (acetonitrile) up to 86% A and 14% B at 20 min.
CLAP Method F: The CLAP method using a reverse phase C18 Zorbax column (4.6 mm x 25 cm, 80 A pore size) at a flow rate of 1.0 ml / min with a mobile phase gradient of 92% D (25 mM ammonium acetate buffer, pH = 6.8) and 8% B (acetonitrile) up to 90% A and 10% B at 20 min.
CLAP Method G: The CLAP method using a reverse phase C18 Zorbax column (4.6 mm x 25 cm, 80 A pore size) at a flow rate of 1.0 ml / min with an isocratic mobile phase of 87% A ( 25 mM ammonium acetate buffer, pH = 6.8) and 13% B (acetonitrile) from 0 to 20 min.
Example 52 Synthesis of 99mTc (3- {[[(3- ({2- 2- (6- (diazenido) (3-pyridyl)) carbonylamino [(2R) -3-sulfopropyl) propyl) -7} - [(imidazol-2-ylamino) methyl] -4 -oxo (3-hydroquinolyl)] carbonylamino) (2S) -2-. { [(2,4,6-trimethylphenyl) sulfonyl] amino} propanoic) (tricine) (TPPTS) To a lyophilized flask containing 4.84 mg of TPPTS, 6.3 mg of tricine, 40 mg of mannitol, succinic acid buffer, pH 4.8 and surfactant Pluronic F-64 0.1%, 1.1 ml of sterile water for injection, 0.2 ml is added ( 20 ug) of the conjugate of example 36 in deionized water or 50% aqueous ethanol and 0.2 ml of 99p? Tc04 ~ (50 + 5 mCi) in saline. The reconstituted equipment is heated in a 100 ° C water bath for 15 min, and allowed to cool 10 minutes at room temperature. A sample of the reaction mixture is analyzed by CLAP. The yield is 89.0% and the retention time is 12.8 and 13.2 min (isomers).
CLAP method Column: Zorbax C18, 25 cm x 4.6 mm Flow rate: 1.0 ml / min Solvent A: 10 mM sodium phosphate buffer, pH 6.0 Solvent B: 100% CH3CN Gradient 0 - 25% B over 20 min.
Utility The pharmaceutical substances of the present invention are useful for imaging of angiogenic tumor vasculature, therapeutic cardiovascular angiogenesis and cardiac pathologies associated with the expression of vitronectin receptors in a patient or for treating cancer in a patient. The radiopharmaceuticals of the present invention are constituted of a gamma isotope or positron emitter are useful for imaging of pathological processes which involve angiogenic neovasculature, including cancer, diabetic retinopathy, macular degeneration, restenosis of blood vessels after angioplasty and healed from wounds, as well as atherosclerotic plaque, damage by myocardial reperfusion and myocardial ischemia, for or infarction. The radiopharmaceuticals of the present invention are constituted by an emitting isotope of beta, alpha or Auger electron radiation are useful for treatment of pathological processes involving angiogenic neovasculature, have provided a cytotoxic dose of radiation to the place of angiogenic neovasculature. The treatment of cancer is affected by the systemic administration of the radiopharmaceuticals that result in a dose of cytotoxic radiation to tumors.
The compounds of the present invention are constituted by one or more paramagnetic metal ions which are selected from gadolinium, dysprosium, iron and manganese and are useful as contrast agents for magnetic resonance imaging (MRI) of pathological processes involving angiogenic neovasculature, as well as atherosclerotic plaque, damage by myocardial reperfusion and myocardial ischemia, arrest or infarction. The compounds of the present invention are composed of one or more heavy atoms with an atomic number of 20 or greater and are useful as X-ray contrast agents for X-ray imaging of pathological processes involving angiogenic neovasculature as well as a plaque. atherosclerotic, damage of myocardial reproduction and myocardial ischemia, arrest or infarction. The compounds of the present invention comprised of a surfactant microsphere containing echogenic gas are useful as ultrasound contrast agents for sonography of pathological processes involving angiogenic neovaculature, as well as atherosclerotic plaque, myocardial reperfusion injury and myocardial ischemia, arrest or infarction. . Representative compounds of the present invention are tested in the following in vitro assays and in vivo models, and have been found to be active.
Human placental avb3 receptor assay immobilized Test conditions were developed and validated using [1-125] vitronectin. The validation test includes Scatchard format analysis (n = 3) where the number of receptor (Bmax) and Kd (affinity) are determined. The assay format is such that the compounds are preliminarily examined at final concentrations of 10 and 100 nM before determination of the IC50. Three standards (vitronectin, antibody against avB3, LM609 and anti-avB5, P1F6) and five reference peptides for the determination of the IC50 have been evaluated. Briefly, the method involves immobilization of previously isolated receptors in 96-well plates and incubation overnight. The receptors are isolated from normal fresh non-infectious human placenta (HIV, hepatitis B and C, syphilis and HTLV-free). The tissue is smoothed and the tissue residues are removed via centrifugation. The lysate is filtered. The receptors are isolated by affinity chromatography using the immobilized avB3 antibody. The plates are then washed 3x with wash buffer. Blocking buffer is added and the plates are incubated for 120 minutes at room temperature.
During this time, the compounds to be tested and the [1-125] vitronectin are premixed in a reservoir plate. The blocking buffer is removed and the compound mixture is pipetted. The competition is carried out for 60 min at room temperature. The material that does not bind after is removed and the wells are separated and counted by gamma scintillation.
OncomouseMR image formation The study involves the use of Oncomouse ™ c-Neu and FVB mice simultaneously, as controls. The mice are anesthetized with sodium phenobarbital and injected with approximately 0.5 mCi of radiopharmaceutical. Before the injection, the tumor location of each Oncomouse ™ is recorded and the size of the tumor is measured using calibrators. The animals are placed with the head towards the camera so that an image of the anterior or posterior part of the animals is formed. Dynamic images of 5 minutes are acquired serially for 2 hours using a 256 x 256 matrix and a 2x zoom lens. Upon completion of the study, images are evaluated by circumscribing the tumor as a target region of interest (ROI) and a background site in the neck area near the salivary glands of the carotid. This model can also be used to determine the effectiveness of the radiopharmaceuticals of the present invention consisting of beta-anisor isotopes, alpha or electron Auger. The radiopharmaceuticals are administered in appropriate amounts and the uptake in the tumors can be quantified non-invasively by imaging for those isotopes with matching gamma-emitting emission, or by cutting the tumors and counting the amount of radioactivity present by standard techniques. The therapeutic effect of radiopharmaceuticals can be determined by monitoring the growth rate of tumors in control mice versus those in mice administered with radiopharmaceuticals of the present invention. This model can also be used to determine the compounds of the present invention constituted of paramagnetic metals as MRI contrast agents. After administration of the appropriate amount of the paramagnetic compounds, the whole animal is placed in a commercially available magnetic resonance imaging formers to image the tumors. The effectiveness of the contrast agents can be easily seen by comparison with the images obtained from animals that are not administered a contrast agent. This model can also be used to determine that the compounds of the present invention are composed of heavy atoms as X-ray contrast agents. After administration of the appropriate amount of X-ray absorbing compounds, the entire animal is placed in a commercially available X-ray imager for imaging tumors. The effectiveness of contrast agents can be easily seen compared to images obtained from animals that are not given a contrast agent. This model can also be used to determine the compounds of the present invention consisting of tensoactive microspheres containing echogenic gas as ultrasound contrast agents. After administration of the appropriate amount of the echogenic compounds, images of the tumors in the animal can be imaged using an ultrasound probe which is kept close to the tumors. The effectiveness of the contrast agents can be easily seen by comparison with the images obtained from animals that are not administered a contrast agent.
Model of Matrigel of rabbit This model is adapted from a matrigel model designed for the study of angiogenesis in mice. Matrigel (Becton &Dickinson, USA) is a basement membrane rich in laminin, collagen IV, entactin, HSPG and other growth factors. When combined with growth factors such as bFGF [500 ng / ml] or VEGF [2 μg / ml] and injected subcutaneously into the middle abdominal region of the mice, solidifies in a gel and stimulates angiogenesis at the injection site in the next 4-8 days. In the rabbit model, New Zeland white mice (2.5-3.0 kg) are injected with 2.0 ml of matrigel, plus 1 μg of bFGF and 4 μg of VEGF. The radiopharmaceutical is injected 7 days later and the images are obtained. This model can also be used to determine the effectiveness of the radiopharmaceuticals of the present invention comprised of isotopes emitting beta, alpha or Auger electron radiation. The radiopharmaceuticals are administered in appropriate amounts and the uptake at the angiogenic sites can be quantified either non-invasively by imaging for those isotopes with matching gamma-emitting emission, or by cutting the angiogenic sites and counting the amount of radioactivity present by standard techniques. The therapeutic effect of the radiopharmaceuticals can be determined by monitoring the growth rate of the angiogenic sites in control rabbits versus those in the rabbits to which the radiopharmaceuticals of the present invention are administered. This model can also be used to determine the compounds of the present invention constituted of paramagnetic metals as MRI contrast agents. After administration of the appropriate amount of the paramagnetic compounds, the whole animal is placed in a commercially available magnetic resonance imaging forceptor to image angiogenic sites. The effectiveness of the contrast agents can be easily seen by comparison with the images obtained from animals that are not administered a contrast agent. This model can also be used to determine that the compounds of the present invention are composed of heavy atoms as X-ray contrast agents. After administration of the appropriate amount of X-ray absorbing compounds, the entire animal is placed in a commercially available X-ray imager for forming images of angiogenic sites. The effectiveness of contrast agents can be easily seen compared to images obtained from animals that are not given a contrast agent. This model can also be used to determine the compounds of the present invention comprised of a surfactant microsphere containing echogenic gas as ultrasound contrast agents. After administration of the appropriate amount of the echogenic compounds, images of the angiogenic sites in the animal can be imaged using an ultrasound probe that is kept close to the tumors. The effectiveness of the contrast agents can be easily seen by comparison with the images obtained from animals that are not administered a contrast agent.
Spontaneous canine tumor model Undergo sedation with xylazine (20 mg / kg) / atropona (1 ml / kg to adult dogs with spontaneous mammary tumors.) Upon sedation, the animals are intubated using ketamine (5 mg / kg) / diazepam (0.25 mg / kg) for complete anesthesia. Chemical restriction is continued with ketamine (3 mg / kg) / xylazine (6 mg / kg) titrating when necessary.If required, the animals are ventilated with ambient air by means of endotracheal tube (12 strokes / min, 25 ml / kg) during the study Peripheral veins are catheterized using 20G IV catheters, one serves as an infusion port for the compound while the other for blood sampling.The heart rate and the EKG are monitored using a cardiotachometer ( Biotech, Grass Quincy, MA) activated from an Electrode II electrocardiogram generated by the electrodes in the extremities Blood samples are usually taken at -10 minutes (control) at the end of the infusion (1 minute), 15 min, 30 min, 60 min, 90 min and 120 min for the number of total blood cells and the count. The radiopharmaceutical dose is 300 μCi / kg administered as a bolus i.v. with washing with saline solution. The parameters are continuously monitored in a polygraph recorder (Model 7E Grass) at a paper speed of 10 mm / min or 10 mm / sec. The formation of images of the lateral parts are for 2 hours with a 256 x 256 matrix, without magnification, dynamic images of 5 minutes. A known source is placed in the image field (20-90 μCi) to evaluate the uptake of the region of interest (ROÍ). The images are also acquired 24 hours after the injection to determine the retention of the compound in the tumor. The uptake is determined by taking the fraction of the total accounts in an iscritized area of ROI / source and multiplying the known μCi. The result is μCi for ROI. This model can also be used to determine the effectiveness of the radiopharmaceuticals of the present invention consisting of isotopes emitting beta, alpha or Auger electron radiation. The radiopharmaceuticals are administered in appropriate quantities and the uptake in the angiogenic sites can be quantified either non-invasively by imaging for these isotopes with matching gamma-emitting emission, or by cutting the tumors and counting the amount of radioactivity present by standard or conventional techniques. The therapeutic effect of radiopharmaceuticals can be determined by monitoring the size of the tumors with respect to time. This model can also be used to determine the compounds of the present invention constituted of paramagnetic metals as MRI contrast agents. After administration of the appropriate amount of the paramagnetic compounds, the whole animal is placed in a commercially available magnetic resonance imaging formers to image the tumors. The effectiveness of the contrast agents can be easily observed by comparison with the images obtained from animals that are not administered a contrast agent. This model can also be used to determine the compounds of the present invention consisting of heavy atoms as X-ray contrast agents. After administration of the appropriate amount of the X-ray absorbing compounds, the whole animal can be placed in a commercially available X-ray imager for imaging tumors. The effectiveness of contrast agents can be easily seen compared to images obtained from animals that are not given a contrast agent. This model can also be used to determine the compounds of the present invention comprised of a surfactant microsphere containing echogenic gas as ultrasound contrast agents. After administration of the appropriate amount of the echogenic compounds, images of the angiogenic sites in the animal can be imaged using an ultrasound probe that is kept close to the tumors. The effectiveness of the contrast agents can be easily observed by comparison with the images obtained from animals that are not administered a contrast agent. Cardiovascular disease models can be used to determine the diagnostic radiopharmaceuticals, magnetic resonance, X-rays and ultrasound contrast agents of the present invention which are reviewed in J. Nuci. Cardiol., 1998, 5, 167-83. There are several well-established models in rabbit for atherosclerosis, a model produces predominantly proliferating smooth muscle cells by desndothelialization by balloon of the infradiaphragmatic abdominal aorta to stimulate restenotic lesions; Another model produces an advanced human atherosclerotic plaque simulated by balloon dendothelialization followed by a diet high in cholesterol. A model of congestive heart failure in .Am is described. J. Physiol., 1998, 274. H1516-23. In general, Yorkshire pigs are randomly assigned to experience three weeks of rapid atrial passage of 240 whites / min or to be false controls. The pigs undergo chronic instrumentation to measure left ventricular function in a conscious state. The pigs are anesthetized. An electrode that stimulates protection is sutured over the left atrium connected to a modified programmable pacemaker and buried in a subcutaneous pocket. The pericardium is closed loosely, the thoracotomy is closed and the air is extracted from the pleural space. After a recovery period of 7-10 days, the pacemaker is activated on the animals that are selected to experience rapid pacemakers. The animals are sedated, the pacemaker is deactivated (only the groups with rhythmic control). After a stabilization period of 30 min, the LV function and geometry indices (by echocardiography as a control) are determined by injecting the radiolabeled compound. For biodistribution, the animals are anesthetized, the heart is removed and the LV apex and the middle ventricular regions are evaluated. A rat model of reversible coronary oncclusion and reperfusion is described in McNulty et al., J. Am. Physiol., 1996, H2283-9. Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. Therefore, it should be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (2)

  1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound, characterized in that it comprises: a target portion and a chelator, wherein the target portion is attached to the chelator, is a non-peptidic quinolone and binds to a receptor that is activated during angiogenesis, and the compound has 0-1 groups binding between the target chooser portion and the chelator.
  2. 2. The compound according to claim 1, characterized in that the receptor is the avß3 or avßs integrin and the compound is of the a formula: (Q) d-Ln-Ch or (Q) d-Ln- (Ch) d, wherein Q is a compound of the formula (II) (II) which includes stereoisomeric forms thereof, or mixtures of the stereoisomeric forms thereof, or pharmaceutically acceptable salt forms or precursor thereof, wherein: Rle is selected from: Aβ is -CH 2 - or -N (R 10e) -; Ale and Be are independently -CH2- or -N (R10e) -; De is -N (R10e) - or -S-; Eß-Fe is -C (R2e) = C (R3e) - O -C (R2e) 2C (R3e) 2-; Je is -C (R2e) - O -N-; Ke, Lß and Mee are independently -C (R2e) - or -C (R3e) -; R2ß and R3e are independently selected from: H, alkoxy of 1 to 4 carbon atoms, NRlleR12e, halogen, N02, CN, CF3, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (e 3 to 7 carbon atoms) alkyl of 1 to 4 carbon atoms, aryl (alkyl of 1 to 6 carbon atoms) -, alkyl (1 to 6 carbon atoms) ca rb on i 1, ( C 1-6 alkoxy) carbonyl, arylcarbonyl and aryl substituted with 0-4 of R 7e, alternatively, when R 2e and R 3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic ring or 5-7 membered aromatic or non-aromatic heterocyclic ring system, the carbocyclic or heterocyclic ring is substituted with 0-2 groups selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, cyano, amino, CF3 and N02; R2ae is selected from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms), aryl, aryl (C 1 -C 4 alkyl) -, (C 2 -C 7 alkyl) carbonyl, arylcarbonyl, (C 2 -C 7 alkoxy) carbonyl, cycloalkoxy (C 2 -C 7) 3 to 7 carbon atoms) carbonyl, bicycloalkoxy (from 7 to 11 carbon atoms), aryloxycarbonyl, aryl (alkoxy of 1 to 10 carbon atoms) carbonyl, alkyl (of 1 to 6 carbon atoms) carbonyloxy (alkoxy of 1) to 4 carbon atoms) carbonyl, arylcarbonyloxy (C 1 -C 4 alkoxy) carbonyl, and cycloalkyl (3 to 7 carbon atoms) ca rb oni 1 oi (C 1 -C 4 alkoxy) carbonyl; R7e is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (C 1 -C 4 alkyl) carbonyl, C02R18ae, S02Rlle, S02NR10eRlle, OR10e and N (Rlle) R12e; U * is selected from: - (CH2) ne-, - (CH2) neO (CH2) me-, - (CH2) neN (R12) (CH2) me-, -NH (CH2) ne-, - (CH2) neC (= 0) (CH2) me-, - (CH2) neS (O) pe (CH2) mS-, - (CH2) neNHNH (CH2) me-, -N (R10e) C (= 0) -, - NHC (= 0) (CH2) ne-, -C (= 0) N (R10e) -, and -N (R10e) S (0) pe-; Ge is N or CR19e; e is -C (= 0) -NR (R10ß) - (alkylene of 1 to 3 carbon atoms) -, in which the alkylene group is substituted by R8e and by R9e: R8e and R9e are independently selected from: H, C02R18bß, C (= 0) Rlßbβ, C0NR17Rlβbe, alkyl of 1 to 10 carbon atoms substituted with 0-1 of Reß, alkenyl of 2 to 10 carbon atoms substituted with 0-1 of R6e, alkynyl of 2 to 10 carbon atoms carbon substituted with 0-1 of RSβ, cycloalkyl of 3 to 8 carbon atoms substituted with 0-1 of R6e, cycloalkenyl of 5 to 6 carbon atoms substituted with 0-1 of R6β, (C 1 -C 10 alkyl) carbonyl, cycloalkyl (3 to 10 carbon atoms) (C 1 -C 4 alkyl) -, phenyl substituted with 0-3 of Ree, naphthyl substituted with 0-3 of RSe, a heterocyclic ring of 5-10 members containing 1-3 heteroatoms of N, 0 or S, wherein the heterocyclic ring may be saturated, partially saturated or fully saturated, the heterocyclic ring is substituted with 0-2 of R7e , alkoxy of 1 to 10 carbon atoms substituted with 0-2 of R7e, hydroxy, nitro, -N (R10e) Rlle, -N (R16e) R17e, aryl (0 to 6 carbon atoms) carbonyl, aryl ( alkyl of 3 to 6 carbon atoms), heteroaryl (alkyl of 1 to 6 carbon atoms), CONR18aeR20e, S02R18ae, and S02NR1BaeR20e, with the proviso that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 of R7e; R6e is selected from: H, alkyl of 1 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, nitro, alkylcarbonyl of 1 to 10 carbon atoms, -N (Rlle) R12e, cyano, halo, CF3 , CHO, C02R18 e, C (= 0) R18be, C0NR17eR18be, OC (= 0) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= O) R10e, NR10eC (= 0) 0R21e, NR10eC (= 0) NR10eRlle, NR10eRlle, NR10eS02R21e, S (0) pRlle, SO2NR10eRlle, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) ) meMe, and -NMe2, aryl (alkyl of 1 to 4 carbon atoms) -, the aryl is substituted with 0-3 groups which are selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 atoms of carbon, CF3, S (0) pSMe, and -NMe2 and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, O or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated , the heterocyclic ring is substituted n 0-2 of R7e; R10e is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, aryl, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl (alkyl of 1 to 4 carbon atoms) carbon) and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R6e; Rlle is selected from: H, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, alkoxy of 1 to 6 carbon atoms carbon, benzyloxy, aryl, heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl, alkyl of 1 to 10 carbon atoms substituted with 0-2 of R4β; R4e is selected from:?, Alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 at 10 carbon atoms) carbonyl, aryl, heteroaryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0 -2 substituents which are independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02, alternatively, when R10β and Rlle are both substituents on the same nitrogen atom (as in -NR10eRlle) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1, 2, 3, 4-tetrahydro-l -quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl and 1-piperazinyl; the heterocycle is substituted with 0-3 groups which are selected from: alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 6 carbon atoms) carbonyl, (C3-C7-cycloalkyl) carbonyl, C1-C6-alkoxy) carbonyl, aryl (C1-C4 alkoxy) carbonyl, alkylsulfonyl of 1 to 6 carbon atoms and aryisulfonyl; R12e is selected from: H, alkyl of 1 to 6 carbon atoms, trif enylmethyl, methoxymethyl, methoxyifildylmethyl, trimethylsilylethoxymethyl, (C 1 -C 6 alkyl) carbonyl, (C 1 -C 6 alkoxy) carboni 1 or, (alkyl of 1 to 6 carbon atoms) aminocarbonyl, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4) carbon atoms) -, aryl, heteroaryl (C 1-6 alkyl) carbonyl, heteroarylcarbonyl, aryl (C 1-6 alkyl) -, (C 1-6 alkyl) carbonyl, arylcarbonyl, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl, aryl (C 1 -C 6 alkyl) sulphonyl, or heteroarylsulfonyl, heteroaryl (C 1 -C 6 alkyl) sulfonyl, aryloxycarbonyl and aryl (alkoxy of 1 to 6) 6 carbon atoms) carbonyl, wherein such aryl groups are substituted with 0-2 s substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, CF3 and nitro; R16ß is selected from: -C (= 0) 0Rx C (= 0) R18be, -C (= 0) N (R: 18be \ -C (= 0) NHS02R18ae, -C (= 0) NHC (= 0) R jl1βbe -C (= 0) NHC (= 0) OR18ae, -C (= 0) NHS02NHRlβbe, -S02R18ae, -S02N (R18be) 2 and -S02NHC (= 0) OR18be; R17e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms), (alkyl of 1 to 4 carbon atoms) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms); R18 e is selected from: alkyl of 1 to 8 carbon atoms optionally substituted with a bond to Ln, cycloalkyl of 3 to 11 carbon atoms optionally substituted with a bond Ln, aryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond L n, heteroaryl (alkyl of 1 to 6 carbon atoms) -optionally substituted with a bond to L n, -alkyl of 1 to 6 carbon atoms-heteroaryl optionally substituted with a bond to L n, diaryl (alkyl of 1 at 6 carbon atoms) optionally substituted with a bond to L n, heteroaryl optionally substituted with a bond to L n, phenyl substituted with 3-4 of R 19e and optionally substituted with a bond to L n, naphthyl substituted with 0-4 of R 19e and optionally substituted with a link to Ln, and a link to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19e; R18be is H 0 Rlßa «. R19e is selected from: H, halogen, CF3, C02H, CN, N02, -NRlleR12e, 0CF3, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl from 3 to 11 carbon atoms, cycloalkyl (3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 6 carbon atoms) -, alkoxy of 1 to 6 carbon atoms carbon, alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-O-, aryl-S02-, heteroaryl and heteroaryl-S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms; R20e is selected from: hydroxy, alkyloxy of 1 to 10 carbon atoms, cycloalkyloxy of 3 to 11 carbon atoms, aryloxy, aryl (alkyl of 1 to 4 carbon atoms) oxy, alkyl (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyl ( alkyl of 1 to 2 carbon atoms) oxy-, cycloalkyl (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy, cycloalkoxy (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy of 3 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyloxy (alkyl) of 1 to 2 carbon atoms) oxy-, arylcarbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 1 to 5 carbon atoms) (alkyl of 1 to 5 carbon atoms) carbonyloxy (alkyl of 1) at 2 carbon atoms) oxy, (5- (C 1-5 alkyl) -1,3-dioxa-cyclopenten-2-one-yl) methyloxy, (5-aryl-l, 3-dioxa-cyclopenten) -2-ona-il) methyloxy, and (R1De) (Rlle) N- (alkoxy of 1 to 10 carbon atoms) -; R21e is selected from: alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of "3 to 11 carbon atoms (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl, aryl ( 1 to 4 carbon atoms) -, and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R7e; R22e is selected from: -C (= 0) -R18be, -C (= 0) N (R18be) 2, -C (= 0) NHS02R18ae, -C (= 0) NHC (= 0) R18bβ, - (= 0) NHC (= 0) OR18ae, and -C (= 0) NHS02NHR18be; Y * is selected from: -COR0e, -S03H, -P03H, -CONHNHS02CF3, -CONHS02R18ae, -CONHS02NHR18be, -NHCOCF3, -NHCONHS02R18ae, -NHS02R18ae, -OP0H2, -OS03H, -P03H2, -S02NHCOR18ae, -S02NHC02R18ae, me is 0-2 ne is 0-4 3 is 0-2 re is 0-2 with the following condition: ne and me are chosen so that the number of atoms connecting Rle and Ye is in the range of 8- 14; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; d 'is 1-100; Ln is a linking group that has the formula: ((W) h- (CR6R7) g) x- (Z) k- ((CR6aR7a) g, - (W) h,) x,; is independently selected, each time it is presented, from the group: 0, S, NH, NHC (= 0), C (= 0) NH, NR8C (= 0), C (= 0) NR8, C (= 0) , C (= 0) 0, 0C (= 0), NHC (= S) NH, NHC (= 0) NH, S02, S02NH, (0CH2CH2) s, (CH2CH20).,, (0CH2CH2CH2) s ", ( CH2CH2CH20) t, and (aa) t ,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, cycloalkyl of 3 to 10 carbon atoms substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and 0 and substituted with 0-3 of R10; R6, R6a, R7, R7a and R8 are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, P03H, alkyl of 1 to 5 carbon atoms substituted with 0-3 of R10, aryl substituted with 0-3 of R10, benzyl substituted with 0-3 of R10 and alkoxy of 1 to 5 carbon atoms substituted with 0-3 of R10, NHC (= 0) R11, C ^ OJNHR11, NHC (= 0) NHRn , NHR11, R11 and a binding to Ch; R10 is independently selected, each time it is presented, from the group: a link to Ch / COOR11, C (= 0) NHR11, NHC (= 0) R1: 1, OH, NHR11, S03H, P03H, -0P03H2, -0S03H, aryl substituted with 0-3 of R11, alkyl of 1 to 5 carbon atoms substituted with 0-1 of R12, alkoxy of 1 to 5 carbon atoms substituted with 0-1 of R12 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and 0 and substituted with 0-3 of R " R11 is independently selected, each time it is presented, from the group: H, alkyl substituted with 0-1 of R12, aryl substituted with 0-1 of R12, a heterocyclic ring system of 5-10 members containing 1-4 heteroatoms that are independently selected from N, S and 0, and substituted with 0-1 of R12, cycloalkyl of 3 to 10 carbon atoms substituted with 0-1 of R12, polyalkylene glycol substituted with 0-1 of R12, carbohydrate substituted with 0 -1 of R12, cyclodextrin substituted with 0-1 of R12, amino acid substituted with 0-1 of R12, polycarboxyalkyl substituted with 0-1 of R12, polyazaalkyl substituted with 0- 1 of R12, peptide substituted with 0-1 of R12, wherein the peptide is composed of 2-10 amino acids, 3,6-0-disulfo-B-D-galactopyranosyl, bis (phosphonomethyl) glycine or a bond for Ch; R12 is a link to Ch; k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; h 'is selected from 0, 1, and 2; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; g 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; e is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; s' is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; s "is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; t 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; x is selected from 0, 1, 2, 3, 4 and 5; x 'is selected from 0, 1, 2, 3, 4 and 5; Ch is a unit that joins metal, which has a formula that is selected from the group: .TO ??? A1, A2, A3, A4, As, A6, A7 and A8 are independently, each time they occur, of the group: NR13, NR13R14, S, SH, S (Pg), O, OH, PR13, PR13R14, P ( 0) R1SR16, and a link to Ln; E is a bond, CH, or a spacer group that is independently selected, each time it is presented, from the group: alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of 3 to 10 carbon atoms substituted with 0-3 of R17, heterocycloalkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, wherein the heterocycle group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and O, aryl (from 6 to 10 carbon atoms) -alkyl from 1 to 10 carbon atoms substituted with 0-3 of R17, alkyl (from 1 to 10 carbon atoms) carbon) -aryl of 6 to 10 carbon atoms-substituted with 0-3 of R17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S, and O and which are replaced with 0-3 of R17; R13 and R1 * are each independently selected from the group: a bond to Ln, hydrogen, alkyl of 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of 1 to 10 carbon atoms. carbon substituted with 0-3 of R17, heterocycloalkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, wherein the heterocycle group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are selected independently of N, S and 0, aryl (of 6 to 10 carbon atoms) -alkyl of 6 to 10 carbon atoms-alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, alkyl (of 1 to 10) carbon atoms) -aromethyl of 6 to 10 carbon atoms-substituted with 0-3 of R17, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and O and substituted with 0-3 of R17, and an electron, with the proviso that when one of R13 or R14 is an electron, the other also be an electron; alternatively, R13 and R14 combine to form = C (R2 °) (R21); R1S and R16 are each independently selected from the group: a bond to Ln, -OH, alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, cycloalkyl of 3 to 10 carbon atoms substituted with 0-3 of R17, heterocycloalkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, wherein the heterocycle group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and O, aryl (from 6 to 10 carbon atoms) -alkyl from 1 to 10 carbon atoms substituted with 0-3 of R17, alkyl (of 1 to 10 carbon atoms) aryl of 6 to 10 carbon atoms-substituted with 0-3 of R17, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are selected independently of N, S and O, and substituted with 0-3 of R17, - R17 is independently selected, each time it is presented from the group: a bond to Ln, = 0, F, Cl, Br, I, -CF3, -CN, -C02R18, -C (= 0) R18, -C (= 0) N (R18) 2, -CHO, -CH2OR18 , -0C (= 0) R1B, -0C (= 0) 0R18a, -OR18, -0C (= 0) N (R18) 2, -NR19C (= 0) R18, -NR19C (= 0) 0R18a, -NR19C (= 0) N (R18) 2, -NR19S02N (R18) 2, -NR19S02R18a, -S03H, -S02R18a, -SR18, -S (= 0) R18a, -S02N (R18) 2, -N (R18) 2 , -NHC (= S) NHR18, = N0R18, N02, -C (= 0) NH0R18, -C (= 0) NHNR18R18a, -0CH2C02H, 2- (1-morpholino) ethoxy, alkyl of 1 to 5 carbon atoms , alkenyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylmethyl of 3 to 6 carbon atoms, alkoxyalkyl of 2 to 6 carbon atoms, aryl substituted with 0-2 of R18 and a ring system 5-10 membered heterocyclic containing 1-4 heteroatoms which are independently selected from N, S and O; R18, R18a and R19 are independently selected, each time they occur, from the group: a bond to Ln, H, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, alkoxy of 1 to 6 carbon atoms, halide, nitro, cyano and trifluoromethyl; Pg is a thiol protecting group: R20 and R21 are independently selected from the group: H, alkyl of 1 to 10 carbon atoms, -CN, -C02R25, -C (= 0) R25, -C (= 0) N (R5) 2, 1-alkene of 2 to 10 carbon atoms substituted with 0-3 of R23, 1-alkyne of 2 to 10 carbon atoms substituted with 0-3 of R23, aryl substituted with 0 -3 of R23, a saturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S, and O and substituted with 0-3 of R23, and a carbocycle of 3 to 10 carbon atoms saturated carbon substituted with 0-3 of R23, alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form: R22 and R23 are independently selected from the group: H, R24, alkyl of 1 to 10 carbon atoms substituted with 0-3 of R24, alkenyl of 2 to 10 carbon atoms substituted with 0-3 of R24, alkynyl of 2 to 10 carbon atoms substituted with 0-3 of R24, aryl substituted with 0-3 of R24, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms that are independently selected from N, S and O and substituted with 0 -3 of R24, and carbocycle of 3 to 10 carbon atoms substituted with 0-3 of R24; alternatively, R22 and R23 taken together form a fused aromatic portion of a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0; a and b indicate the positions of the optional double bonds and n is 0 or 1; R24 is independently selected, each time it is presented, from the group: = 0, F, Cl, Br, I, -CF3, -CN, -C02R25 -C (= 0) R25, -C (= 0) N (R2S ) 2, -N (R25) 3+, -CH20R25, -0C (= 0) R25 -0C (= 0) R2 -OR2 -0C (= 0) N (R2S) 2, -NR26C (= 0) R2 -NR26C (= 0) 0R2 -NR26C (= 0) N (R 5) 2, -NR26S02N (R25) 2, -NR26S02R2Ba, -S03H, -S02R25a -SR25, -S (= 0) R25a, -S02N (R25) 2, -N (R25) ) 2, = N0R25, -C (= 0) NHOR25 -0CH2C02H and 2- (1-morpholino) ethoxy; and R25, R25a and R26 are each independently selected, each time they are presented from the group: hydrogen and alkenyl of 1 to 6 carbon atoms, - and a pharmaceutically acceptable salt thereof. [3] In a more preferred embodiment, the present invention provides a compound therein: Q is a compound of the formula (IV): (IV) That includes stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or precursor forms thereof, wherein: Rle is selected from: R2e and R3e are independently selected from: H, C 1 -C 4 alkoxy, NRlle R 12 β, halogen, N 2, CN, CF 3, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 cycloalkyl at 7 carbon atoms, cycloalkyl (3 to 7 carbon atoms) -alkyl of 1 to 4 carbon atoms, aryl (alkyl of 1 to 6 carbon atoms) -, (alkyl of 1 to 6 carbon atoms) carbonyl , (C 1-6 alkoxy) carbonyl, arylcarbonyl and aryl substituted with 0-4 of R 7e, alternatively, when R 2e and R 3e are substituents on adjacent atoms, can be taken together with the carbon atoms which are attached to forming a 5 to 7 membered carboxylic ring system or 5-7 membered heterocyclic aromatic or non-aromatic ring system, the carboxylic or heterocyclic ring is substituted with 0-2 groups selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, cyano, amino, CF3 and N02; R e is selected from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 4) carbon atoms), aryl, aryl (C 1-4 -alkyl) -, (C 2-7 -alkyl) carbonyl, arylcarbonyl, (C 2 -C 10 -alkoxy) carbonyl, cycloalkoxy carbonyl or of 3 to 7 carbon atoms, bicycloalkoxycarbonyl of 7 to 11 carbon atoms, aryloxycarbonyl, aryl (alkoxy of 1 to 10 carbon atoms) carbonyl, or alkyl (of 1 to 6 carbon atoms) carbon i 1 ox i (C 1 -C 4 alkoxy) carbonyl, arylcarbonyloxy (C 1 -C 4 alkoxy) carbonyl, and cycloalkyl (3 to 7 carbon atoms) ca rb on i 1 ox i ( C 1 -C 4 alkoxy) carbonyl; R7e is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 4 carbon atoms) carbon), carbonyl, C02R18ae, S02Rllβ, S02NR10eRlle, OR10e and N (Rlle) R12e; U8 is selected from: - - (CH2) ne-, - (CH2) neO (CH2) me-, -NH (CH2) ne-, -N (R10ß) C (= 0) -, -NHC (= 0) (CH2) ne- and -C (= 0) N (R10e) -; Gß is N or CR19e; R8e is selected from: H, C02R18be, C (= 0) R18be, C0NR17eR18be, alkyl of 1 to 10 carbon atoms substituted with 0-1 of R6e, alkenyl of 2 to 10 carbon atoms substituted with 0-1 of R6e, alkenyl of 2 to 10 carbon atoms substituted with 0-1 of R6e, cycloalkyl of 3 to 8 carbon atoms substituted with 0-1 of R6e, cycloalkenyl of 5 to 6 carbon atoms substituted with 0-1 of RSe, (alkyl) from 1 to 10 carbon atoms) carbonyl, cycloalkyl (from 3 to 10 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, phenyl substituted with 0-3 of R6e, naphthyl substituted with 0-3 of R6, a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, 0 or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 of R7e; R9e is selected from: alkyl of 1 to 10 carbon atoms substituted with 0-1 of RSe, alkoxy of 1 to 10 carbon atoms substituted with 0-2 of R7e, H, nitro, N (Rlle) R12e, OC ( = 0) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= O) R10e, NR10eC (= 0) OR21e, NR10eC (= 0) NR10eRlle, NR10eS02NR10eRlle, NR10eSO2R21e, hydroxy, OR22e, -N (R10e) Rlle, -N (R16e) R17e, aryl (0 to 6 carbon atoms) carbonyl, aryl (alkyl of 1 to 6 carbon atoms) heteroaryl (alkyl of 1 to 6 carbon atoms), CONR18aeR20e, S02R18ae and S02NR18aeR20e, with the proviso that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups can be unsubstituted or independently substituted with 1-2 of R7e; R6e is selected from: H, alkyl of 1 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, nitro, alkylcarbonyl of 1 to 10 carbon atoms, -N (Rlle) R12e, cyano, halo, CF3 , CHO, C02R18be, C (= 0) R18be, CONR17eR18be, OC (= 0) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= 0) R10e, NR10eC (= 0) 0R21e, NR10eC (= 0) NR10eRlle , NR10eS02NR10eRlle, NR10eSO2R21e, S (0) peRlle, S02NR10eRlle, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) meMe and -NMe2, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) meMe and -NMe2, aryl ( 1 to 4 carbon atoms) -, aryl which is substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) peMe, and -NMe2 and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, O or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 R7e; R10e is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, aryl, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl (alkyl of 1 to 4 carbon atoms) carbon) and alkyl of 1 to 10 carbon atoms substituted with 0-2 of Ree; Rlle is selected from: H, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, alkoxy of 1 to 6 carbon atoms, benzyloxy, aryl, heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R4e; R4e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, heteroaryl , aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0-2 substituents which are independently selected from the group consisting of of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02 / R12e is selected from: H, alkyl of 1 to 6 carbon atoms, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl , trimethylsilylethoxymethyl, (C 1-6 alkyl), carbonyl, (C 1-6 alkoxy), carbonyl, (C 1 -C 6 alkyl) aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl (C 1 -C 6 alkyl) 1 to 4 carbon atoms) -, aryl, heteroaryl (alkyl of 1 to 6 carbon atoms) carbonyl, heteroaryl carbonyl, aryl (C 1-6 alkyl) -, (C 1-6 alkyl), carbonyl, arylcarbonyl, alkylsulfonyl of 1 to 6 carbon atoms, aryisulfonyl, aryl (alkyl of 1 to 6 carbon atoms) sulfonyl, heteroarylsulfonyl, heteroaryl (alkyl of 1 to 6 carbon atoms) sulfonyl, aryloxycarbonyl and aryl (alkoxy of 1 to 6 carbon atoms) carbonyl, wherein the aryl groups are substituted with 0-2 substituents which are selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo CF3 and nitro; R16e is selected from: -C (= 0) OR18aß, -C (= 0) R18be, -C (= 0) N (R18be) 2, -S02R18ae, and -S02N (R18be) 2; R17e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) - Ri8ae s ^ is selected from: alkyl of 1 to 8 carbon atoms optionally substituted with a bond to Ln, cycloalkyl of 3 to 11 carbon atoms optionally substituted with a bond to Ln, aryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to Ln, heteroaryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a linkage to L n, (C 1-6 alkyl) heteroaryl optionally substituted with a bond to L n, varyl (C 1-6 alkyl) optionally substituted with a bond to L n, heteroaryl optionally substituted with a bond to Ln, phenyl substituted with a 3-4 of R19e and optionally substituted with a bond to Ln, naphthyl substituted with 0-4 of R19e and optionally substituted with a bond to Ln, and a bond to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19e; R18be is H or R18ae; R19e is selected from: H, halogen, CF3, C02H, CN, N02, -NRlleR12e, 0CF3_ alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 6 carbon atoms) -, (alkoxy of 1 to 6 carbon atoms) carbon), alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-O-, aryl-S02-, heteroaryl and heteroaryl -S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen , halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms, - R0ß is selected from: hydroxy, alkyloxy of 1 to 10 carbon atoms, cycloalkyloxy of 3 to 11 carbon atoms, aryloxy , aryl (1 to 4 carbon atoms) oxy, alkyl (2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (2 to 10 carbon atoms) carbon) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkyl (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10 carbon atoms) carbonyl ( 1 to 2 carbon atoms) oxy-, aryloxycarbonyl (1 to 2 carbon atoms) oxy-, aryloxycarbonyloxy (1 to 2 carbon atoms) oxy-, arylcarbonyloxy (1 to 2 carbon atoms) ) oxy-, alkoxy (of 1 to 5 carbon atoms) (alkyl of 1 to 5 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy, (5- (alkyl of 1 to 5 carbon atoms) -1,3-dioxa-cyclopenten-2-one-yl) methyloxy, (5-aryl-1,3-dioxacyclopenten-2-yl) methyloxy, and (R10e) (Rlle) N-alkoxy 1 to 10 carbon atoms), - R21e is selected from: alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl, aryl (alkyl of 1 to 4 carbon atoms) - , and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R7e; R22e is selected from: -C (= 0) -R18be, -C (= 0) N (R18be) -C ^ OjNHSO? 1 -C (= 0) NHC (= 0) R18be, -C (= 0) NHC (= 0) OR18ae and -C (= 0) NHS02NHR18be; mß is 0-2; ne is 0-4; and pe is 0-2; with the following condition: ne u me are chosen so that the number of atoms that connect to R1 and -C0R20e in the formula (IV) is in the range of 8-14; d is selected from 1, 2, 3, 4 and 5; d 'is 1-50; W is independently selected, each time it is presented, from the group; 0, NH, NHC (= 0), C (= 0) NH, NR8C (= 0), C (= 0) NR8, C (= 0), C (= 0) 0, 0C (= 0), NHC (= S) NH, NHC (= 0) NH, S02, (0CH2CH2) s, (CH2CH20) s, (0CH2CH2CH2) s ", (CH2CH2CH20) t and (aa) t ,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-1 of R10, cycloalkyl of 3 to 10 carbon atoms substituted with 0-1 of R10 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0, and substituted with 0-1 of R10; Re, R6a, R7, R7a and R8 are independently selected, each time they occur in the group: H, = 0, COOH, S03H, alkyl of 1 to 5 carbon atoms substituted with 0-1 of R10, aryl substituted with 0 -1 of R10, benzyl substituted with 0-1 of R10 and alkoxy of 1 to 5 carbon atoms substituted with 0-1 of R10, NHC (= 0) R ", C ^ ONHR11, NHC (= 0) NHR11, NHR11 , R11 and a bond to Ch; k is 0 or 1; s is selected from 0, 1, 2, 3, 4 and 5; s' is selected from 0, 1, 2, 3, 4 and 5; select from 0, 1, 2, 3, 4 and 5; t is selected from 0, 1, 2, 3, 4 and 5; A1, A2, A3, A4, A5, A6, A7 and A8 are independently, each time they occur, of the group: NR13, NR13R14, S, SH, S (Pg), OH and a link to Ln; E is a bond, CH, or a spacer group that is independently selected, each time it is presented, from the group: alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, 3-cycloalkyl 10 carbon atoms substituted with 0-3 of R17 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and which are substituted with 0-3 of R? "; R13 and R14 are each independently selected from the group: a bond to Ln, hydrogen, alkyl of 1 to 10 carbon atoms substituted with 0-3 of R17, aryl substituted with 0-3 of R17, a heterocyclic ring system of 5-10 members that contains 1-4 heteroatoms that are independently selected from N, S, and O and substituted with 0-3 of R17, and an electron, with the proviso that when one of R13 or R14 is an electron, the another is also an electron, alternatively, R13 and R14 combine to form = C (R20) (R21); R17 is independently selected, each time it is presented, from the group: a bond to Ln, = 0, F, Cl, Br, I, -CF3 -CN, C02R18, -C (= 0) R18, -C (= 0) N (R18) 2, -CH2OR18, -OC (= 0) R18 -0C (= 0) 0R18a, - OR18, -0C (= 0) N (R18) 2, -NR19C (= 0) R18, -NR19C (= 0) 0R18a -NR19C (= 0) N (R18) 2, -NR19S02N (R18) 2, -NR19S02R18a , -S03H, -S02R18a -S (= 0) R1 -S02N (R18) -N (RX8) NHC (= S) NHR1 = N0R: -C (= 0) NHNR18R1 -0CH2C02H, and 2- (1-morpholino) ethoxy, R18, R18a and R19 are independently selected, each time they occur, from the group: a link to Ln, H and alkyl of 1 to 6 carbon atoms, - R20 and R21 are independently selected from the group: H, alkyl of 1 to 5 carbon atoms, -C02R25, 1-alkene of 2 to 5 carbon atoms substituted with 0-3 of R23, -alquino of 2 to 5 carbon atoms substituted with 0-3 of R23, aryl substituted with 0-3 of R23 and an unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and 0 and substituted with 0-3 of R23; alternatively, R20 and R21, taken together with the divalent carbon radical to which they are attached form: R22 and R23 are independently selected from the group: H and R24; alternatively, R22, R23 taken together, form a 5-10 membered fused or heterocyclic aromatic ring system containing 1-4 heteroatoms that are independently selected from N, S, and O; R24 is independently selected, each time it is presented, from the group: -C02R25, -C (= 0) N (R25) 2, -CH2OR25, -OC (= 0) R2S, -OR25, -S03H, -N (R25 ) 2, and -0CH2C02H; and R25 is independently selected, each time they occur from the group: H and alkyl of 1 to 3 carbon atoms. 4. A compound according to claim 3, characterized in that it includes stereoisomeric forms thereof, or mixtures of the stereoisomeric forms thereof, or pharmaceutically acceptable salts or forms of precursors thereof, wherein: Rle is selected from: R2e and R3ß are independently selected from:. ?, C 1-4 alkoxy, NRlleR12e, halogen, N02, CN, CF3, C6 alkoyl, C3 to C6 alkenyl, C3 to C7 cycloalkyl, 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms), aryl (alkyl of 1 to 6 carbon atoms) -, alkyl (1 to 6 carbon atoms) carbonyl, (alkoxy of 1 to 6 carbon atoms) carbon) carbonyl, arylcarbonyl and aryl substituted with 0-4 of R7e, alternatively, when R2e and R3e are substituents on adjacent atoms, can be taken together with the carbon atoms to which they are attached to form a carbocyclic ring system of -7 members or 5-7 membered heterocyclic aromatic or non-aromatic, the carbocyclic or heterocyclic ring is substituted with 0-2 groups selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo , cyano, amino, CF3 and N02; Rae is selected from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms), aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (C2-C7 alkyl) carbonyl, arylcarbonyl, (C2-C10-alkoxy) carbonyl, C2-C2-C3-C3-C3-C3, Bicycloalkoxycarbonyl with 7 to 11 carbon atoms carbon, aryloxycarbonyl, aryl (C 1 -C 10 alkoxy) carbonyl, alkyl (1 to 6 carbon atoms) carbonyloxy (C 1 -C 4 alkoxy) carbonyl, arylcarbonyloxy (C 1 -C 4 alkoxy) carbonyl, and cycloalkyl (3 to 7 carbon atoms) carbonyloxy (alkoxy of 1 to 4 carbon atoms) carbonyl; R7e is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 4 carbon atoms) carbon) carbonyl, C02R18aß, S02Rlle, S02NR10eRlle, OR10e and N (Rlle) R12e; Ue is selected from: - (CH2) ne-, -NHÍCHj) ^ -, -N (R10e) C (= O) -, and -NHC (= 0) (CH2) ne; Ge is N or CR19e; R8e is H; R9e is selected from: H, nitro, -N (Rlle) R12, OC (= O) R10e, OR10e, OC (= 0) NR10eRlle, NR10ßC (= 0) R10e, NR10eC (= 0) OR21e, NR10eC (= 0 ) NR10eRlle, NR10eS02NR10eRlle, NR10eSO2R21e, hydroxy, OR22e, -N (R10e) Rlle, -N (R16e) R17e, aryl (C0-4 alkyl) carbonyl, aryl (C1 to C4 alkyl), heteroaryl (alkyl of 1 to 4 carbon atoms), CONR18aeR20e, S02R18ae and S02NR18aeR20e, with the proviso that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 of R7e; R10ß is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, (cycloalkyl of 3 to 6 carbon atoms) methyl, aryl (alkyl of 1 to 4 carbon atoms) carbon) and alkyl of 1 to 4 carbon atoms substituted with 0-2 of R6e; R6e is selected from: H, alkyl of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, nitro, alkylcarbonyl of 1 to 4 carbon atoms, -N (Rlle) R12e, cyano, halo, CF3 , CHO, C02R18be, C (= 0) R18be, C0NR17eR18be, OC (= O) R10e, OR10e, OC (= 0) NR10eRlle, NR10eC (= O) R10e, NR10ßC (= 0) OR 1e, NR10eC (= 0) NR10eRlle, NR10eS02NR10eRlle, NR10eS02R21ß, S (0) pRllβ, S02NR10eRlle, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, CF3, S (0 ) meMe, and -NMe2, aryl (alkyl of 1 to 4 carbon atoms) -, the aryl is substituted with 0-3 groups which are selected from halogen, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 atoms carbon, CF3, S (0) peMe, and -NMe2 and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, O or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated , the heterocyclic ring and is substituted with 0-2 of R7 =; Rlle is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (cycloalkyl of 3 to 6 carbon atoms) methyl, alkoxy of 1 to 4 carbon atoms, benzyloxy, aryl, heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl and alkyl of 1 to 4 carbon atoms substituted with 0-2 of R4e; R4e is selected from: H, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, heteroaryl , aryl (alkyl of 1 to 4 carbon atoms) -, and heteroaryl (alkyl of 1 to 4 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0-2 substituents which are independently selected from the group consisting of of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02, R12e is selected from: H, alkyl of 1 to 4 carbon atoms, (alkyl of 1 to 4 carbon atoms) carbonyl, (C 1 -C 4 alkoxy) carbonyl, phenyl (C 1 -C 4 alkyl) -phenylsulfonyl, phenyloxycarbonyl and phenyl (C 1 -C 4 alkoxy) 4 carbon atoms) carbonyl, wherein the phenyl groups are substituted with 0-2 substituents which are selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, halo, CF3 and nitro; R1Se is selected from: -C (= 0) OR18ae, - C (= 0) R18 e, - C (= 0) N (R18be) 2, - S02R18ae and -S02N (Ra8be) 2 2; 1 R 1177ee is selected from: H, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl (of 3 to 6 carbon atoms), (alkyl of 1 to 4 carbon atoms) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms); R18ae is selected from: alkyl of 1 to 8 carbon atoms optionally substituted with a bond to Ln, cycloalkyl of 3 to 11 carbon atoms optionally substituted with a bond to Ln, aryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to L n, heteroaryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to L n, (alkyl of 1 to 6 carbon atoms) heteroaryl optionally substituted with a bond to L n, diaryl ( the 6 carbon atoms) optionally substituted with a bond to Ln, heteroaryl optionally substituted with a bond to Ln, phenyl substituted with 3-4 of R19e and optionally substituted with a bond to Ln, naphthyl substituted with 0-4 of R19e and optionally substituted with a link to Ln, and a link to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19e; Rl be gg JJ 0 Rlßae. R19e is selected from: H, halogen, CF3, C02H, C0, N02, -NRlleR12β, 0CF3, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkyl (of 3 to 6 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms) -, alkoxy of 1 to 6 carbon atoms carbon, alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-O-, aryl-S02-, heteroaryl and heteroaryl-S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 3 carbon atoms, - R20e is selected from: hydroxy, alkyloxy of 1 to 6 carbon atoms, cycloalkyloxy of 3 to 6 carbon atoms, aryloxy, aryl (alkyl of 1 to 4 carbon atoms) oxy, alkyl (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) ono) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkyl (of 3 to 10 carbon atoms) carbonyloxy (1 to 2 carbon atoms) oxy-, cycloalkoxy (3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy of 3 to 10 carbon atoms) carbonyl (alkyl) 1 to 2 carbon atoms) oxy-, aryloxycarbonyl (1 to 2 carbon atoms) oxy-, aryloxycarbonyloxy (1 to 2 carbon atoms) oxy-, arylcarbonyloxy (1 to 2 carbon atoms) oxy-, alkoxy (of 1 to 5 carbon atoms) (alkyl of 1 to 5 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy, (5- (alkyl of 1 to 5 carbon atoms) - 1,3-dioxa-cyclopenten-2-one-yl) methyloxy, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl) methyloxy, and (R10β) (Rlle) N- (1-alkoxy) to 10 carbon atoms) -; R21ß is selected from: alkenyl of 1 to 4 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms (cycloalkyl of 3 to 6 carbon atoms) methyl, aryl, aryl (alkyl) from 1 to 4 carbon atoms) -, and alcguil of 1 to 10 carbon atoms substituted with 0-2 of R7e; R22e is selected from: -C (= 0) -R18bβ, -C (= 0) N (R18be) 2, -C (= 0) NHS02R18ae, C (= 0) NHC (= 0) R18be, -C (= 0) NHC (= 0) 0R18ae, and -C (= 0) NHS02NHR > 18be is 0-2; nß is 0-4; Pe is 0-2; Ch is A1 is selected from the group: OH and a bond to Ln; A2, A4 and A6 are each N; A3, A5 and A8 are each OH; A7 is a link to Ln or NH- link to Ln; E is an alkyl of 2 carbon atoms substituted with -1 of R17, 7- R17 is = 0; alternatively, Ch is A1, is selected from the group: OH and a bond to Ln; A2, A3 and A4 are each N; A5, A6 and A8 are each OH; A7 is a link to Ln; E is an alkyl of 2 carbon atoms substituted with -1 of R1 R17 is = 0, - alternatively, Ch is ^: - A A A1 is NH2 O N = C (R20) (R21); E is a link; A2 is NHR13; R13 is a heterocycle substituted with R17, the heterocycle is selected from pyridine and pyrimidine; R17 is selected from a bond to Ln, C (= 0) NHR18 and C (= 0) R18 R18 is a bond to Ln; R24 is selected from the group: -C02R25, -OR25, -S03H and -N (R25) 2; and R25 is independently selected, each time it is presented from the group: hydrogen and methyl. 5. A compound according to claim 2, characterized in that it includes the enantiomeric or diastereomeric forms thereof, or mixtures of the enantiomeric or diastereomeric forms thereof, or pharmaceutically acceptable salt forms or precursor thereof, wherein Q is selected from group: 3- [7- [(imidazolin-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (3,5-dimethylisoxazol-4-yl sulfonylamino ) propionic, 3- [7- [(imidazolin-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3- [7- [ (imidazolin-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (n-butyloxycarbonylamino) propionic acid, -3§9-3- [7- [(imidazolin -2-ylamino) methyl] -l-methyl-6,8-di f luor oquinol in4-ona-3-i 1 carboni 1 amino] -2- (n-butylene sulfonylamino) propionic, 3- [7- [ (tetrahydropyrimid-2-ylamino) methyl] -1- methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1-methyl-6,8-difluoroquinol in - ona-3-ylcarbonylamino] -2- (n-butyloxycarbonylamino) ropionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] - 2- (phenylsulfonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (n-butylsulfonyl) aminopropionic acid, 3- [7- [(2-aminothiazol-4-yl) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3- [7- [ (imidazolin-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethyl-enyl) sulfonylamino) propionic acid, 3- [7 - [(Tetrahydropyrimid-2-ylamino) methyl] -1-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) sul f onylamino) propionic, 3- [7- ((imidazol-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (3,5-dimethyl isoxazole -4 -ylsulf onylamino) propionic, 3- [7- [(imidazol-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3- [7- [(imidazol-2-ylamino) methyl] -l-methyl-6,8-difluorooquinol i n 4 -one-3-ylcarbonylamino] -2 - ((2,4,6-trimethylphenyl) sulfonylamino] ) propionic, 3- [7- [(imidazol-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino) -2 ((4-biphenyl) sulfonylamino) propionic acid, - [7- [(imidazol-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (1-naphthylsulphonylamino) propionic acid, 3- [7- [ (benzimidazol-2-ylamino) methyl] -1-methyl-6, 8-dif luoroquinclin4-ona-3-II carboni lamino] -2 - (2,4,6-trimethylf-enyl) sulfonylamino) propionic acid, 3- [ 7- [(4-metili midazol-2-ylamino) methyl] -1-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethyl-enyl) sulfonylamino) propionic acid, 3- [7 - [(4,5-dimethylimidazol-2-ylamino) methyl] -1-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) sulfonylamino) propionic, 3- [7- [(4,5,6,7-tetrahydrobenzimidazol-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-lcarbonylamino] -2 - ((2, 4,6-trimethylphenyl) sulfonylamino) propionic acid, 3- [7- [(pyridin-2-ylamino) methyl] -l-methyl-6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2 , 4,6-trimethylphenyl) sulfonylamino) propionic acid, 3- [7- (2-aminopyridin-6-yl) -1-methyl-6,8-difluoroquinolin-4-one-3-ylcar onylamine-2- ((2 , 4, 6-trimethyl-ylp-enyl) -sulfonylamino) -propionic acid, 3- [7- [(7-azabenzimidazol-2-yl) methyl] -1-methyl-6, 8 -dif luo roqui nol in4- ona- 3 -carbonylamino] -2 - ((2,4-, 6-trimethylphenyl) sulfonylamino) propionic acid, 3- [7- [(benzimidazol-2-ylamino) methyl] -1- (2-f-enylethyl) -6, 8 -dif luoroquinolin-4-ona-3-ylcarbonylamino] propionic acid, 3 - [7 - [(pyridin-2-ylamino) methyl] -1- (2-f-enylethyl) -6,8-dif luoroquinolin-3-a-3 - ilcarbonylamino] propionic acid, 3- [7- [(imidaz) olin-2-ylamino) methyl] -1- (2-f-enylethyl) -6,8-dif luoroquinolin-4-amino-3-ylcarbonylamino] propionic acid, 3- [7- [(imidazol-2-yl-amino) methyl] -1- (2-f-enylethyl) -6,8-dif luoroquinolin-4-a-3-ylcarbonylamino] propionic acid, 3- [7- [(imidazolin-2-ylamino) methyl] -1- (2-phenylethyl) - 6, 8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3- [7- [(imidazolin-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinoline4 -one-3-ylcarbonylamino] -2- (n-butyloxycarbonylamino) propionic acid, 3- [7- [(imidazolin-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinoline-4-one- 3-ylcarbonylamino] -2- (phenylsulfonylamino) propionic acid, 3- [7- [(imidazolin-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] - 2- (n-Butylsulfonylamino) propionic acid, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ( benzyloxycarbonylamino) p ropionic, 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (n-butyloxycarbonylamino) propionic acid, acid 3- [7- [(tetrahydropyrimid-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (phenylsulfonylamino) propionic acid, 3- [7-] [(tetrahydropyrimid-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (n-butylsulfonyl) aminopropionic acid, 3- [7- [ (2-N-thiazol-4-yl) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (f -unsulfonyl-amino) propionic acid, 3- [7- [(2-aminothiazol-4-yl) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, 3- [7] - [(imidazole-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) sulfonylamino] ) propionic acid, 3- [7- [(tetrahyd opyrimid-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-di-fluoroquinolin-4-one-3-ylcarbonylamino] -2 - ((2,4,6-trimethyl-phenyl) sulfonylamino) -propionic, 3 [7- [(imidazol-2-ylamino) methyl] -1- (2-phenyl ethyl) 6,8-dif luoroquinolin-4-yne-3-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, acid [7] - [(imidazol-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- (phenylene onylamino) propionic acid, 3 - [7 - [ (imidazol-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2 - ((2,6-dichlorophenyl) eulphonylamino) propionic acid 3- [7- [(imidazol-2-ylamino) methyl] -1- (2-phenyl ethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6) -trimethylphenyl) sulfonylamino) propionic acid, 3 - [7 - [. { imidazol-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((4-biphenyl) sulfonylamino) propionic acid, 3- [7 - [(benzimidazol-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2 - ((2, 4, 6-trimethylphenyl) sulf onyl amino) propionic acid, 3- [7- [(4-methylimidazol-2-ylamino) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one] -3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) sulfonylamino) propionic acid, 3- [7- [(4,5-dimethylimidazol-2-ylamino) methyl] -1- (2-f) enylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) sulfonylamino) propionic acid, 3- [7- [(4,5,6 , 7-tet rahydrobenz imidazol-2-ylamino) methyl] -1- (2-f-enylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2 - ((2,4,6-trimethylphenyl) sulfonylamino) propionic, 3- [7- [(pyridin-2-ylamino) methyl] -1- (2-f-phenylethyl) -6,8-difluoroquinoline-4-one-3-ylcarbonylamino] -2 - ((2, 4, 6-trimethylphenyl) sulfonylamino) propionic acid, 3- [7- (2-aminopyridin-6-yl) -1- (2-phenylethyl) -6,8-di-fluorine orquinol in4 -one-3-yl carbonylamino] -2- ((2,4,6-trimethylphenyl) sulfonylamino) propionic acid and 3- [7- [(7 azabenzimidazol-2-yl) methyl] -1- (2-phenylethyl) -6,8-difluoroquinolin-4-one-3-ylcarbonylamino] -2- ((2,4,6-trimethylphenyl) sulfonylamino) propionic acid. - 355 - [6] In another even more preferred embodiment, the present invention provides a compound selected from the group: 2- (((4- (4- (((3- (2- (2- (3- ((6- ((l-aza-2- (2-sul fofenyl) vini 1) amino) (3-pyridi 1)) carbonyl amino) propoxy) ethoxy) -ethoxy) propyl) amino) sulfonyl) phenyl) phenyl ) -sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -1-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic acid; 3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) -2- (4- (4- (3- (2- (2)} - (3- (2- (1, 4, 7, 1 0-tetraaza-4, 7, 1 0 -tris (carboxylmethyl) cyclododecyl) acetylamino) -propoxy) ethoxy) ethoxy) propyl) amino) sulf onyl) -phenyl phenyl) sulf onyl) amino) propanoic; 2- (((4- (3- (N- (3- (2- (2- (3- ((6- ((1-aza-2- (2-sulfophenyl) vinyl) amino) (3 - pyridyl)) carbonylamino) -propoxy) ethoxy) ethoxy (propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulf onyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l- methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic acid: 3 - ((1- (3 - ((6 - ((1-aza-2 - (2-sulphonyl) vinyl) amino) (3 -pyridyl)) carbonylamino) propyl) -7- ((imidazol-2-yl-amino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2 - (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic; - 3 ^ 6 - 3 - ((l - (3 - ((6 - ((l-aza-2 - (2-sulofofenyl) vinyl) amino) (3-pyridyl)) carbonylamino) ropil) -1 - (((1-hydroxyimidazole-2-yl) amino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic acid; 3- ((1- (3- (3- (N- (3- (2- (2- (3- ((6- ((1-aza-2- (2-sulfophenyl) vinyl) amino)) ( 3-pyridyl)) carbonyl amino) propoxy) e toxi) -ethoxy) propyl) carbamoyl) propanoylamino) propyl) -7 ((imidazol-2-ylamino) methyl) -4 -oxo (3-hydroquinolyl)) carbonylamino) -2 - (((2,4, 6-trimethylphenyl) sulfonyl) amino) propanoic; acid 2- (2-aza-2- (5- (N- (1, 3-bis (3- (2- (2- (3- (3- (N- (3- (3- (N- ( 3-carboxy-2- (((2,4,6-trimethylphenyl) sulfonyl) amino) -ethyl) carbamoyl) -7- ((imidazol-2-ylamino) methyl) 4-oxohydroquinolyl) propyl) carbamoyl) propanoylamino) propoxy) -ethoxy) ethoxy) propyl) carbamoyl) (2-pyridyl)) amino) vinyl) benzenesulfonic; 3§7 β-cyclodextrin 0 0 Jl il »" M! O CO2H C02H? \ I n = 114, bird 2- (((4- (3- (N- (3- (2- (2- (3- (2- (1, 4, 7, 10-tetraaza-4, 7, 10-tris (carboxymethyl)) cyclododecylacetylamino) -6-aminohexanoylamino) propoxy) ethoxy) ethoxy) -propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) - l-methyl-4-oxo (3-hydroquinolyl)) -carbonylamino) propanoic acid; acid conjugate 2- (((4- (3- (N- (3- (2- (2- (3- (2- (1,4,7,1-tetraaza-4,7,1-tris ( carboxymethyl) -cyclododecylacetylamino) -6- (2 (bis- (fosf onomethyl) amino) • ac ethyl ami no) h exan oil ami no) r or ox i) -ethoxy) ethoxy) propyl) carbamoyl) propoxy) -2, 6-dimethylphenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroquinolyl)) carbonylamino) propanoic acid; 2- (((4- (3- (N- (3- (2- (2- (3- (2- (2- ((2- ((2- (bis (carboxymethyl) -amino) ethyl)) (carboxymethyl) amino) ethyl) - (carboxymethyl) amino) acetylamino) -3-sulfopropyl) propoxy) ethoxy) -ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethyl phenyl) sulfonyl) -amino) -3- (( 7- ((imidazol-2-ylamino) methyl) -l-methyl-4 -oxo (3-hydr oquinol il)) carbonylamino) propanoic acid; fifteen 25 fifteen or a pharmaceutically acceptable salt form thereof. 7. An element, characterized in that it comprises a compound according to claim 2, or a pharmaceutically acceptable salt form thereof and a pharmaceutically acceptable carrier. 8. The equipment according to claim 7, characterized in that the equipment further comprises one or more auxiliary ligands and a reducing agent. 9. The conformance equipment with claim 8, characterized in that the auxiliary ligands are tricine and TPPTS. 10. The conformance equipment with claim 8, characterized in that the reducing agent is tin (II). 11. A diagnostic or therapeutic metal-pharmaceutical composition, characterized in that it comprises: a metal, a chelator, capable of chelating the metal and a target-choosing portion, wherein the target-choosing portion is attached to the chelator, and is a non-peptidic quinolone and is binds to a receptor that is activated during angiogenesis and the compound has 0-1 linkers between the target-choosing portion and the chelator. 12. A composition according to claim 11, characterized in that the metapharmaceutical substance is a diagnostic radiopharmaceutical, the metal is a radioisotope selected from the group: 99mTc, 95Tc, l?: Ln, 62Cu, S4Cu, S7Ga, and s8Ga, and the linking group is present between the non-peptide targeting moiety and the chelator. 13. A composition according to claim 12, characterized in that the target targeting portion is a non-peptidic quinolone and the receptor is avß3 or avß5- 14. A composition according to claim 13, characterized in that the radioisotope is 99mTc or 9STc, the radiopharmaceutical further comprises a first auxiliary ligand and a second auxiliary ligand capable of stabilizing the radiopharmaceutical. 15. A composition according to claim 14, characterized in that the radioisotope is 16. A composition according to claim 15, characterized in that the radiopharmaceutical is selected from the group: 99mTc (2- (((4- (4- (((3- (2- (2- (3- ((6- (diazenido) (3-pyridyl)) carbonylamino) -ropoxy) -toxy) -ethoxy) propylamino) sulfonyl) phenyl) phenyl) sulfonyl) amino) -3- ((7- ((imidazol-2-ylamino) methyl) ) l-RETHYL-4-OXO (3-HYDROCYUINOLYL)) carbonylamino) -propanoic acid (tricine) (TPPTS); "" Te (acid (2 - (((4- (3 - (N- (3 - (2 - (2 - (3 - ((6- (diazenido) (3-pyridyl)) carbonylamino) propoxy) ethoxy) -ethoxy) propyl) carbamoyl) propoxy) -2,6-dimethylphenyl) sulfonyl) -amino) -3 - ((7- ((imidazol-2-ylamino) methyl) -l-methyl-4-oxo (3-hydroxy-quinolyl)) carbonylamino) propanoic) (tricine) (TPPDS); 99mTc (3 - ((1 - (3 - ((6- (diazenido) (3-pyridyl)) carbonylamino) propyl) -7- ((imidazol-2-ylamino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2- (( (2, 4, 6 -trimethylphenyl) sulf onyl) amino) propanoic) (tric ina) (TPPTS); 99raTc ((3 - ((1- (3 - ((6- (diazenido) (3-pyridyl)) carbonylamino) propyl) -7- (((1-hydroxy imidazol-2-yl) amino) methyl) - 4 -oxo- (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl) sulfonyl) amino) propanoic) (tricine) (PPTS), - 99raTc (3- ((1- (3- (3- (N- (3- (2- (2- (3- ((6- (diazenido) (3-pyridyl)) carbonylamino) propoxy) ) ethoxy) -ethoxy) propyl) carbamoyl) propanoylamino) propyl) -7 ((imidazol-2-ylamino) methyl) -4-oxo (3-hydroquinolyl)) carbonylamino) -2- (((2,4,6-trimethylphenyl)) sulfonyl) amino) propanoic) (tricine) (TPPTS); 99mTc (2- (2- (5- (3- (3- (3- (3- (3- (3- (3- (3- N- (3- (3- (N- (3-carboxy- 2- (((2,4,6-trimethylphenyl) ul-fonyl) amino) -ethyl) carbamoyl) -7- ((imidazol-2-ylamino ) methyl) 4-oxohydroquinolyl) propyl) carbamoi]) propanoylamino) propoxy) -ethoxy) ethoxy) propyl) carbamoyl) (2-pyridyl) diazenido)) (tricine) (TPPTS); 99mTc (3 - { [ 1- (3- { 2- [(6- (diazenido) (3-pyridyl)) carbonylamino] (2R) -3-sulfopropyl) propyl) -7- [(imidazol-2-ylamino) methyl] -4 -oxo (3-hydroquinolyl) lcarbonyl amino}. (2S) -2- { [(2,4,6-Trimethylphenyl) sulf onyl janoline.) propanoic) (tricine) (TPPTS). 17. A composition according to claim 13, characterized in that the radioisotope is 111 In. 18. A composition according to claim 17, characterized in that the radiopharmaceutical substance is selected from the group: 10 25 19. A composition according to claim 11, characterized in that the metapharmaceutical substance is a therapeutic radioafiaceutical substance, the metal is a radioisotope that is selected from the group.- 186Re, 188Re, 1S3Sm, 166Ho, 177Lu, 149Pm, 90Y, 212Bi, 103Pd , 109Pd, 159Gd, 140La, 198Au, 199Au, lß9Yb, 175Yb, 16SDy, 166Dy, 67Cu, 105Rh, 11: LAg and 192Ir and the linking group is present between the non-peptide target-choosing portion and the chelator. 20. A composition according to claim 19, characterized in that the target-choosing portion is a non-peptidic quinolone and the receptor is avß3 or 21. A composition according to claim 20, characterized in that the radioisotope is 153 Sm. 22. A composition according to claim 20, characterized in that the radioisotope is 177LU. A composition according to claim 22, characterized in that the radiopharmaceutical is selected from the group: 24. A composition according to claim 20, characterized in that the radio-isotope is 90Y. 25. A composition according to claim 24, characterized in that the radiopharmaceutical sound is selected from the group, - 25 26. A composition according to claim 11, characterized in that the metapharmaceutical substance is a contrast agent for MRI, the metal is a paramagnetic metal ion selected from the group: Gd (III), Dy (III), Fe (III) _ 'and Mn (II), the target-choosing portion is a non-peptidic quinolone and the linking group is present between the targeting portion and the chelator. 27. A composition according to claim 26, characterized in that the target-choosing portion is a non-peptidic quinolone and the receptor is avß3 or a3ß5. 28. A composition according to claim 27, characterized in that the metal ion is Gd (III). 29. A composition according to claim 28, characterized in that the contrast agent is 30. A composition according to claim 11, characterized in that the metapharmaceutical substance is an X-ray contrast agent, the metal is selected from the group: Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir, the target-choosing portion is a non-peptidic quinolone, the receptor is avß3 or aßs, and the linking group is present between the targeting portion and the chelator. 31. A method for treating rheumatoid arthritis in a patient, characterized in that it comprises: administering in a patient by means of injection or infusion a radiological substance of armac i t ion and of c onf m rmity with claim 19, capable of l ocal i a new angiogenic vasculature. 32. A method of treating cancer in a patient, characterized by comprising: administering to a patient in need thereof a therapeutic radiopharmaceutical sleep according to claim 19, by injection or infusion. 33. A method for forming an image image of therapeutic angiogenesis in a patient, characterized by comprising: (1) administering to a patient by injection or infusion a diagnostic radiopharmaceutical, an MRI contrast agent, or a lightning contrast agent X, according to claim 11; (2) forming an image of the patient's area where the desired formation of new blood vessels is located. 34. A method for forming a cancer image in a patient, comprising: (1) administering to a patient by injection or infusion a diagnostic radiopharmaceutical in accordance with claim 12; (2) image the patient using flat scintigraphy or gamma SPECT, or positron emission tomography. 35. A method for forming a cancer image in a patient, characterized in that it comprises: (1) administering an MRI contrast agent in accordance with the claim 26; and (2) forming images of the patient using magnetic resonance imaging. 36. A method for forming an image of cancer in a patient, characterized by comprising: (1) administering an X-ray contrast agent according to claim 30; and (2) image the patient using X-ray computed tomography. 37. A compound characterized in that it comprises: a targeting portion and a surfactant, wherein the target-choosing portion is attached to the surfactant, which is a non-peptide and binds to a receptor that is activated during angiogenesis and the compound has 0- 1 linking groups between the target-choosing portion and the surfactant. 38. The compound according to claim 37, characterized in that the target-choosing portion comprises a non-peptidic quinolone and the linking group is present between the target-choosing portion and the surfactant. 39. The compound according to claim 38, characterized in that the receptor is the avß3 or avß5 integrin and the compound is of the formula: (Q) d- nsf wherein Q is a compound of the formula (II) (II) which includes stereoisomeric forms thereof, or mixtures of the stereoisomeric forms thereof, or pharmaceutically acceptable salt or precursor forms thereof, wherein: R1 * is selected from: 6 is -CH2- or -N (R10e) -; Ale and Bß are independently -CH2- or -N (R10e) -; Dß ee -N (R10e) - or -S-; Ee-Fe is -C (R2e) = C (R3e) - or -C (Re) 2C (R3ß) a-; Je is -C (R2e) - or -N-; Ke, Le and Mee are independently -C (R2e) - or -C (R3e) -; R 2 and R 3e are independently selected from: H, alkoxy of 1 to 4 carbon atoms, NRlleR12e, halogen, N02, CN, CF3, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 at 7 carbon atoms, cycloalkyl (3 to 7 carbon atoms) alkyl of 1 to 4 carbon atoms, aryl (alkyl of 1 to 6 carbon atoms) -, alkyl (1 to 6 carbon atoms) carbonyl, ( "C 1 -C 6 alkoxy") carbonyl, arylcarbonyl and aryl substituted with 0-4 of alternatively, when R2e and R3e are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic ring system or 5-7 membered aromatic or non-aromatic heterocyclic ring system , the carbocyclic or heterocyclic ring is substituted with 0-2 groups selected from alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, cyano, amino, CF3 and N02; R2ae is selected from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms), aryl, aryl (C 1-4 alkyl) -, (C 2 -C 7 alkyl) carbonyl, arylcarbonyl, (C 2 -C 7 alkoxy) carbonyl, cycloalkoxy (C 3 -C 7) to 7 carbon atoms) carbonyl, bicycloalkoxy (from 7 to 11 carbon atoms), aryloxycarbonyl, aryl (C 1 -C 10 alkoxy) carbonyl, alkyl (from 1 to 6 carbon atoms) carbonyloxy (alkoxy from 1 to C) 4 carbon atoms) carbonyl, arylcarbonyloxy (C 1 -C 4 alkoxy) carbonyl, and cycloalkyl (3 to 7 carbon atoms) C arb on i 1 Oxy (C 1 -C 4 alkoxy) carbonyl; R7e is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 4 carbon atoms) carbon) carbonyl, C02R18ae, S02Rlle, S02NR10eRlle, OR10e and N (Rlle) R12e; U * is selected from: - (CH2) ne-, - (CH2) neO (CH2) me-, - (CH2) neN (R12) (CH2) me-, -NH (CH2) ne-, - (CH2) neC (= 0) (CH2) me-, - (CH2) neS (0) pS (CH2) rae-, - (CH2) neNHNH (CH2) me-, -N (R10ß) C (= O) -, - NHC (= 0) (CH2) ne-, -C (= 0) N (R10e) -, and -N (R "e) S (0) pe-; Ge is N O CR19e; e is -C (= 0) -NR (R10e) - (alkylene of 1 to 3 carbon atoms) -, in which the alkylene group is substituted by R8e and by R9e: R8e and R9e are independently selected from: H, C02R18be, C (= 0) R18be, CONR17R18be, alkyl of 1 to 10 carbon atoms substituted with 0-1 Ree, alkenyl of 2 to 10 carbon atoms substituted with 0-1 of R6e, alkynyl of 2 to 10 carbon atoms substituted with 0-1 of R6e, cycloalkyl of 3 to 8 carbon atoms substituted with 0-1 of R6e, cycloalkenyl of 5 to 6 carbon atoms substituted with 0-1 of R6e, (C 1 -C 10 alkyl) carbonyl, cycloalkyl (of 3 to 10 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, phenyl substituted with 0-3 of Ree, naphthyl substituted with 0-3 of R6e, a heterocyclic ring of 5-10 members containing 1-3 heteroatom of N, O or S, wherein the heterocyclic ring may be saturated, partially saturated or completely saturated, the heterocyclic ring is substituted with 0-2 of R7ß, alkoxy of 1 to 10 carbon atoms substituted with 0-2 of R7e, hydroxy, nitro, -N (R10β) Rlle, -N (R16e) R17e, aryl (alkyl) 0 to 6 carbon atoms) carbonyl, aryl (alkyl of 3 to 6 carbon atoms), heteroaryl (alkyl of 1 to 6 carbon atoms), C0NR18aeR20e, S02R18ae, and SO2NR18aeR20e, with the proviso that any of the above groups alkyl, cycloalkyl, aryl or heteroaryl may be unsubstituted or substituted independently with 1-2 of R7e; Ree is selected from: H, alkyl of 1 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, nitro, alkylcarbonyl of 1 to 10 carbon atoms, -N (Rlle) R12e, cyano, halo, CF3, CHO, C02R18bβ, C (= 0) R18be, C0NR17eR18be, OC (= O) R10e, 0R10e, OC (= 0) NR10eRlle, NR10eC (= O) R10e, NR10eRlle, NR10eRlle, NR10eRlle, (= 0) OR21e, NR10eC (= 0), NR10eS02R21ß, S (0) pRlle, S02NR10eRlle, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) meMe, and -NMe2, aryl (alkyl of 1 to 4 carbon atoms) -, the aryl is substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3 , S (0) pSMe, and -NMe2 and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, O or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 of R7e; R10e is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, aryl, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl (alkyl of 1 to 4 carbon atoms) carbon) and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R6β; Rlle is selected from: H, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, alkoxy of 1 to 6 carbon atoms, benzyloxy, aryl, heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl, alkyl of 1 to 10 carbon atoms substituted with 0-2 of R4e; R4e is selected from: • 'H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, (alkyl) from 1 to 10 carbon atoms) carbonyl or, aryl, heteroaryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 6 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0- 2 substituents which are independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02, alternatively, when R10e and Rlle are both substituents in the same nitrogen atom (as in -NR10eR1: le) can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from: 3-azabicyclononyl, 1, 2, 3, 4-tetrahydro- lC [uinolinyl, 1,2,3,4-tetrahydro-2-isoc [uinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl and 1-piperazinyl; the heterocycle is substituted with 0-3 groups which are selected from: alkyl of 1 to 6 carbon atoms, aryl, heteroaryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 6 carbon atoms) carbonyl, (C3-C7-cycloalkyl) carbonyl, C1-C6-alkoxy) carbonyl, aryl (C1-C4 alkoxy) carbonyl, alkylsulfonyl of 1 to 6 carbon atoms and aryisulfonyl; R12e is selected from: H, alkyl of 1 to 6 carbon atoms, trif enylmethyl, methoxymethyl, methoxy-3-enylmethylmethyl, trimethylsilylethoxymethyl, (alkyl of 1 to 6 carbon atoms) carb on i 1, (alkoxy of 1 to 6 carbons atoms) ca rb on i 1 o, (C 1-6 alkyl) aminocarbonyl, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 atoms) carbon) (alkyl of 1 to 4 carbon atoms) -aryl, heteroaryl (C 1-6 alkyl) carbonyl heteroarylcarbonyl, aryl (C 1-6 alkyl) - (alkyl of 1 to 6 carbon atoms) carbonyl, arylcarbonyl alkylsulfonyl of 1 to 6 carbon atoms, aryisulfonyl aryl (C 1-6 alkyl) sulphonyl heteroarylsulfonyl, heteroaryl (C 1-6 alkyl) sulfonyl, aryloxycarbonyl and aryl (C 1-6 alkoxy) carbonyl, wherein such aryl groups are substituted with 0-2 suetituyentee that are selected from the group consisting of alguilo of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, CF3 and nitro, - R16e is selected from: -C (= 0 ) ORa -C (= 0) Rx -C (= 0) N (R18be) -C (= 0) NHS02R18ae, -C (= 0) NHC (= 0) R18be, -C (= 0) NHC (= 0) ) 0R18ae, -C (= 0) NHS02NHR18be, -S02R18ae, -S02N (R18 e) 2 and -S02NHC (= 0) 0R18be; R17e is selected from: H, C1 to 6 carbon atom, C3 to C7 cycloalkanoyl, C3 to C7 cycloalkyl (C1 to C4 alkyl) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) R18 e is selected from: alkyl of 1 to 8 carbon atoms optionally substituted with a bond to Lp, cycloalkyl of 3 to 11 carbon atoms optionally substituted with a bond Ln, aryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond Ln, heteroaryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a linkage to Ln, -alkyl of 1 to 6 carbon atoms-heteroaryl optionally substituted with a bond to L n, diaryl (C 1-6 alkyl) optionally substituted with a bond to L n, optionally substituted heteroaryl with a bond to L n , phenyl substituted with 3-4 of R19e and optionally substituted with a bond to Ln, nafti it is substituted with 0-4 of Rx9β and optionally substituted with a bond to Ln, and a bond to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19e; R18be ee H or R18ae; R19e is selected from: H, halogen, CF3, C02H, CN, N02, -NRlleR12e, OCF3, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl from 3 to 11 carbon atoms, cycloalkyl (from 3 to 7 carbon atoms) (alkyl from 1 to 4 carbon atoms) -, aryl (alkyl from 1 to 6 carbon atoms) -, alkoxy from 1 to 6 atoms of carbon carbon, alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-O-, aryl-S02-, heteroaryl and heteroaryl-S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups which are selected from hydrogen, halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms; R2 De is selected from: hydroxy, alkyloxy of 1 to 10 carbon atoms, cycloalkyloxy of 3 to 11 carbon atoms, aryloxy, aryl (C 1 -C 4 alkyl) oxy, alkyl (2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, coxy (of 2 to 10 carbon atoms) carbonyl (1 to 2 carbon atoms) oxy-, cycloalkyl (3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy, cycloalkoxy (of 3 to 10 carbon atoms) carbonyloxy (alkyl) from 1 to 2 carbon atoms) oxy-, cycloalkoxy of 3 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyl (alkyl of 1 to 2 carbon atoms) oxy-, aryloxycarbonyloxy ( alkyl of 1 to 2 carbon atoms) oxy-, arylcarbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 1 to 5 carbon atoms) (alkyl of 1 to 5 carbon atoms) carbonyloxy (1 to 2 carbon atoms) oxy, (5- (C 1-5 alkyl) -1,3-dioxa-cyclopenten-2-one-yl) methyloxy, (5-aryl-1, 3-dioxa-cyclopenten-2-one-yl) methyloxy, and (R10e) (Rlle) N- (C 1-10 alkoxy) -, - R21e is selected from: alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms (cycloalkyl of 3 to 11 carbon atoms) ethyl, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R7β; R22e is selected from: -C (= 0) -R18be, -C (= 0) N (R18be) 2, -C (= 0) NHS02R18ae, -C (= 0) NHC (= 0) R 18be (= 0) NHC (= 0) 0R18ae, and -C (= 0) NHS02NHR 18be Yß is selected from: -COR20β, -S03H, -P03H, -C0NHNHS02CF3, -C0NHS02R18ae, -C0NHS02NHR18be, -NHC0CF3, -.NHC0N? S02R18ae, -NHS02R18ae, -0P03H2, -0S03H, -P03H2, -S02NHC0R18ae, -S02NHC02R18ae, me is 0-2 nß is 0-4 p3 is 0-2, re is 0-2 with the following condition: ne and me are chosen so that the number of atoms connecting Rle and Ye is in the range of 8 -14; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; d 'is 1-100; Ln is a linking group that has the formula: ((W) h- (CR6R7) _) x- (Z) k- ((CReaR7a) _. - (W) h,) x,; W is independently selected, each time it is presented, from the group: O, S, NH, NHC (= 0), C (= 0) NH, NR8C (= 0), C (= 0) NR8, C (= 0) ), C (= 0) 0, 0C (= 0), NHC (= S) NH, NHC (= 0) NH, S02, S02NH, (0CH2CH2) 8, (CH2CH20) s ,, (OCH2CH2CH2) g ", (CH2CH2CH20) t, and (aa) t ,; aa is independently, each time it is presented, an amino acid; Z is selected from the group: aryl substituted with 0-3 of R10, cycloalkyl of 3 to 10 carbon atoms substituted with 0-3 of R10, and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which is independently selected from N, S and 0 and substituted with 0-3 of R10, - R6, R6a, R7, R7a and R8 are independently selected, each time they occur, from the group: H, = 0, COOH, S03H, P03H , alkyl of 1 to 5 carbon atoms substituted with 0-3 of R10, aryl substituted with 0-3 of R10, benzyl substituted with 0-3 of R10 and alkoxy of 1 to 5 carbon atoms substituted with 0-3 of R10 , NHC (= 0) R11, C (= 0) NHR11, NHC (= 0) NHR11, NHR11, R11 and a binding to Sf; R10 is independently selected, each time it is presented, from the group.- a bond to Ch, COOR11, C (= 0) NHR11, NHC (= 0) R1: L, OH, NHR11, S03H, P03H, -0P03H2, - OS03H, aryl substituted with 0-3 of R11, alkyl of 1 to 5 carbon atoms substituted with 0-1 of R12, alkoxy of 1 to 5 carbon atoms substituted with 0-1 of R12 and a heterocyclic ring system of 5. -10 members containing 1-4 heteroatoms that are independently selected from N, S, and 0 and substituted with 0-3 of R11, -R11 is independently selected, each time it occurs, from the group: H, alkyl substituted with 0 -1 of R12, aryl substituted with 0-1 of R12, a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms which are independently selected from N, S and O, and substituted with 0-1 of R12, cycloalkyl of 3 to 10 carbon atoms substituted with 0-1 of R12, polyalkylene glycol substituted with 0-1 of R12, carbohydrate substituted with 0-1 of R12, cyclodextrin substituted with 0-1 of R12, amino acid substituted with 0-1 of R1, polycarboxyalkyl substituted with 0-1 of R12, polyazaalkyl substituted with 0-1 of R12, peptide substituted with 0-1 of R12, wherein the peptide is constituted of 2-10 amino acids, 3, 6-0-disulfo-BD-galactopyranosyl, bis (phosphonomethyl) glycine or a bond for Sf; R12 is a link to Sf; k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; h "'is selected from 0, 1, and 2; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; gt is selected from 0, 1, 2, 3 , 4, 5, 6, 7, 8, 9 and 10; t 'is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; x is selected from 0, 1, 2, 3, 4 and 5; x1 is selected from 0, 1, 2, 3, 4 and 5, - Sf is a teneoactive which is a lipid or a compound of the formula: -A 10 1/9 A9 is selected from the group: OH and OR27; A10 is OR27; R 27 is C (= 0) alkyl of 1 to 20 carbon atoms; • E1 is alkylene of 1 to 10 carbon atoms substituted with 1-3 of R28, - R28 is independently selected, each time it is present, from the group: R30, -P03H-R30, = 0, -C02R29, -C ( = 0) R29, -C (= 0) N (R29) 2, -CH20R29, -OR29, -N (R29) 2, alkyl of 1 to 5 carbon atoms and alkenyl of 2 to 4 carbon atoms, - R29 is independently selected, each time it is presented, from the group: R 30, H, alkyl of 1 to 6 carbon atoms, phenyl, benzyl and trifluoromethyl; R30 is a link to Ln; and a pharmaceutically acceptable salt thereof. 40. A compoteto de confmiency with claim 39, characterized in that the compoteto is of the formula: Q-Ln-Sf wherein Q is a compound of the formula (IV) (IV) which includes eetereoisomeric formae of the mole, or mixture of the stereoisomeric forms thereof, or a pharmaceutically acceptable salt or precursor forms thereof, wherein: Rle is selected from: R 2e and R 3e are independently selected from H, alkoxy of 1 to 4 carbon atoms, NRlleR12e, halogen, N02, CN, CF3, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 at 7 carbon atoms, cycloalkyl (3 to 7 carbon atoms) -alkyl of 1 to 4 carbon atoms, aryl (alkyl of 1 to 6 carbon atoms) -, (alkyl of 1 to 6 carbon atoms) carbonyl , (alkoxy of 1 to 6 carbon atoms) carbonyl, arylcarbonyl, and aryl tituted with 0-4 of R7ß, alternatively, when R 2e and R 3e are suetituyentee on adjacent atoms can be taken together with loe carbon atoms which are bonded to form a carbocyclic ring or 5 to 7 membered heterocyclic aromatic 5 to 7 membered aromatic or not, the carbocyclic or heterocyclic ring is tituted with 0-2 groups selected from alkyl of 1 to 4 carbon atoms, alkoxy 1 to 4 carbon atoms, halo, cyano, amino, CF3 and N02 / - R2ae s chosen from: H, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) -alkyl of 1 to 4 carbon atoms carbon, aryl, aryl (C 1-4 alkyl) -, (C 2 -C 7 alkyl) carbonyl, arylcarbonyl, (C 2 -C 10 alkoxy) carbonyl, cycloalkoxy carbonyl of 3 to 7 atoms carbon, bicycloalkoxy carbonyl of 7 to 11 carbon atoms, aryloxy carbonyl, aryl alkoxy of 1 to 10 carbon atoms) carbonyl, alkyl (of 1 to 6 carbon atoms) carbonyloxy (alkoxy of 1 to 4 carbon atoms) carbonyl , arylcarbonyloxy (alkoxy of 1 to 4 carbon atoms) carbonyl and cycloalkyl (of 3 to 7 carbon atoms) ca rb on i 1 oxy (alkoxy of 1 to 4 carbon atoms) carbonyl; R7e is selected from: H, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 4 carbon atoms) carbon), carbonyl, C02R18ae, S02Rlle, S02NR10eRlle, OR10e and N (Rlle) R12e; U * is selected from: '- (CH2) ne-, - (CH2) neO (CH2) me-, -NH (CH2) ne-, -N (R10e) C (= O) -, -NHC (= 0 ) (CH2) ne- and -C (= 0) N (R10e) -; Gß ee N o CR19e; R 8e is selected from: H, C02R18be, C (= 0) R18be, C0NR17 and alkyl of 1 to 10 carbon atoms tituted with 0-1 R 6e of, alkenyl of 2 to 10 carbon atoms tituted with 0-1 of R6ß , alkynyl of 2 to 10 carbon atoms tituted with 0-1 of R6e, cycloalkyl of 3 to 8 carbon atoms tituted with 0-1 of R6e, cycloalkenyl of 5 to 6 carbon atoms tituted with 0-1 of Ree, ( alkyl of 1 to 10 carbon atoms) carbonyl, cycloalkyl (of 3 to 10 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, phenyl tituted with 0-3 of R6e, naphthyl tituted with 0-3 of R6e , a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, O or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is tituted with 0-2 of R7β; R9e is selected from: alkyl of 1 to 10 carbon atoms tituted with 0-1 of Ree, alkoxy of 1 to 10 carbon atoms tituted with 0-2 of R7e, H, nitro, N (Rlle) R12e, OC (= O) R 10e, OR10ß, OC (= 0) NR10eRlle, NR10eC (= O) R 10e, NR1DeC (= 0) OR21e, NR10eC (= 0) NR10eRlle, NR10eS02NR10eRlle, NR10eS02R21e, hydroxy, OR22e, -N (R 10e) Rlle, - N (R16E) R17e, aryl (0 to 6 carbon atoms) carbonyl, aryl (C1-C6 alkyl) heteroaryl (1 to 6 carbon atoms), CONR18aeR0e, S02R18ae and S02NR18aeR0 \ with provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be untituted or independently tituted with 1-2 of R7e; RSe is selected from: H, alkyl of 1 to 10 carbon atoms, hydroxy, alkoxy of 1 to 10 carbon atoms, nitro, alkylcarbonyl of 1 to 10 carbon atoms, -N (Rlle) R12e, cyano, halo, CF3 , CHO, C02R18be, C (= 0) R18be, C0NR17βR18be, OC (= 0) R10e, 0R10e, OC (= 0) NR10 ^ 1 NR10eC (= 0) R: NR:! C (= 0) 0R: NR3! C (= 0) NR10eR: NR10eS02NR10eRlle, NR10eS02R21e, S (0) peRlle, S02NR10eRlle, aryl substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3, S (0) mSMe and -NMe2, aryl (alkyl of 1 to 4 carbon atoms) -, aryl is substituted with 0-3 groups selected from halogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, CF3 , S (0) peMe and -NMe2, and a 5-10 membered heterocyclic ring containing 1-3 heteroatoms of N, 0 or S, wherein the heterocyclic ring may be saturated, partially saturated or completely unsaturated, the heterocyclic ring is substituted with 0-2 R7e; R10e is selected from: H, CF3, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, aryl, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl (alkyl of 1 to 4 carbon atoms) carbon) and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R6e; Rllβ is selected from: H, hydroxy, alkyl of 1 to 8 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, cycloalkyl of 3 to 11 carbon atoms) methyl, alkoxy of 1 to 6 carbon atoms, benzyloxy, aryl, 'heteroaryl, heteroaryl (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 4 carbon atoms), adamantylmethyl and alkyl of 1 to 10 carbon atoms substituted with 0-2 of R4e; R4e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, heteroaryl , aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -, wherein the aryl or heteroaryl groups are substituted with 0-2 substituents which are independently selected from the group that establishes of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, F, Cl, Br, CF3 and N02, R12e is selected from: H, alkyl of 1 to 6 carbon atoms, trif enylmethyl, methoxymethyl, methoxy-enyldifenylmethyl, trimethylsilylethyloxymethyl, (C 1-6 -alkyl), carbonyl, (C 1-6 -alkoxy), carbonyl, (C 1-6 -alkyl) aminocarbonyl, alkenyl, 3-6 -alpha. of carbon, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) carbon) -, aryl, heteroaryl (C 1-6 alkyl), carbonyl, heteroarylcarbonyl, aryl (C 1-6 alkyl) -, (C 1-6 alkyl), carbonyl, arylcarbonyl, alkylsulfonyl of 1 to 6 carbon atoms, arylsulfonyl, aryl (C 1-6 alkyl) sulfonyl, heteroarylsulfonyl, heteroaryl (C 1-6 alkyl) sulfonyl, aryloxycarbonyl and aryl (alkoxy of 1 to 6 carbon atoms) carbon) carbonyl, wherein the aryl groups are substituted with 0-2 substituents which are selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, CF3 and nitro, - R16e is selected from: -C (= 0) 0R18ae, -C (= 0) R18be, -C (= 0) N (R18be) 2, -S02R18ae, and -S02N (R18bB) 2; R17e is selected from: H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl (of 3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl, aryl (alkyl of 1 to 6 carbon atoms) -, and heteroaryl (alkyl of 1 to 6 carbon atoms) -; R18ae is selected from: alkyl of 1 to 8 carbon atoms optionally substituted with a bond to Ln, cycloalkyl of 3 to 11 carbon atoms optionally substituted with a bond to Ln, aryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to L n, heteroaryl (alkyl of 1 to 6 carbon atoms) - optionally substituted with a bond to L n, (alkyl of 1 to 6 carbon atoms) teroaryl or optionally substituted with a bond to L n, biaryl ( alkyl of 1 to 6 carbon atoms) optionally substituted with a bond to L n, heteroaryl optionally substituted with a bond to L n, phenyl substituted with a 3-4 of R 19e and optionally substituted with a bond to L n, naphthyl substituted with 0-4 of R19e and optionally substituted with a bond to Ln, and a bond to Ln, wherein the aryl or heteroaryl groups are optionally substituted with 0-4 of R19β; R18 e is H or R18aβ; R19β is selected from: H, halogen, CF3, C02H, CN, N02, -NRlleR12e, OCF3, alkyl of 1 to 8 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl from 3 to 11 carbon atoms, cycloalkyl (3 to 7 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, aryl (alkyl of 1 to 6 carbon atoms) -, (alkoxy of 1 to 6 atoms) carbon), alkoxycarbonyl of 1 to 4 carbon atoms, aryl, aryl-0-, aryl-S02-, heteroaryl and heteroaryl-S02-, wherein the aryl and heteroaryl groups are substituted with 0-4 groups which are selected from hydrogen, halogen, CF3, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon atoms, - R20e is selected from: hydroxy, alkyloxy of 1 to 10 carbon atoms, cycloalkyloxy of 3 to 11 carbon atoms, aryloxy, aryl (alkyl of 1 to 4 carbon atoms) oxy, alkyl (of 2 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbon) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, alkoxy (of 2 to 10 carbon atoms) carbonyl (alkyl of 1 to 2 carbon atoms) ox i -, cycloalkyl (of 3 to 10 atoms) carbon) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy-, cycloalkoxy (of 3 to 10 carbon atoms) ) carbonyl (1 to 2 carbon atoms) oxy-, aryloxycarbonyl (1 to 2 carbon atoms) oxy-, aryloxycarbonyloxy (1 to 2 carbon atoms) oxy-, arylcarbonyloxy (1 to 2 alkyl) carbon atoms) oxy-, alkoxy (of 1 to 5 carbon atoms) (alkyl of 1 to 5 carbon atoms) carbonyloxy (alkyl of 1 to 2 carbon atoms) oxy, (5-. { alkyl of 1 to 5 carbon atoms) -1,3-dioxa-cyclopenten-2-one-yl) methyl i, (5-aryl-l, 3-dioxa-cyclopenten-2-yl) methyloxy y (R10e ) (Rllβ) N- (alkoxy of 1 to 10 carbon atoms), - R21ß is selected from: alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 11 carbon atoms, (cycloalkyl of 3 to 11 carbon atoms) methyl, aryl, aryl (alkyl of 1 to 4 carbon atoms) -, and alkyl of 1 to 10 carbon atoms and substituted with 0-2 of R7e; R 2ß ee selects from: -C (= 0) -R18be, - C (= 0) N (R18be) - C (= 0) NHS02Rx -C (= 0) NHC (= 0) R18bβ, -C (= 0) NHC (= 0) OR18ae and -C (= 0) NHS02NHR18be; . mß is 0-2; ne is 0-4; and pe is 0-2; with the following condition: ne and me are chosen so that the number of atoms that connect to R1 and -COR20e in the formula (IV) is in the range of 8-14; it is independently selected, each time it is presented, from the group; 0, S, NH, NHC (= 0), C (= 0) NH, NR8C (= 0), -C (= 0) NR8, C (= 0), C (= 0) 0, 0C (= 0) ), NHC (= S) NH, NHC (= 0) NH, S02, S02NH, 20-2oo (CH2CH02) 20_20o, (0CH2CH2CH-,) 20_200, (CH2CH2CH20) 20_ IDO (3-9-) 7 aa is independently, each time it occurs, an amino acid; Z is selected from the group: aryl substituted with 0-1 of R10, cycloalkyl of 3 to 10 carbon atoms substituted with 0-1 of R10 and a cyclic heterophenyl ring of 5-10 members containing 1-4 heteroatoms which are independently selected from N, S and 0, and substituted with 0-1 of R10; R6, R6a, R7, R7a and Rβ are independently selected, each time they occur in the group: H, = 0, COOH, S03H, alkyl of 1 to 5 carbon atoms substituted with 0-1 of R10, aryl substituted with 0 -1 of R10, benzyl substituted with 0-1 of R10 and alkoxy of 1 to 5 carbon atoms substituted with 0-1 of R10, NHC (= 0) R ", C (= 0) NHRα, NHC (= 0) NHR11, NHR11, R11 and a bond to Sf; k ee 0 or 1; Sf is a surfactant which is a lipid or a compound of the formula: A9 is OR27; A10 is OR27; R27 is C (= 0) alkyl of 1 to 15 carbon atoms, - E1 is alkylene of 1 to 4 carbon atoms substituted with 1-3 of R28; R28 is independently selected, each time it is presented, from the group. R30, -P03H-R30, = 0, -C02R29, -C (= 0) R29, -CHaOR29, -OR29 and alkyl of 1 to 5 carbon atoms. carbon; . R29 is independently selected, each time it is presented, from the group: R30, H, alkyl of 1 to 6 carbon atoms, phenyl and benzyl; R3D is a link to Ln; and a pharmaceutically acceptable salt thereof. 41 An ultrashorting agent, characterized in that it comprises: (a) a compound according to claim 39, comprising: a quinolone that binds the cevß3 integrin, a surfactant and a linking group between the quinolone and the surfactant; (b) a parenterally acceptable carrier; and (c) an ecogenic gene. 42. An ultrasound contrast agent composition according to claim 41, further comprising: 1,2-dipalmi toyl-in-glycero-3-phemphotidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine and N- (methoxypolyethylene glycol 5000 carbamoyl) -1, 2 -dipamitoyl-sn-glycero-3-phosphatidylethanolamine. 43. The contrast agent composition for ulstraeonide, according to claim 42, characterized in that the ecogenic gae is a perfluorocarbon of 2 to 5 carbon atoms. 44. A method for imaging cancer in a patient, characterized in that it comprises: (1) administering to a patient by injection or infusion, an ultrasound contrast agent composition according to claim 41; and (2) patient image formation using sonography. 45. A method for imaging new blood vessels in a patient, characterized in that it comprises: (1) administering to a patient by injection or infusion, a contrast agent composition for ultrasound according to claim 41; (2) forming an image of the patient's area where the desired formation of the new blood vessels is located. 46. A method for imaging therapeutic angiogenesis in a patient, characterized in that it comprises: (1) administering to a patient by injection or infusion, an ultrasound contrast agent composition according to claim 41; (2) forming an image of the patient's area where the desired formation of new blood vessels is located. 47. A method for image forming atherosclerosis in a patient, comprising: (1) administering to a patient by injection or infusion an ultrasound contrast agent composition according to claim 41 to a patient; (2) form an image of the patient's area where the atherosclerosis is located. 48. A method for restenosis imaging in a patient, characterized in that it comprises: (1) administering to a patient by injection or infusion, a composition of an antisense agent according to claim 41; (2) image the area of the patient where the restenosis is located. 49. A method for imaging cardiac ischemia in a patient, characterized in that it comprises: (1) administering, by injection or infusion, an ultrasound contrast agent composition according to claim 41; (2) image the area of the myocardium where the ischemic region is located. 50. A method for forming an image of myocardial reperfusion injury in a patient, characterized in that it comprises: (1) administering to a patient by injection or infusion, a contrast agent composition for ultrasound according to claim 41; (2) image the area of the myocardium where the reperfusion damage is located. 51. A therapeutic radiopharmaceutical composition, characterized in that it comprises: (a) a therapeutic radiopharmaceutical sleep according to claim 19, and (b) a parenterally acceptable carrier. 52. A diagnostic pharmaceutical composition characterized in that it comprises: (a) a diagnostic radiopharmaceutical, an MRI contrast agent or an X-ray contrast agent according to claim 11; and (b) a parenterally acceptable carrier. 53. A method for treating restenosis in a patient, characterized in that it comprises: (1) administering to a patient, either systemically or locally, a therapeutic radiopharmaceutical according to claim 19 capable of being located in the restenotic area and providing an effective dose of radiation. 54. A method for forming an image of atherosclerosis in a patient, characterized in that it comprises: (1) administering a radiopharmaceutical diagnostic serum, a contrast agent for MRI or an X-ray contrast agent, according to claim 11, patient by injection or infusion; (2) form an image of the patient's area where the atherosclerosis is located. 55. A method for restenosis imaging in a patient, characterized in that it comprises: (1) administering to a patient by injection or infusion a diagnostic radiopharmaceutical, an MRI contrast agent, or an X-ray contrast agent in accordance with claim 11; (2) forming an image of the patient's area where the restenosis is located. 56. A method for forming an image of cardiac ischemia in a patient, characterized in that it comprises: (1) administering to a patient by injection or infusion a diagnostic radiopharmaceutical, a contrast agent for MRI or an X-ray contrast agent in accordance with with claim 11; (2) image the area of the myocardium where the ischemic region is located. 57. A method for forming an image of reperfusion damage of the myocardium in a patient, characterized in that comprises: (1) administering to a patient by injection or infusion a diagnostic radiopharmaceutical, a contrast agent for MRI or a contrast agent for X-ray, according to claim 11; (2) image the area of the myocardium where the reperfusion damage is located.
MXPA/A/2001/006151A 1998-12-18 2001-06-15 Vitronectin receptor antagonist pharmaceuticals MXPA01006151A (en)

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