WO2001097861A2 - Agents pharmaceutiques antagonistes du recepteur de la vitronectine destines a etre utilises dans une therapie combinee - Google Patents

Agents pharmaceutiques antagonistes du recepteur de la vitronectine destines a etre utilises dans une therapie combinee Download PDF

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WO2001097861A2
WO2001097861A2 PCT/US2001/020203 US0120203W WO0197861A2 WO 2001097861 A2 WO2001097861 A2 WO 2001097861A2 US 0120203 W US0120203 W US 0120203W WO 0197861 A2 WO0197861 A2 WO 0197861A2
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substituted
group
independently selected
bond
carbamoyl
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PCT/US2001/020203
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WO2001097861A3 (fr
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Edward H. Cheesman
John A. Barrett
Alan P. Carpenter, Jr.
Milind Rajopadhye
Michael Sworin
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Bristol-Myers Squibb Pharma Company
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Priority to AU2001271435A priority Critical patent/AU2001271435A1/en
Priority to CA002412849A priority patent/CA2412849A1/fr
Priority to EP01950446A priority patent/EP1311292A2/fr
Publication of WO2001097861A2 publication Critical patent/WO2001097861A2/fr
Publication of WO2001097861A3 publication Critical patent/WO2001097861A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
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    • C07K7/52—Cyclic peptides containing at least one abnormal peptide link with only normal peptide links in the ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions

  • the present invention provides novel pharmaceuticals useful for the diagnosis and treatment of cancer, methods of imaging tumors in a patient, and methods of treating cancer in a patient
  • the invention is also directed to novel pharmaceutical compositions and combination therapy comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and at least one agent selected from the group consisting of an anti-cancer agent and a radiosensitizer agent.
  • the invention is directed to novel pharmaceutical compositions and combination therapy comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and a photosensitizing agent.
  • the pharmaceuticals are comprised of a targeting moiety that binds to the vitronectin receptor that is expressed in tumor vasculature, an optional linking group, and a therapeutically effective radioisotope or diagnostically effective imageable moiety.
  • the therapeutically effective radioisotope emits a gamma ray or alpha particle sufficient to be cytotoxic.
  • the imageable moiety is a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.
  • Cancer is a major public health concern in the United States and around the world. It is estimated that over 1 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.
  • the imaging procedures include X-ray computed tomography, magnetic resonance imaging, ultrasound imaging and radionuclide scintigraphy.
  • a contrast agent is administered to the patient to enhance the image obtained by X-ray CT, MRI and ultrasound, and the administration of a radiopharmaceutical that localizes in tumors is required for radionuclide scintigraphy.
  • Treatment of cancer typically involves the use of external beam radiation therapy and chemotherapy, either alone or in combination, depending on the type and extent of the disease.
  • a number of chemotherapeutic agents are available, but generally they all suffer from a lack of specificity for tumors versus normal tissues, resulting in considerable side-effects.
  • the effectiveness of these treatment modalities is also limited, as evidenced by the high mortality rates for a number of cancer types, especially the more prevalent solid tumor diseases . More effective and specific treatment means continue to be needed.
  • a metallophar aceutical that localizes specifically in the tumor by binding to a receptor expressed only in tumors or expressed to a significantly greater extent in tumors than in other tissue.
  • the location of the metallopharmaceutical could then be detected externally either by its imageable emission in the case of certain radiopharmaceuticals or by its effect on the relaxation rate of water in the immediate vicinity in the case of magnetic resonance imaging contrast agents .
  • This tumor specific metallopharmaceutical approach can also be used for the treatment of cancer when the metallopharmaceutical is comprised of a particle emitting radioisotope.
  • the radioactive decay of the isotope at the site of the tumor results in sufficient ionizing radiation to be toxic to the tumor cells.
  • the specificity of this approach for tumors minimizes the amount of normal tissue that is exposed to the cytotoxic agent and thus may provide more effective treatment with fewer side-effects.
  • radionuclide labeled monoclonal antibodies, antibody fragments and other proteins or polypeptides that bind to tumor cell surface receptors have centered on the use of radionuclide labeled monoclonal antibodies, antibody fragments and other proteins or polypeptides that bind to tumor cell surface receptors .
  • the specificity of these radiopharmaceuticals is frequently very high, but they suffer from several disadvantages.
  • due to their molecular weight do not extravasate readily at the site of the tumor and then only slowly diffuse through the extravascular space to the tumor cell surface. This results in a very limited amount of the radiopharmaceutical reaching the receptors and thus very low signal intensity in imaging and insufficient cytotoxic effect for treatment.
  • Angiogenesis is the process by which new blood vessels are formed from pre-existing capillaries or post capillary venules; it is an important component of a variety of physiological processes including ovulation, embryonic development, wound repair, and collateral vascular generation in the myocardium. It is also central to a number of 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 a variety of cytokines and growth factors . Tumor released cytokines or angiogenic factors stimulate vascular- endothelial cells by interacting with specific cell surface receptors for the factors.
  • the activated endothelial cells secrete enzymes that degrade the ' basement membrane of the vessels.
  • the endothelial cells then proliferate and invade into the tumor tissue.
  • the endothelial cells differentiate to form lumens, making new vessel offshoots of pre-existing vessels.
  • the new blood vessels then provide nutrients to the tumor permitting further growth and a route for metastasis .
  • endothelial cell proliferation is a very slow process, but it increases for a short period of time during embryogenesis, ovulation and wound healing. This temporary increase in cell turnover is governed by a combination of a number of growth stimulatory factors and growth suppressing factors. In pathological angiogenesis, this normal balance is disrupted resulting in continued increased endothelial cell proliferation.
  • proangiogenic factors include basic fibroblast growth factor (bFGF) , angiogenin, TGF- alpha, TGF-beta, and vascular endothelium growth factor (VEGF) . While interferon-alpha, interferon-beta and thrombospondin are examples of angiogenesis suppressors.
  • Integrins are a diverse family of heterodimeric cell surface receptors by which endothelial cells attach to the extracellular matrix, each other and other cells.
  • the integrin ⁇ v ⁇ 3 is a receptor for a wide variety for a wide variety of extracellular matrix proteins with an exposed tripeptide Arg-Gly-Asp moiety and mediates cellular adhesion to its ligand: vitronectin, fibronectin, and fibrinogen, among others.
  • the integrin o ⁇ 3 is minimally expressed on normal blood vessels, but is significantly upregulated on vascular cells within a variety of human tumors.
  • the role of the ⁇ v ⁇ 3 receptors is to mediate the interaction of the endothelial cells and the extracellular matrix and facilitate the migration of the cells in the direction of the angiogenic signal, the tumor cell population.
  • Angiogenesis induced by bFGF or TNF-alpha depend on the agency of the integrin ⁇ v ⁇ 3
  • angiogenesis induced by VEGF depends on the integrin ⁇ * v ⁇ 3 (Cheresh et . al . , Science, 1955, 270, 1500-2).
  • Induction of expression of the integrins ⁇ i ⁇ i and ⁇ on the endothelial cell surface is another important mechanism by which VEGF promotes angiogenesis (Senger, et. al . , Proc. Natl. Acad, Sci USA, 1997, 84, 13612-7).
  • Angiogenic factors interact with endothelial cell surface receptors such as the receptor tyrosine kinases EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, tie, neuropilin-1, endoglin, endosialin, and Axl.
  • the receptors Flk-1/KDR, neuropilin-1, and Flt-1 recognize VEGF and these interactions play key roles in VEGF- induced angiogenesis.
  • the Tie subfamily of receptor tyrosine kinases are also expressed prominently during blood vessel formation.
  • angiostatin is a 38 kDa fragment of plasminogen that has been shown in animal models to be a potent inhibitor of endothelial cell proliferation.
  • Endostatin is a 20 kDa C-terminal fragment of collagen XVIII that has also been shown to be a potent inhibitor.
  • Endostatin Systemic therapy with endostatin has been shown to result in strong anti-tumor activity in animal models.
  • human clinical trials of these two chemotherapeutic agents of biological origin have been hampered by lack of availability.
  • Another approach to anti-angiogenic therapy is to use targeting moieties that interact with endothelial cell surface receptors expressed in the angiogenic vasculature to which are attached chemotherapeutic agents.
  • Burrows and Thorpe (Proc. Nat. Acad. Sci, USA, 1993, 90, 8996-9000) described the use of an antibody- imunotoxin conjugate to eradicate tumors in a mouse model by destroying the tumor vasculature.
  • the antibody was raised against an endothelial cell class II antigen of the major histocompatibility complex and was then conjugated with the cytotoxic agent, deglycosylated ricin A chain.
  • the same group (Clin. Can. Res., 1995, 1, 1623-1634) investigated the use of antibodies raised against the endothelial cell surface receptor, endoglin, conjugated to deglycosylated ricin A chain. Both of these conjugates exhibited potent anti-tumor activity in mouse models.
  • the major advantage of combined anti-cancer agents and angiogenesis-targeted therapeutic radiopharmaceuticals, over each therapeutic modality alone, is improved tumor response without substantial increases in toxicity over either treatment alone.
  • the advantage of using neovascular-specific radiopharmaceuticals, versus a tumor-cell targeted antibody, is that there is much lower systemic radiation exposure to the subject being treated.
  • the receptor targets for the radiopharmaceutical compounds, used in this method of treatment are expressed on the luminal side of tumor vessels, there is no requirement that these compounds traverse the capillary bed and bind to the tumor itself.
  • Photodynamic therapy has also been used in the treatment of cancer. Photodynamic therapy involves the administration of a photosensitive agent and subsequent irradiation with light to excite the photosensitizer, thus producing a cytotoxic effect. Spears, U.S. Pat. No.
  • the photosensitizers used are capable of localizing in malignant cells, either by natural tendency or because they have been intentionally targeted to a specific type of tissue, or both. When irradiated, they may be capable of fluorescing and, thus, may also be useful in diagnostic methods related to detecting target tissue.
  • the photosensitizer has the capacity, when irradiated with light at a wavelength which the compound absorbs, of causing a cytotoxic effect against whatever cells or other tissue in which the photosensitizer has localized.
  • a photosensitizer agent having a characteristic light absorption waveband is first administered to the patient, typically either orally or by injection.
  • Abnormal tissue in the body is known to selectively absorb certain photosensitizer agents to a much greater extent than normal tissue. More effective selectivity can be achieved using a photoreactive agent that is bound to an antibody, which links with antigens on targeted cells. The cancerous or abnormal tissue that has absorbed or linked with the photosensitizer dye is then destroyed by administering light of an appropriate wavelength or waveband corresponding to the absorption wavelength or waveband of the photosensitizer agent .
  • Photosensitizing agents such as Photofrin, a haematoporphyrin derivative, are known.
  • Photosensitizers therapy and detection of malignant tumours. Photochem. Photobiol., 45, 879-889, and Boyle R. W. and D. David (1996) Structure and biodistribution relationships of photodynamic sensitizers. Photochem. Photobiol. 64, 469-485)
  • Rodgers,et al . United States Patent No.
  • 6,225,333 discloses treating cancers with a variety of photosensitizing agents for example naphthalocyanine photosensitizing agents; tetrapyrrole-based photosensitizers; including porphyins; chlorins;, phthalocyanines; napthalocyanines ; coumarins and psoralens. Furthermore, Mazur, et al . , United States Patent No.
  • 6,229,0408 discloses a method for treatment of solid tumors by photodynamic therapy comprising administering a photosensitizer selected from the group consisting of: 1, 3 , 4, 6-tetrahydroxyhelianthrone; 1,3,4, 6-tetramethoxyhelianthrone; 10, 13-dimethyl- 1,3,4, 6-tetrahydroxyhelianthrone; 10, 13- di (methoxycarbonyl) -1, 3 , 4 , 6-tetramethoxyhelianthrone; 1, 6-di-N-butylamino-3, 4-dimethoxy-helianthrone; 1, 6-di- N-butylamino-3 , 4-dimethoxy-10, 13-dimethyl-helianthrone; 1, 6-di- (N-hydroxyethylamino) -3 , 4-dimethoxy-helianthrone; 2 , 5-dibromo-l, 3 , 4, 6-tetrahydroxyhelianthrone; and 2,5- dibromo
  • green porphyrins have been used in photodynamic therapy with light having a wavelength range around 670-780 nm. See for example, Levy et al . , U.S. Pat. No. 5,399,583 Levy et al . , U.S. Pat. No. 4,920,143, Levy et al . , U.S. Pat. No.
  • a method must be found for the irradiating light to reach the targeted tissue where the photosensitizer has been localized.
  • a light-emitting balloon catheter may be used or alternatively, a form of "liquid light” may be injected into the vascular tree such that the "liquid light”, perfuses the vasculature at the target site. Spears, U.S. Pat. No. 4,512,762. Alternatively,
  • the targeted tissues are visually located by imaging the treatment site through a fiber optic system so that light from a laser source can be accurately directed through the optical fiber to destroy the abnormal tissue. Even when the internal treatment site is accessible through natural body orifices, an endoscope is usually required to visualize the targeted tissue and accurately direct the light therapy, administered to the treatment site.
  • Chen, United States Patent No. 6,210,425 discloses an apparatus and a method to identify an internal treatment site within a patient's body for administration of light therapy and treatment of the site.
  • a photosensitizer agent as part of photodynamic therapy
  • an angiogenesis-targeted therapeutic radiopharmaceutical and an anti-cancer agent or a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, which target the luminal side of the neovasculature of tumors, to provide a surprising, and enhanced degree of tumor suppression relative to each treatment modality alone without significant additive toxicity.
  • RA rheumatoid arthritis
  • V ⁇ GF 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 a number of laboratories are for improving cardiac blood flow and in improving peripheral vessal blood flow in the limbs. For example, Henry, T. et . al . (J. Amer.
  • cardiovascular diseases need to be improved, including restenosis, atherosclerosis, myocardial reperfusion injury, and myocardial ischemia, stunning or infarction. It has recently been determined that in all of these disease conditions, the integrin receptor o * v ⁇ 3 plays an important role.
  • neointimal hyperplasia and ultimate reocclusion is caused by aggressively proliferating vascular smooth muscle cells that express ⁇ v ⁇ 3 .
  • Atherosclerosis proceeds from an intial endothelial damage that results in the recruitment and subintimal migration of monocytes at the site of the injury. Growth factors are released which induce medial smooth muscle cells to proliferate and migrate to the intimal layer. The migrating smooth muscle cells express ⁇ v ⁇ 3 .
  • neutrophil transmigration is integrin dependent and the integrins moderate initial infiltration into the viable border zone.
  • the induction of ⁇ 5 ⁇ , ⁇ 4 ⁇ and 0C v ⁇ 5 in infiltrating neutrophils occurs within 3 to 5 hours after reperfusion as neutrophils move from the border zone to the area of necrosis. (Circulation, 1999, 100, 1-275)
  • Acute or chronic occlusion of a coronary artery is known to result in angiogenesis in the heart as native collateral vessels are recruited to attempt to relieve the ischemia.
  • Cardiac angiogenesis has been associated with increased expression of the growth factors VEGF and FGF and the upregulation of the growth factor receptors flt-1 and flk-1/KDR. (Drugs, 1999, 58, 391-396)
  • the vitronectin receptor binding compounds target the radioisotope to the tumor neovasculature.
  • the beta or alpha-particle emitting radioisotope emits a cytotoxic amount of ionizing radiation which results in cell death. The penetrating ability of radiation obviates the requirement that the cytotoxic agent diffuse or be transported into the cell to be cytotoxic .
  • These pharmaceuticals comprise a targeting moiety that binds to a receptor that is upregulated during angiogenesis, an optional linking group, and a radioisotope that emits cytotoxic radiation (i.e., beta particles, alpha particles and Auger or Coster-Kronig electrons) .
  • cytotoxic radiation i.e., beta particles, alpha particles and Auger or Coster-Kronig electrons
  • the radiopharmaceuticals of the present invention that emit cytotoxic radiation could be used to destroy the new angiogenic vasculature that results and thus treat the disease.
  • kits and therapeutic radiopharmacutical compositions for use in combination therapy comprising a radiopharmacutical of the invention and at least one agents selected from the group consisting of an anti- cancer agent and a radiosensitizer agent.
  • kits and therapeutic radiopharmacutical compositions for use in combination therapy comprising a radiopharmacutical of the invention and a photosensitising agent.
  • It is another object of the present invention to provide a method of treating cancer comprising administering to a patient in need of such treatment a therapeutic radiopharmaceutical composition of the invention in combination with photodynamic therapy.
  • imaging agents comprised of vitronectin receptor binding compounds conjugated to an imageable moiety, such as a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.
  • imageable moiety such as a gamma ray or positron emitting radioisotope, a magnetic resonance imaging contrast agent, an X-ray contrast agent, or an ultrasound contrast agent.
  • imaging agents are useful for imaging tumor neovasculature, therapeutic angiogenesis interventions in the heart, natural angiogenic processes in response to acute or chronic coronary vessel occlusion, restenosis post-angioplasty, atherosclerosis and plaque formation, and reperfusion injury.
  • These compounds are comprised of a non-peptide benzodiazepine, benzodiazepinedione, or dibenzotrihydroannulene containing targeting moiety that binds to a receptor that is upregulated during angiogenesis or during cardiovascular diseases, Q, an optional linking group, L n , and a metal chelator or bonding moiety, C h -
  • the compounds may have one or more protecting groups attached to the metal chelator or bonding moiety. The protecting groups provide improved stability to the reagents for long-term storage and are removed either immediately prior to or concurrent with the synthesis of the radiopharmaceuticals.
  • the compounds of the present invention are comprised of a peptide or peptidomimetic targeting moiety that binds to a receptor that is upregulated during angiogenesis or during cardiovascular diseases, Q, an optional linking group, L n , and a surfactant, S f .
  • the pharmaceuticals of the present invention may be used for diagnostic and/or therapeutic purposes.
  • Diagnostic radiopharmaceuticals of the present invention are pharmaceuticals comprised of a diagnostically useful radionuclide (i.e., a radioactive metal ion that has imageable gamma ray or positron emissions) .
  • Therapeutic radiopharmaceuticals of the present invention are pharmaceuticals comprised of a therapeutically useful radionuclide, a radioactive metal ion that emits ionizing radiation such as beta particles, alpha particles and Auger or Coster-Kronig electrons.
  • the pharmaceuticals comprising a gamma ray or positron emitting radioactive metal ion are useful for imaging tumors and by gamma scintigraphy or positron emission tomography.
  • the pharmaceuticals comprising a gamma ray or positron emitting radioactive metal ion are also useful for imaging therapeutic angiogenesis, natural angiogenic processes in response to acute or chronic coronary vessel occlusion, restenosis post- angioplasty, atherosclerosis and plaque formation, and reperfusion injury by gamma scintigraphy or positron emission tomography.
  • the pharmaceuticals comprising a particle emitting radioactive metal ion are useful for treating cancer by delivering a cytotoxic dose of radiation to the tumors.
  • the pharmaceuticals comprising a particle emitting radioactive metal ion are also useful for treating rheumatoid arthritis by destroying the formation of angiogenic vasculature.
  • the pharmaceuticals comprising a paramagnetic metal ion are useful as magnetic resonance imaging contrast agents .
  • the pharmaceuticals comprising one or more X-ray absorbing or "heavy" atoms of atomic number 20 or greater are useful as X-ray contrast agents .
  • the pharmaceuticals comprising a microbubble of a biocompatible gas, a liquid carrier, and a surfactant microsphere, are useful as ultrasound contrast agents.
  • the present invention provides a kit for treating cancer, comprising a compound of the formula (I) and at least one agent selected from the group consisting of an anti-cancer agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the compound of the formula
  • R 1 and R 3 are independently selected from the group: C ⁇ - C 6 alkyl, benzyl, phenethyl, and a bond to L n ; provided that one of R 1 and R 3 is a bond to L n ;
  • R 2 is independently selected from the group: 2- benzimidazolylmethyl, 2-guanidinoethyl, 2-amino-2- pyridyl, 2-amino-2-pyridylmethyl, 5-amino-2- imidazolylmethyl, and 2-imidazolylmethyl;
  • R 4 is independently selected from H, C -Q alkyl or benzyl ;
  • R 2a is (CH 2 ) 3 R 3a ;
  • R 3a is selected from the group:
  • R 4a is independently selected from C -Q alkyl substituted with a bond to L n or benzyl substituted with a bond to
  • R 2b is independently selected from the group:
  • Q is a peptide selected from the group :
  • R 1 ? is L-valine, D-valine or L-lysine optionally substituted on the ⁇ amino group with a bond to L n ;
  • R 2 P is L-phenylalanine, D-phenylalanine,
  • R 3 P is D-valine
  • R 4 P is D-tyrosine substituted on the hydroxy group with a bond to L n ;
  • R 1 ⁇ and R 2 P in each Q is substituted with a bond to L n , and further provided that when R 2 P is 2-aminothiazole-4-acetic acid, K is N-methylarginine;
  • At least one Q is a compound of Formula la lb, or Ic;
  • d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • d' is 1-100
  • L n is a linking group having the formula: ( (W) h - (CR6R7 ) ) ⁇ - ( Z ) k - ( (CR6 R7a) , - (W) h , x' /
  • NHC( 0)NH, S0 2 , S0 2 NH, (OCH 2 CH 2 ) s , (CH 2 CH 2 0) s ., (0CH 2 CH 2 CH 2 ) S ", (CH 2 CH 2 CH 2 0) t , and (aa) t - ;
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-3 R 10 , C 3 _ ⁇ o cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 10 ;
  • R 11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 12 , C 3 -- 10 cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, 3 , 6-O-disulfo-B-D- galactopyranosyl , bis (phosphonomethyl)
  • R 12 is a bond 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 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
  • 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;
  • C h is a metal bonding unit having a formula selected from the group:
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), 0, OH, PR 13 , PR 1 R 14 , P(0)R 15 R 16 , and a bond to L n
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Ci-Cio alkyl substituted with 0-3 R ⁇ "7 , aryl substituted with 0-3 R 17 / C 3 _ ⁇ o cycloalkyl substituted with 0-3 R 17 , heterocyclo-Ci-io alkyl substituted with 0-3
  • heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and
  • R 13 and R-*- 4 are each independently selected from the group: a bond to L n , hydrogen, Ci-Cio alkyl substituted with 0-3 ⁇ "7 , aryl substituted with 0-3 R 17 , C ⁇ _ o cycloalkyl substituted with 0-3 R ⁇ 7 , heterocyclo-Ci-io alkyl substituted with 0-3 R 17 ; wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, C ⁇ -io aryl-C ⁇ _ ⁇ o alkyl substituted with 0-3 R ⁇ "7 , C ⁇ _ ⁇ o al yl-C ⁇ -io aryl- substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or
  • R 15 and R 16 are each independently selected from the group: a bond to L n , -OH, Ci-Cio alkyl substituted with 0-3 R 17 , Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3 - 1 0 cycloalkyl substituted with 0-3 R 17 , heterocyclo-C ⁇ _ ⁇ o alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, C 6 - 10 aryl-C ⁇ _ ⁇ o alkyl substituted with 0-3 R 17 , C ⁇ _ ⁇ o alkyl-C 6 - ⁇ o aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17
  • R 18 , R ⁇ 8a , and R ⁇ are independently selected at each occurrence from the group: a bond to L n , H, Ci-C ⁇ alkyl, phenyl, benzyl, C1-C6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
  • Pg is a thiol protecting group
  • R 20 and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group: H, R 24 , C1-C10 alkyl substituted with 0-3 R 24 , C2-C10 alkenyl substituted with 0-3 R 24 , C2-C10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 24 , and C 3 - 10 carbocycle substituted with 0-3 R 24 ;
  • a and b indicate the positions of optional double bonds and n is 0 or 1;
  • R 25 , R 25a , and R 26 are each independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl ;
  • the present invention provides a kit according to Embodiment [1] wherein: d is selected from 1, 2, 3, 4, and 5;
  • d' is 1-50;
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-1 R 10 , C 3 _ ⁇ o cycloalkyl substituted with 0-1 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 10 ;
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Ci-Cio alkyl substituted with 0-3 R 7 , aryl substituted with 0-3 R 7 , C 3 -- 10 cycloalkyl substituted with 0-3
  • R 7 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 ;
  • R 13 , and R 14 are each independently selected from the group: a bond to L n , hydrogen, C ⁇ -C ⁇ o alkyl substituted with 0-3 R 7 , aryl substituted with 0-3
  • R 7 a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 7 , and an electron, provided that when one of R 13 or R 4 is an electron, then the other is also an electron;
  • R 8 , R 18a , and R 9 are independently selected at each occurrence from the group: a bond to L n , H, and 1-C6 alkyl;
  • R 20 and R 21 are independently selected from the group:
  • R 23 aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 23 ;
  • R 20 and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group: H, and R 24 ;
  • R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0;
  • R 25 is independently selected at each occurrence from the group: H and C1-C3 alkyl.
  • the present invention provides a kit according to Embodiment [1] , wherein:
  • R a is benzyl substituted with a bond to L n ;
  • a 1 is selected from the group: OH, and a bond to L n ;
  • a 2 , A 4 , and A 6 are each N;
  • a 3 , A 5 , and A 8 are each OH;
  • a 7 is a bond to L n or NH-bond to L n ;
  • E is a C2 alkyl substituted with 0-1 R 7 ;
  • a 1 is selected from the group: OH, and a bond to L n ;
  • a 2 , A 3 and A 4 are each N;
  • a 5 , A 6 and A 8 are each OH;
  • a 7 is a bond to L n ;
  • E is a C2 alkyl substituted with 0-1 R 17 ;
  • R 17 0; ⁇ E-A 2 alternatively, C h is A
  • a 2 is NHR 13 ;
  • R 13 is a heterocycle substituted with R 17 , the heterocycle being selected from pyridine and pyrimidine;
  • R 18 is a bond to L n ;
  • R24 is selected from the group: -C0 2 R 25 , -OR 25 , -SO 3 H, and -N(R 25 ) ; and,
  • R 25 is independently selected at each occurrence from the group : hydrogen and methyl .
  • the present invention provides a kit according to Embodiment [1] , wherein the compound of formula (I) is selected from the group :
  • the present invention provides a kit according to Embodiment [1] , wherein the kit further comprises one or more ancillary ligands and a reducing agent .
  • the present invention provides a kit according to Embodiment [5] , wherein the ancillary ligands are tricine and TPPTS. [7] In another embodiment, the present invention provides a kit according to Embodiment [5] , wherein the reducing agent is tin (II).
  • the present invention provides a kit according to Embodiment [1] , wherein the anti-cancer agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine-, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethi ide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, e
  • the present invention provides a kit according to Embodiment [1] , wherein the anti-cancer agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etre
  • the present invention provides a kit according to Embodiment [1] wherein the anti-cancer agent is selected from the group consisting of oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, and formestane.
  • the anti-cancer agent is selected from the group consisting of oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, and formestane.
  • the present invention provides a kit according to Embodiment [1] wherein the anti-cancer agent is selected from the group consisting of interferon-alpha, interferon-2 alpha, interferon- beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor.
  • the anti-cancer agent is selected from the group consisting of interferon-alpha, interferon-2 alpha, interferon- beta, interferon-gamma, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, and leutinizing hormone releasing factor.
  • the present invention provides a kit according to Embodiment [1] , wherein radiosensitizer agent is selected from the group consiting of 2- (3-nitro-l, 2, 4-triazol-l-yl) -N- (2- methoxyethyl) acetamide, N- (3-nitro-4-quinolinyl) -4- morpholinecarboxamidine, 3-amino-l,2, 4-benzotriazine- 1, 4-dioxide, N- (2-hydroxyethyl) -2-nitroimidazole-l- acetamide, 1- (2-nitroimidazol-l-yl) -3- (1-piperidinyl) - 2-propanol, and 1- (2-nitro-l-imidazolyl) -3- (1- aziridino) -2-propanol .
  • radiosensitizer agent is selected from the group consiting of 2- (3-nitro-l, 2, 4-triazol-l-yl) -N- (2
  • the present invention provides a therapeutic radiopharmaceutical composition
  • a therapeutic radiopharmaceutical composition comprising at least one agent selected from the group consisting of an anti-cancer agent and a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, and a radiopharmaceutical comprising: a) a radioisotope; b) a chelator capable of chelating the radioisotope; and c) a targeting moiety; wherein the targeting moiety is bound to the chelator through 0-1 linking groups, and the targeting moiety is a benzodiazepine, benzodiazepinedione, or dibenzotrihydroannulene nonpeptide that binds to a receptor that is upregulated during angiogenesis .
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [13], wherein the radiopharmaceutical comprises : a) a radioisotope selected from the group 33p ; 125 ⁇ t 186 Re , 188 Re , 153 Sm , 166 Ho , 177 Lu , 149p m , 90 Y/ 212 Bi , iOSpd, 109 PDF 159 G d, ⁇ a, 19 8 A u, 19 Au, 169 ⁇ b,
  • R 1 and R 3 are independently selected from the group: C ⁇ - C 6 alkyl, benzyl, phenethyl, and a bond to L n ; provided that one of R 1 and R 3 is a bond to L n ;
  • R 2 is independently selected from the group: 2- benzimidazolylmethyl, 2-guanidinoethyl, 2-amino-2- pyridyl, 2-amino-2-pyridylmethyl, 5-amino-2- imidazolylmethyl, and 2-imidazolylmethyl;
  • R 4 is independently selected from H, Ci-e alkyl or benzyl
  • R 2a is (CH 2 )3R 3a ;
  • R 3 a is selected from the group :
  • R a is independently selected from C ⁇ _ 6 alkyl substituted with a bond to L n or benzyl substituted with a bond to Ln;
  • R b is independently selected from the group :
  • Q is a peptide selected from the group:
  • R 1 P is L-valine, D-valine or L-lysine optionally substituted on the ⁇ amino group with a bond to L n ;
  • R 2 P is L-phenylalanine, D-phenylalanine,
  • R 3 P is D-valine
  • RP is D-tyrosine substituted on the hydroxy group with a bond to L n ;
  • R ⁇ -P and R 2 P in each Q is substituted with a bond to L n , and further provided that when RP is 2-aminothiazole-4-acetic acid, K is N-methylarginine;
  • At least one Q is a compound of Formula la lb, or Ic;
  • d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • d' is 1-100
  • L n is a linking group having the formula: ( (W) h - ( CR6R 7 ) g ) x- ( Z ) k - ( ( CR ⁇ R 7 ) g , - (W) h ' ) x' ;
  • NHC( 0)NH, S0 2 , S0 2 NH, (0CH 2 CH 2 ) s , (CH 2 CH 2 0) s ., (0CH 2 CH 2 CH 2 ) S ", (CH 2 CH 2 CH 2 0) t , and (aa) t -;
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-3 R 10 , C 3 - 10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R 10 ;
  • R 11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 12 , C 3 _ ⁇ o cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, 3 , 6-O-disulfo-B-D- galactopyranosyl , bis (phosphonomethyl
  • R 12 is a bond to C n ;
  • 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 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
  • 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;
  • C h is a metal bonding unit having a formula selected from the group:
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), 0, OH, PR 13 , PR 13 R 14 , P(0)R 15 R 16 , and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3 _ ⁇ o cycloalkyl substituted with 0-3 R 17 , heterocyclo-C ⁇ _ ⁇ o alkyl substituted with 0-3
  • heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and
  • R 13 and R 14 are each independently selected from the group: a bond to L n , hydrogen, Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 7 , C ⁇ _ ⁇ o cycloalkyl substituted with 0-3 R 17 , heterocyclo-Ci-io alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, Cg-io aryl-Ci-io alkyl substituted with 0-3 R 17 , C ⁇ _ ⁇ o alkyl-C 6 - ⁇ o aryl- substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 4 is an electron, then the other is
  • R 15 and R 16 are each independently selected from the group: a bond to L n , -OH, C ⁇ -C ⁇ o alkyl substituted with 0-3 R 17 , Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3 _ ⁇ o cycloalkyl substituted with 0-3 R 7 , heterocyclo-C ⁇ _ ⁇ o alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, C ⁇ -io aryl-Ci-io alkyl substituted with 0-3 R 17 , C ⁇ _ ⁇ o alkyl-C 6 - ⁇ o aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17
  • R 18 , R 18a , and R 19 are independently selected at each occurrence from the group: a bond to L n , H, C ⁇ -C6 alkyl, phenyl, benzyl, C1-C6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
  • Pg is a thiol protecting group
  • R 20 and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group: H, R 24 , C1-C10 alkyl substituted with 0-3 R 24 , c 2 _ C ⁇ o alkenyl substituted with 0-3 R 24 , C2-C10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 24 , and C 3 - 10 carbocycle substituted with 0-3 R 24 ;
  • R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0;
  • a and b indicate the positions of optional double bonds and n is 0 or 1;
  • R 25 , R 5a , and R 26 are each independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl ;
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [13], wherein the targeting moiety is a benzodiazepine, benzodiazepinedione, or dibenzotrihydroannulene nonpeptide and the receptor is ⁇ v ⁇ 3 or ⁇ v ⁇ s-
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [14] wherein the radioisotope is 4 9pm.
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [16] , wherein the radiopharmaceutical is selected from the group:
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [14] , wherein the radioisotope is 177 Lu.
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [18] wherein the radiopharmaceutical is selected from the group:
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [14] wherein the radioisotope is 90 Y.
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [20] wherein the radiopharmaceutical is selected from the group:
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [13] , wherein the anti-cancer agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifl
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [13] , wherein radiosensitizer agent is selected from the group consiting of 2- (3- nitro-1 , 2 , 4-triazol-l-yl) -N- (2-methoxyethyl) acetamide, N- (3-nitro-4-quinolinyl) -4-morpholinecarboxamidine, 3- amino-1, 2 , 4-benzotriazine-l, 4-dioxide, N- (2- hydroxyethyl ) -2-nitroimidazole-l-acetamide, 1- (2- nitroimidazol-1-yl) -3- (1-piperidinyl) -2-propanol, and 1- (2-nitro-l-imidazolyl) -3- (1-aziridino) -2-propanol.
  • radiosensitizer agent is selected from the group consiting of 2- (3- nitro-1 , 2 , 4-tria
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [13], wherein the radioisotope is selected from the group 33 ⁇ 125 ⁇ / 186 R ⁇ / 188 Re ⁇ 153 Sm , 166 Ho , 177 Lu, i4 9 Pm, 9 0 ⁇ , 212 Bi# 103 Pd , 109 Pd/ 159 Gd 140 La , 198 AU/ 199 Au , 169 ⁇ b , 175 ⁇ b; 165 D ⁇ , 166 D ⁇ ;
  • the present invention provides a method of treating cancer in a patient comprising: administering to a patient in need thereof a therapeutic radiopharmaceutical comprising: a) a radioisotope; b) a chelator capable of chelating the radioisotope; and c) a targeting moiety; wherein the targeting moiety is bound to the chelator through a linking group, and the targeting moiety is a is a benzodiazepine, benzodiazepinedione, or dibenzotrihydroannulene nonpeptide that binds to a receptor that is upregulated during angiogenesis, and the radioisotope is a radioisotope selected from the group: 33 P, 125 I, 186 Re, 188 Re, 153 Sm, 166 Ho, 177 Lu
  • the present invention provides a method according to Embodiment [25] , wherein the targeting moiety is a benzodiazepine, benzodiazepinedione, or dibenzotrihydroannulene and the receptor is ⁇ v ⁇ 3 or O ⁇ s •
  • the present invention provides a method according to Embodiment [25] , wherein the therapeutic radiopharmaceutical comprises: a) a radioisotope selected from the group: 3 P, 12 5 / 186 R ⁇ / 188 Re , 153 Sltl 166 Ho , 1 7 Lu, 149pm, 90 ⁇ , 212 Bi , 103 Pd/ 109 Pd; 159 Gd , 140 La , 198 Au , 199 AU/ 169 ⁇ b ,
  • R 1 and R 3 are independently selected from the group: C ⁇ - Cg alkyl, benzyl, phenethyl, and a bond to L n ; provided that one of R 1 and R 3 is a bond to L n ;
  • R 2 is independently selected from the group: 2- benzimidazolylmethyl, 2-guanidinoethyl, 2-amino-2- pyridyl, 2-amino-2-pyridylmethyl, 5-amino-2- imidazolylmethyl, and 2-imidazolylmethyl;
  • R 4 is independently selected from H, C ⁇ _ 6 alkyl or benzyl
  • R a is (CH 2 ) 3 R 3a ;
  • R 3a is selected from the group:
  • R a is independently selected from C ⁇ _ 6 alkyl substituted with a bond to L n or benzyl substituted with a bond to L n ;
  • R 2b i independently selected from the group:
  • Q is a peptide selected from the group:
  • R 1 is L-valine , D-valine or L-lysine optionally substituted on the • amino group with a bond to L n ;
  • R 2 P is L-phenylalanine, D-phenylalanine,
  • R 3 P is D-valine
  • RP is D-tyrosine substituted on the hydroxy group with a bond to L n ;
  • R ⁇ P and R 2 in each Q is substituted with a bond to L n , and further provided that when R 2 P is 2-aminothiazole-4-acetic acid, K is N-methylarginine; provided that at least one Q is a compound of Formula la lb, or Ic;
  • d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • d' is 1-100
  • L n is a linking group having the formula:
  • NHC( 0)NH, S0 2 , S0 2 NH, (OCH 2 CH 2 ) s , (CH 2 CH 2 0) s ., (OCH 2 CH 2 CH 2 ) s » , (CH 2 CH 2 CH 2 0) t , and (aa) t «;
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-3 R 10 , C3-.10 cycloalkyl substituted with 0-3 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 10 ;
  • R 11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R 12 , aryl substituted with 0-1 R 12 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 12 , C 3 -- 10 cycloalkyl substituted with 0-1 R 12 , polyalkylene glycol substituted with 0-1 R 12 , carbohydrate substituted with 0-1 R 12 , cyclodextrin substituted with 0-1 R 12 , amino acid substituted with 0-1 R 12 , polycarboxyalkyl substituted with 0-1 R 12 , polyazaalkyl substituted with 0-1 R 12 , peptide substituted with 0-1 R 12 , wherein the peptide is comprised of 2-10 amino acids, 3 , 6-0-disulfo-B-D- galactopyranosyl, bis (phosphonomethyl) g
  • R 12 is a bond to C h ; 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; 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; 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;
  • C h is a metal bonding unit having a formula selected from the group:
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), 0, OH, PR 13 , PR 13 R 14 , P(0)R 15 R 16 , and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3 _ ⁇ o cycloalkyl substituted with 0-3
  • heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, C 6 _ ⁇ o aryl-C ⁇ _ ⁇ o alkyl substituted with 0-3 R 7 ,
  • R 13 and R ⁇ are each independently selected from the group: a bond to L n , hydrogen, Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C ⁇ _ ⁇ o cycloalkyl substituted with 0-3 R 7 , heterocyclo-C ⁇ _ ⁇ o alkyl substituted with 0-3 R 17 , wherein the heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, Cs-io aryl-C ⁇ _ ⁇ o alkyl substituted with 0-3 R 17 , C ⁇ _ ⁇ o alkyl-Ce-io aryl- substituted with 0-3 R 17 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 , and an electron, provided that when one of R 13 or R 1 ⁇ is an electron, then the
  • R 15 and R 16 are each independently selected from the group: a bond to L n , -OH, Ci-C ⁇ o alkyl substituted with 0-3 R 17 , Ci-Cio alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3 -.
  • heterocyclo group is a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0, Cg-io aryl-C ⁇ _ ⁇ o alkyl substituted with 0-3 R 17 , C ⁇ _ ⁇ o alkyl-C 6 - ⁇ o aryl- substituted with 0-3 R 17 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 ;
  • R 18 , R 18 a and R 19 are independently selected at each occurrence from the group: a bond to L n , H, C ⁇ -C6 alkyl, phenyl, benzyl, C1-C6 alkoxy, halide, nitro, cyano, and trifluoromethyl;
  • Pg is a thiol protecting group
  • R 20 and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group: H, R 24 , Ci-Cio alkyl substituted with 0-3 R 24 , C2-C10 alkenyl substituted with 0-3 R 24 , C2-C10 alkynyl substituted with 0-3 R 24 , aryl substituted with 0-3 R 24 , a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 24 , and C 3 -. 1 0 carbocycle substituted with 0-3 R 24 ;
  • R 22 , R 23 taken together form a fused aromatic or a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0;
  • a and b indicate the positions of optional double bonds and n is 0 or 1;
  • R 25 , R 25a , and R 26 are each independently selected at each occurrence from the group: hydrogen and C1-C6 alkyl ;
  • the present invention provides a method according to Embodiment [27] wherein:
  • d is selected from 1, 2, 3, 4, and 5;
  • d' is 1-50;
  • aa is independently at each occurrence an amino acid
  • Z is selected from the group: aryl substituted with 0-1 R 10 , C 3 _ ⁇ o cycloalkyl substituted with 0-1 R 10 , and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-1 R 10 ;
  • 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;
  • a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected at each occurrence from the group: NR 13 , NR 13 R 14 , S, SH, S(Pg), OH, and a bond to L n ;
  • E is a bond, CH, or a spacer group independently selected at each occurrence from the group: C1-C10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3 R 17 , C 3 _ ⁇ o cycloalkyl substituted with 0-3
  • R 7 and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 17 ;
  • R 13 , and R 14 are each independently selected from the group: a bond to L n , hydrogen, C1-C10 alkyl substituted with 0-3 R 17 , aryl substituted with 0-3
  • R 17 a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 7 , and an electron, provided that when one of R 13 or R 1 ⁇ is an electron, then the other is also an electron;
  • R 18 , R 18a , and R 1 are independently selected at each occurrence from the group: a bond to L n , H, and Ci-C ⁇ alkyl;
  • R 20 and R 21 are independently selected from the group:
  • R 23 aryl substituted with 0-3 R 23 , and unsaturated 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and 0 and substituted with 0-3 R 23 ;
  • R 20 and R 21 taken together with the divalent carbon radical to which they are attached form:
  • R 22 and R 23 are independently selected from the group H, and R 24 ;
  • R 25 is independently selected at each occurrence from the group: H and C1-C3 alkyl.
  • the present invention provides a method according to Embodiment [27] wherein:
  • R a is benzyl substituted with a bond to L n ;
  • a 1 is selected from the group: OH, and a bond to L n ;
  • a 2 , A 4 , and A 6 are each N;
  • a 3 , A 5 , and A 8 are each OH;
  • a 7 is a bond to L n or NH-bond to L n ;
  • E is a C2 alkyl substituted with 0-1 R 17 ;
  • a 1 is selected from the group: OH, and a bond to L n ;
  • a 2 , A 3 and A 4 are each N;
  • a 5 , A 6 and A 8 are each OH;
  • a 7 is a bond to L n ;
  • E is a C2 alkyl substituted with 0-1 R 17 ;
  • C h is A ;
  • a 2 is NHR 13 ;
  • R 13 is a heterocycle substituted with R 17 , the heterocycle being selected frompyridine and pyrimidine;
  • R 18 is a bond to L n ;
  • R 24 i s selected from the group: -C0 2 R 25 , -OR 25 , -SO 3 H, and -N(R 5 ) 2 ; and, R 25 is independently selected at each occurrence from the group : hydrogen and methyl .
  • the present invention provides a method according to Embodiment [27] , wherein the compound of formula (I) is selected from the group consisting of:
  • the present invention provides a method according to Embodiment [27] wherein administering the therapeutic radiopharmaceutical and agent is concurrent.
  • the present invention provides a method according to Embodiment [27] wherein administering the therapeutic radiopharmaceutical and agent is sequential.
  • the present invention provides a method according to Embodiment [27] wherein the cancer is selected from the group consisting of carcinomas of the lung, breast, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, and neuroblastomas .
  • the cancer is selected from the group consisting of carcinomas of the lung, breast, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas
  • the present invention provides a method according to Embodiment [27] wherein the anti-cancer agent is selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, cytarabine, bicalutamide, vinorelbine, vesnarinone, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate
  • the present invention provides a method according to Embodiment [27] wherein the radiosensitizer agent is selected from the group consisting of 2- (3-nitro-l, 2, 4-triazol-l-yl) -N- (2- methoxyethyl) acetamide, N- (3-nitro-4-quinolinyl) -4- morpholinecarboxamidine, 3-amino-l, 2, 4-benzotriazine- 1,4-dioxide, N- (2-hydroxyethyl) -2-nitroimidazole-l- acetamide, 1- (2-nitroimidazol-l-yl) -3- (1-piperidinyl) - 2-propanol, and 1- (2-nitro-l-imidazolyl) -3- (1- aziridino) -2-propanol.
  • the radiosensitizer agent is selected from the group consisting of 2- (3-nitro-l, 2, 4-triazol-l-yl) -N- (2- me
  • the present invention provides a method according to Embodiment [27] wherein the anti-cancer agent is a anti-cancer agent agent.
  • the present invention provides a method of treating cancer according to Embodiment [27], wherein the administration is by injection or infusion.
  • the present invention provides a method of Embodiment [27] , further comprising treating the cancer by brachytherapy, external beam radiation, laser therapy or surgical removal.
  • the present invention provides a kit comprising packaging material, and a therapeutic radiopharmaceutical composition of Embodiment [14] , contained within said packaging material, wherein the packaging material comprises a label or package insert which indicates that said therapeutic radiopharmaceutical composition can be used for treating cancer.
  • the present invention provides a therapeutic radiopharmaceutical composition of Embodiment [14] , further comprising a photosensitizing agent.
  • the present invention provides a therapeutic radiopharmaceutical composition according to Embodiment [41] , wherein the photosensitizing agent is selected from the group consisting of photofrin; naphthalocyanine photosensitizing agents; tetrapyrrole-based photosensitizers; porphyins; chlorins;, phthalocyanines; napthalocyanines; coumarins, psoralens, 1,3,4,6- tetramethoxyhelianthrone; 10, 13-dimethyl-l, 3,4,6- tetrahydroxyhelianthrone; 10 , 13-di (methoxycarbonyl) - 1,3,4, 6-tetramethoxyhelianthrone; 1, 6-di-N-butylamino- 3 , 4-dimethoxy
  • the present invention provides a kit according to Embodiment [40] , further comprising a photosensitizing agent.
  • the present invention provides a kit according to Embodiment [43], wherein the photosensitizing agent is selected from the group consisting of photofrin; naphthalocyanine photosensitizing agents; tetrapyrrole-based photosensitizers; porphyins; chlorins;, phthalocyanines; napthalocyanines; coumarins, psoralens, 1,3,4,6- tetramethoxyhelianthrone; 10, 13-dimethyl-l, 3,4,6- tetrahydroxyhelianthrone; 10, 13-di (methoxycarbonyl) - 1,3,4, 6-tetramethoxyhelianthrone; 1, 6-di-N-butylamino- 3 , 4-dimethoxy-helianthrone; 1, 6-di-N-butylamino-3 , 4- dimethoxy-10, 13-dimethyl-helianthrone; 1, 6-di- (N- hydroxye
  • the present invention provides a method of treating cancer according to
  • Embodiment [25] further comprising treating the patient with photodynamic therapy.
  • the present invention provides a method of treating cancer according to Embodiment [45] , wherein the photodynamic therapy comprises: a) administering a therapeutic radiopharmaceutical of the present invention and a photosensitive agent (photoreactive agent) to a patient, said photosensitive agent having a characteristic light absorption waveband and being preferentially absorbed by abnormal tissue; b) roviding an imaging device that is integral with a plurality of light sources and produces a signal used for imaging abnormal tissue at the internal treatment site, said light sources emitting light in a waveband corresponding to the characteristic light absorption waveband of the photosensitive agent, said waveband including wavelengths sufficiently long to penetrate through a dermal layer of the patient to the internal treatment site;
  • a photosensitive agent photoreactive agent
  • the present invention provides a method of treating cancer according to Embodiment [46] , wherein the photosensitive agent (photoreactive agent) is specifically targeted at the targeted tissue by including a binding agent that selectively links the photosensitive agent to the targeted tissue.
  • the photosensitive agent photoreactive agent
  • the present invention provides a method of treating cancer according to Embodiment [46] , wherein the photosensitizing agent is selected from the group consisting of photofrin; naphthalocyanine photosensitizing agents; tetrapyrrole- based photosensitizers; porphyins; chlorins;, phthalocyanines; napthalocyanines; coumarins, psoralens, 1, 3 , 4, 6-tetramethoxyhelianthrone; 10, 13-dimethyl- 1,3,4, 6-tetrahydroxyhelianthrone; 10, 13- di (methoxycarbonyl) -1,3,4, 6-tetramethoxyhelianthrone; 1, 6-di-N-butylamino-3 , 4-dimethoxy-helianthrone; 1, 6-di- N-butylamino-3 , 4-dimethoxy-10, 13-dimethyl-helianthrone; 1, 6-di- (N-hydroxye
  • Diagnostic kits of the present invention comprise one or more vials containing the sterile, non-pyrogenic, formulation comprised of a predetermined amount of a reagent of the present invention, and optionally other components such as one or two ancillary ligands, reducing agents, transfer ligands, buffers, lyophilization aids, stabilization aids, solubilization aids and bacteriostats .
  • the inclusion of one or more optional components in the formulation will frequently improve the ease of synthesis of the radiopharmaceutical by the practicing end user, the ease of manufacturing the kit, the shelf-life of the kit, or the stability and shelf-life of the radiopharmaceutical.
  • the inclusion of one or two ancillary ligands is required for diagnostic kits comprising reagent comprising a hydrazine or hydrazone bonding moiety.
  • the one or more vials that contain all or part of the formulation can independently be in the form of a sterile solution or a lyophilized solid.
  • Another aspect of the present invention contemplates a method of imaging cancer in a patient involving: (1) synthesizing a diagnostic radiopharmaceutical of the present invention, using a reagent of the present invention, capable of localizing in tumors; (2) administering said radiopharmaceutical to a patient by injection or infusion; (3) imaging the patient using planar or SPECT gamma scintigraphy, or positron emission tomography.
  • Another aspect of the present invention contemplates a method of imaging cancer in a patient involving: (1) administering a paramagnetic metallopharmaceutical of the present invention capable of localizing in tumors to a patient by injection or infusion; and (2) imaging the patient using magnetic resonance imaging.
  • Another aspect of the present invention contemplates a method of imaging cancer in a patient involving: (1) administering a X-ray contrast agent of the present invention capable of localizing in tumors to a patient by injection or infusion; and (2) imaging the patient using X-ray computed tomography.
  • Another aspect of the present invention contemplates a method of imaging cancer in a patient involving: (1) administering a ultrasound contrast agent of the present invention capable of localizing in tumors to a patient by injection or infusion; and (2) imaging the patient using sonography.
  • Another aspect of the present invention contemplates a method of treating cancer in a patient involving: (1) administering a therapeutic radiopharmaceutical of the present invention capable of localizing in tumors to a patient by injection or infusion.
  • Another aspect of the present invention contemplates the combination of anti-cancers and angiogenesis-targeted therapeutic radiopharmaceuticals of the invention, which target the luminal side of the neovasculature of tumors, to provide a surprising, and enhanced degree of tumor suppression relative to each treatment modality alone without significant additive toxicity.
  • Another aspect of the present invention contemplates the compounds of the present invention (i.e. a compound comprising: a targeting moiety and a chelator, wherein the targeting moiety is bound to the chelator, is a benzodiazepine, benzodiazepinedione, or dibenzotrihydroannulene nonpeptide, and binds to a receptor that is upregulated during angiogenesis and the compound has 0-1 linking groups between the targeting moiety and chelator) which is administered in combination therapy, with one or more anti-cancer agent (s) selected from the group consisting of mitomycin, tretinoin, ribomustin, gemcitabine, vincristine, etoposide, cladribine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin
  • This combination therapy may further, optionally, include a radiosensitizer agent, or a pharmaceutically acceptable salt thereof, to enhance the radiotherapeutic effect together with the anti-cancer agent, said radiosensitizer agent being selected from the group consisting of 2- (3-nitro-l, 2 , 4-triazol-l-yl) -N- (2- methoxyethyl) acetamide, N- (3-nitro-4-quinolinyl) -4- morpholinecarboxamidine, 3-amino-l, 2 , 4-benzotriazine- 1, 4-dioxide, N- (2-hydroxyethy1) -2-nitroimidazole-l- acetamide, 1- (2-nitroimidazol-l-yl) -3- (1-piperidinyl) - 2-propanol, and 1- (2-nitro-l-imidazolyl) -3- (1- aziridino) -2-propanol .
  • a radiosensitizer agent being selected
  • radiosensitizer agents are provided in the following: Rowinsky-EK, Oncology-Huntingt . , 1999 Oct; 13(10 Suppl 5): 61-70; Chen-AY et al . , Oncology-Huntingt. 1999 Oct; 13(10 Suppl 5): 39-46; Choy-H, Oncology-Huntingt. 1999 Oct; 13(10 Suppl 5): 23-38; and Herscher-LL et al, Oncology-Huntingt. 1999 Oct; 13(10 Suppl 5): 11-22, which are incorporated herein by reference .
  • kits having a plurality of active ingredients (with or without carrier) which, together, may be effectively utilized for carrying out the novel combination therapies of the invention.
  • the present invention provides a method for treating cancer in a patient in need of such treatment, said method including the steps of administering a therapeutically effective amount of a compound of the present invention and administering a therapeutically effective amount of at least one agent selected from the group consisting of an anti-cancer agent and a radiosensitizer agent.
  • any variable occurs more than one time in any substituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence.
  • a group is shown to be substituted with 0-2 R 52 , then said group may optionally be substituted with up to two R 52 , and R 52 at each occurrence is selected independently from the defined list of possible R 5 .
  • R 52 at each occurrence is selected independently from the defined list of possible R 5 .
  • each of the two R 53 substituents on N is independently selected from the defined list of possible R 53 .
  • Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds .
  • a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring.
  • nonpeptide means preferably less than three amide bonds in the backbone core of the targeting moiety or preferably less than three amino acids or amino acid mimetics in the targeting moiety.
  • metallopharmaceutical means a pharmaceutical comprising a metal.
  • the metal is the cause of the imageable signal in diagnostic applications and the source of the cytotoxic radiation in radiotherapeutic applications.
  • Radiopharmaceuticals are metallopharmaceuticals in which the metal is a radioisotope.
  • reagent is meant a compound of this invention capable of direct transformation into a metallopharmaceutical of this invention. Reagents may be utilized directly for the preparation of the metallopharmaceuticals of this invention or may be a component in a kit of this invention.
  • binding agent means a metallopharmaceutical of this invention having affinity for and capable of binding to the vitronectin receptor.
  • binding agents of this invention have Ki ⁇ lOOOnM.
  • 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 reaction mixture, and formulation into an efficacious pharmaceutical agent .
  • substituted means that one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's or group's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • bond means either a single or double bond.
  • salt is used as defined in the CRC Handbook of Chemistry and Physics, 65th Edition, CRC Press, Boca Raton, Fla, 1984, as any substance which yields ions, other than hydrogen or hydroxyl ions.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds modified by making acid or base salts.
  • 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.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • prodrugs as used herein means those prodrugs of the compounds useful according to the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug means compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Functional groups which may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention.
  • alkanoyl such as acetyl, propionyl, butyryl, and the like
  • unsubstituted and substituted aroyl such as benzoyl and substituted benzoyl
  • alkoxycarbonyl such as ethoxycarbonyl
  • trialkylsilyl such as trimethyl- and triethysilyl
  • monoesters formed with dicarboxylic acids such as succinyl
  • the compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group.
  • prodrugs A thorough discussion of prodrugs is provided in the following: Design of Prodrugs, H. Bundgaard, ed. , Elsevier, 1985; Methods in Enzymology,
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making 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.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, ' propionic, succinic, glycolic, stearic, lactic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, gluta ic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, ' propionic, succinic, glycolic, stearic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • 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 the two; generally, nonaqueous media like 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 disclosure of which is hereby incorporated by reference .
  • 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; "cycloalkyl” or “carbocycle” is intended to include saturated and partially unsaturated ring groups , including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl; "bicycloalkyl” or "bicyclic” is intended to include saturated bi
  • alkene or “alkenyl” is intended to include hydrocarbon chains having the specified number of carbon atoms of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
  • alkyne or “alkynyl” is intended to include hydrocarbon chains having the specified number of carbon atoms of either a straight or branched configuration and one or more unsaturated carbon-carbon triple bonds which may occur in any stable point along the chain, such as propargyl, and the like.
  • aryl or “aromatic residue” is intended to mean phenyl or naphthyl, which when substituted, the substitution can be at any position.
  • heterocycle or “heterocyclic system” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1.
  • aromatic heterocyclic system is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
  • heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5, 2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2, 5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl,
  • oxazolyl oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,
  • Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles .
  • alkaryl means an aryl group bearing an alkyl group of 1-10 carbon atoms
  • aralkyl means an alkyl group of 1-10 carbon atoms bearing an aryl group
  • arylalkaryl means an . aryl group bearing an alkyl group of 1-10 carbon atoms . bearing an aryl group
  • heterocycloalkyl means an alkyl group of 1-10 carbon atoms bearing a heterocycle.
  • polyalkylene glycol is a polyethylene glycol, polypropylene glycol or polybutylene glycol having a molecular weight of less than about 5000, terminating in either a hydroxy or alkyl ether moiety.
  • a “carbohydrate” is a polyhydroxy aldehyde, ketone, alcohol or acid, or derivatives thereof, including polymers thereof having polymeric linkages of the acetal type.
  • a "cyclodextrin” is a cyclic oligosaccharide.
  • cyclodextrins include, but are not limited to, -cyclodextrin, hydroxyethyl- -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, dihydroxypropy1- ⁇ -eye1odextrin, hydroxyethyl- ⁇ -cyclodextrin, 2,6 di-O-methyl- ⁇ -cyclodextrin, sulfated- ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, dihydroxypropyl- ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, and sulfated ⁇ -cyclodextrin.
  • polycarboxyalkyl means an alkyl group having between two and about 100 carbon atoms and a plurality of carboxyl substituents; and the term “polyazaalkyl” means a linear or branched alkyl group having between two and about 100 carbon atoms, interrupted by 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 relatively unreactive, high oxidation state compound, to lower its oxidation state by transferring electron (s) to the radionuclide, thereby making it more reactive.
  • Reducing agents useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals include but are not limited to stannous chloride, stannous fluoride, formamidine sulfinic acid, ascorbic acid, cysteine, phosphines, and cuprous or ferrous salts. 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 prevent unwanted side-reactions but labile enough to be converted to a metallopharmaceutical .
  • the formation of the intermediate complex is kinetically favored while the formation of the metallopharmaceutical is thermodynamically favored.
  • Transfer ligands useful in the preparation of metallopharmaceuticals and in diagnostic kits useful for the preparation of diagnostic radiopharmaceuticals include but are not limited to gluconate, glucoheptonate, mannitol, glucarate, N,N,N' ,N' -ethylenediaminetetraacetic acid, pyrophosphate and methylenediphosphonate .
  • transfer ligands are comprised of oxygen or nitrogen donor atoms .
  • the term "donor atom” refers to the atom directly attached to a metal by a chemical bond.
  • Radionuclide coordination sphere is composed of one or more chelators or bonding units from one or more reagents and one or more ancillary or co-ligands, provided that there are a total of two types of ligands, chelators or bonding units.
  • a radiopharmaceutical comprised of one chelator or bonding unit from one reagent and two of the same ancillary or co-ligands and a radiopharmaceutical comprised of two chelators or bonding units from one or two reagents and one ancillary or co-ligand are both considered to be comprised of binary ligand systems.
  • the radionuclide coordination sphere is composed of one or more chelators or bonding units from one or more reagents and one or more of two different types of ancillary or co-ligands, provided that there are a total of three types of ligands, chelators or bonding units.
  • a radiopharmaceutical comprised of one chelator or bonding unit from one reagent and two different ancillary or co-ligands is considered to be comprised of a ternary ligand system.
  • Ancillary or co-ligands useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals are comprised of one or more oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, selenium, and tellurium donor atoms.
  • a ligand can be a transfer ligand in the synthesis of a radiopharmaceutical and also serve as an ancillary or co-ligand in another radiopharmaceutical.
  • a ligand is termed a transfer or ancillary or co-ligand depends on whether the ligand remains in the radionuclide coordination sphere in the radiopharmaceutical, which is determined by the coordination chemistry of the radionuclide and the chelator or bonding unit of the reagent or reagents .
  • a "chelator” or “bonding unit” is the moiety or group on a reagent that binds to a metal ion through the formation of chemical bonds with one or more donor atoms .
  • binding site means the site in vivo or in vitro that binds a biologically active molecule.
  • a “diagnostic kit” or “kit” comprises a collection of components, termed the formulation, in one or more vials which are used by the practicing end user in a clinical or pharmacy setting to synthesize diagnostic radiopharmaceuticals.
  • the kit provides all the requisite components to synthesize and use the diagnostic radiopharmaceutical except those that are commonly available to the practicing end user, such as water or saline for injection, a solution of the radionuclide, equipment for heating the kit during the synthesis of the radiopharmaceutical, if required, equipment necessary for administering the radiopharmaceutical to the patient such as syringes and shielding, and imaging equipment.
  • Radiopharmaceuticals X-ray contrast agent pharmaceuticals, ultrasound contrast agent pharmaceuticals and metallopharmaceuticals for magnetic resonance imaging contrast are provided to the end user in their final form in a formulation contained typically in one vial, as either a lyophilized solid or an aqueous solution.
  • the end user reconstitutes the lyophilized with water or saline and withdraws the patient dose or just 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 the glass transition temperature, and is added to the formulation to improve the physical properties of the combination of all the components of the formulation for lyophilization.
  • a “stabilization aid” is a component that is added to the metallopharmaceutical or to the diagnostic kit either to stabilize the metallopharmaceutical or to prolong the shelf-life of the kit before it must be 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 or the metallopharmaceutical.
  • a “ solubilization aid” is a component that improves the solubility of one or more other components in the medium required for the formulation.
  • a "bacteriostat” is a component that inhibits the growth of bacteria in a formulation either during its storage before use of after a diagnostic kit is used to synthesize radiopharmaceutical.
  • Trp tryptophan
  • bubbles 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 precursor thereto.
  • Exemplary bubbles include, for example, liposomes, micelles and the like.
  • lipid refers to a synthetic or naturally-occurring amphipathic compound which comprises a hydrophilic component and a hydrophobic component.
  • Lipids include, for example, fatty acids, neutral fats, phosphatides, glycolipids, aliphatic alchols and waxes, terpenes and steroids.
  • lipid composition refers to a composition which comprises a lipid compound.
  • lipid compositions include suspensions, emulsions and vesicular compositions.
  • lipid formulation refers to a composition which comprises a lipid compound and a bioactive agent.
  • 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 mono- or bilayer lipids may be used to form one of more mono- or bilayers. In the case of more than one mono- or bilayer, the mono- or bilayers are generally concentric.
  • the lipid vesicles described herein include such entities commonly referred to as liposomes, micelles, bubbles, microbubbles, microspheres and the like.
  • the lipids may be used to form a unilamellar vesicle (comprised of one monolayer or bilayer) , an oligolamellar vesicle (comprised of about two or about three monolayers or bilayers) or a multilamellar vesicle (comprised of more than about three monolayers or bilayers) .
  • the internal void of the vesicles may be filled with a liquid, including, for example, an aqueous liquid, a gas, a gaseous precursor, and/or a solid or solute material, including, for example, a bioactive agent, as desired.
  • a liquid including, for example, an aqueous liquid, a gas, a gaseous precursor, and/or a solid or solute material, including, for example, a bioactive agent, as desired.
  • vesicular composition refers to a composition which is formulate from lipids and which comprises vesicles.
  • vesicle formulation refers to a composition which comprises vesicles and a bioactive agent.
  • lipo es refers to a generally spherical cluster or aggregate of amphipathic compounds, including lipid compounds, typically in the form of one or more concentric layers, for example, bilayers . They may also be referred to herein as lipid vesicles .
  • Angiogenesis is the process of formation of new capillary blood vessels from existing vasculature. It is an important component of a variety of physiological processes including ovulation, embryonic development, wound repair, and collateral vascular generation in the myocardium. It is also central to a number of 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 a variety of cytokines and growth factors.
  • the activated endothelial cells secrete enzymes that degrade the basement membrane of the vessels .
  • the endothelial cells then proliferate and migrate into the extracellular matrix first forming tubules and subsequently new blood vessels .
  • endothelial cell proliferation is a very slow process, but it increases for a short period of time during embryogenesis, ovulation and wound healing. This temporary increase in cell turnover is governed by a combination of a number of growth stimulatory factors and growth suppressing factors. In pathological angiogenesis, this normal balance is disrupted resulting in continued increased endothelial cell proliferation.
  • pro- angiogenic factors include basic fibroblast growth factor (bFGF) , angiogenin, TGF- alpha, TGF-beta, and vascular endothelium growth factor (VEGF)
  • interferon-alpha, interferon-beta and thrombospondin are examples of angiogenesis suppressors.
  • Angiogenic factors interact with endothelial cell surface receptors such as the receptor tyrosine kinases EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, and Axl .
  • the receptors Flk-1/KDR, neuropilin-1, and Flt-1 recognize VEGF and these interactions play key roles in VEGF- induced angiogenesis .
  • the Tie subfamily of receptor tyrosine kinases are also expressed prominently during blood vessel formation.
  • Integrins are a diverse family of heterodimeric cell surface receptors by which endothelial cells attach to the extracellular matrix, each other and other cells.
  • Angiogenesis induced by bFGF or TNF-alpha depend on the agency of the integrin avb3
  • angiogenesis induced by VEGF depends on the integrin avb5 (Cheresh et. al . ,
  • the pharmaceuticals of the present invention are comprised of a non-peptide targeting moiety for the vitronectin receptor that is expressed or upregulated in angiogenic tumor vasculature.
  • the ultrasound contrast agents of the present invention comprise a plurality of vitronectin receptor targeting moieties attached to or incorporated into a microbubble of a biocompatible gas, a liquid carrier, and a surfactant microsphere, further comprising an optional linking moiety, L n , between the targeting moieties and the microbubble.
  • the term liquid carrier means aqueous solution
  • surfactant means any amphiphilic material which produces a reduction in interfacial tension in a solution.
  • surfactant microsphere includes nanospheres, liposomes, vesicles and the like.
  • the biocompatible gas can be air, or a fluorocarbon, such as a C 3 -C 5 perfluoroalkane, which provides the difference in echogenicity and thus the contrast in ultrasound imaging.
  • the gas is encapsulated or contained in the microsphere to which is attached the biodirecting group, optionally via a linking group. The attachment can be covalent, ionic or by van der Waals forces.
  • specific examples of such contrast agents include lipid encapsulated perfluorocarbons with a plurality of tumor neovasculature receptor binding peptides, polypeptides or peptidomimetics .
  • X-ray contrast agents of the present invention are comprised of one or more vitronectin receptor targeting moieties attached to one or more X-ray absorbing or "heavy" atoms of atomic number 20 or greater, further comprising an optional linking moiety, L n , between the targeting moieties and the X-ray absorbing atoms.
  • the frequently used heavy atom in X-ray contrast agents is iodine.
  • X-ray contrast agents comprised of metal chelates (Wallace, R. , U.S. 5,417,959) and polychelates comprised of a plurality of metal ions (Love, D. , U.S. 5,679,810) have been disclosed. More recently, multinuclear cluster complexes have been disclosed as X-ray contrast agents (U.S. 5,804,161, PCT WO91/14460, and PCT WO 92/17215).
  • MRI contrast agents of the present invention are comprised of one or more vitronectin receptor targeting moieties attached to one or more paramagnetic metal ions, further comprising an optional linking moiety, L n , between the targeting moieties and the paramagnetic metal ions .
  • the paramagnetic metal ions are present in the form of metal complexes or metal oxide particles.
  • U.S. 5,412,148, and 5,760,191 describe examples of chelators for paramagnetic metal ions for use in MRI contrast agents.
  • U.S. 5,801,228, U.S. 5,567,411, and U.S. 5,281,704 describe examples of polychelants useful for complexing more than one paramagnetic metal ion for use in MRI contrast agents.
  • U.S. 5,520,904 describes particulate compositions comprised of paramagnetic metal ions for use as MRI contrast agents.
  • Administration of a compound of the present invention in combination with such additional therapeutic agents may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each.
  • a lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
  • the combination of a compound of the present invention with such additional therapeutic agents is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul . 22:27-55 (1984) , occurs when the therapeutic effect of the compound and agent when administered in combination is greater than the additive effect of the either the compound or agent when administered alone.
  • synergistic effect is most clearly demonstrated at levels that are (therapeutically) sub-optimal for either the compound of the present invention, an anti-cancer agent or a radiosensitizer agent alone, but which are highly efficacious in combination.
  • Synergy can be in terms of improved tumor response without substantial increases in toxicity over individual treatments alone, ' or some other beneficial effect of the combination compared with the individual components.
  • the compounds of the present invention, and an anti-cancer agent or a radiosensitizer agent, utilized in combination therapy may be administered simultaneously, in either separate or combined formulations, or at different times e.g., sequentially, such that a combined effect is achieved.
  • the amounts and regime of administration will be adjusted by the practitioner, by preferably initially lowering their standard doses and then titrating the results obtained.
  • the invention also provides kits or single packages combining two or more active ingredients useful in treating cancer.
  • a kit may provide (alone or in combination with a pharmaceutically acceptable diluent or carrier) , the compound of the present invention and additionally at least one agent selected from the group consisting of an anti-cancer agent and a radiosensitizer agent (alone or in combination with diluent or carrier) .
  • the pharmaceuticals of the present invention have the formulae, (Q) d -L n - (C h -X) , (Q) d ⁇ L n - (C h -X 1 )d' (Q) d -L n - (X 2 ) d" , and (Q) d -L n - (X 3 ) , wherein Q represents a non-peptide that binds to a receptor expressed in angiogenic tumor vasculature, d is 1-10, L n represents an optional linking group, C h represents a metal chelator or bonding moiety, X represents a radioisotope, X 1 represents paramagnetic metal ion, X 2 represents a paramagnetic metal ion or heavy atom containing insoluble solid particle, d" is 1-100, and X 3 represents a surfactant microsphere of an echogenic gas .
  • Q represents a non-peptide that binds to a receptor
  • the pharmaceuticals of the present invention can be synthesized by several approaches.
  • One approach involves the synthesis of the targeting non-peptide moiety, Q, and direct attachment of one or more moieties, Q, to one or more metal chelators or bonding moieties, C , or to a paramagnetic metal ion or heavy atom containing solid particle, or to an echogenic gas microbubble.
  • Another approach involves the attachment of one or more moieties, Q, to the linking group, L n , which is then attached to one or more metal chelators or bonding moieties, C h , or to a paramagnetic metal ion or heavy atom containing solid particle, or to an echogenic gas microbubble.
  • Another approach involves the synthesis of a non-peptide, Q, bearing a fragment of the linking group, L n , one or more of which are then attached to the remainder of the linking group and then to one or more metal chelators or bonding moieties, C , or to a paramagnetic metal ion or heavy atom containing solid particle, or to an echogenic gas microbubble.
  • non-peptide vitronectin binding moieties, Q optionally bearing a linking group, L n , or a fragment of the linking group, can be synthesized using standard synthetic methods known to those skilled in the art. Preferred methods include but are not limited to those methods described below.
  • linking groups, L n to the non- peptides, Q; chelators or bonding units, C , to the non- peptides, Q, or to the linking groups, L n ; and non- peptides, bearing a fragment of the linking group to the remainder of the linking group, in combination forming, the moiety, (Q) d -L n , and then to the moiety C h ;
  • standard techniques include, but are not limited to, amidation, esterification, alkylation, and the formation of ureas or thioureas . Procedures for performing these attachments can be found in Brinkley, M. , Bioconjugate Chemistry 1992, 3 (1) , which is incorporated herein by reference .
  • a number of methods can be used to attach the non- peptides, Q, to paramagnetic metal ion or heavy atom containing solid particles, X 2 , by one of skill in the art of the surface modification of solid particles.
  • the targeting moiety Q or the combination can be used to attach the non- peptides, Q, to paramagnetic metal ion or heavy atom containing solid particles, X 2 , by one of skill in the art of the surface modification of solid particles.
  • the coupling groups can be any of a number of silanes which react with surface hydroxyl groups on the solid particle surface, as described in co-pending United States Patent Application No. 09/356,178, and can also include polyphosphonates, polycarboxylates, polyphosphates or mixtures thereof which couple with the surface of the solid particles, as described in U.S. 5,520,904.
  • reaction schemes can be used to attach the non-peptides, Q, to the surfactant microsphere, X 3 . These are illustrated in following reaction schemes where S f represents a surfactant moiety that forms the surfactant microsphere.
  • Y is a leaving group or active ester
  • the linking group L n can serve several roles . First it provides a spacing group between the metal chelator or bonding moiety, C h , the paramagnetic metal ion or heavy atom containing solid particle, X 2 , and the surfactant microsphere, X 3 , and the one or more of the non-peptides, Q, so as to minimize the possibility that the moieties C n -X, C h -X 1 , X 2 , and X 3 , will interfere with the interaction of the recognition sequences of Q with angiogenic tumor vasculature receptors.
  • a linking group also provides a means of independently attaching multiple non-peptides, Q, to one group that is attached to C h -X/ C h -X 1 , X 2 , or X 3 .
  • the linking group also provides a means of incorporating a pharmacokinetic modifier into the pharmaceuticals of the present invention.
  • the pharmacokinetic modifier serves to direct the biodistibution of the injected pharmaceutical other than by the interaction of the targeting moieties, Q, with the vitronectin receptors expressed in the tumor neovasculature .
  • a wide variety of functional groups can serve as pharmacokinetic modifiers, including, but not limited to, carbohydrates, polyalkylene glycols, peptides or other polyamino acids, and cyclodextrins.
  • the modifiers can be used to enhance or decrease hydrophilicity and to enhance or decrease the rate of blood clearance.
  • the modifiers can also be used to direct the route of elimination of the pharmaceuticals.
  • Preferred pharmacokinetic modifiers are those that result in moderate to fast blood clearance and enhanced renal excretion.
  • the metal chelator or bonding moiety, C h is selected to form stable complexes with the metal ion chosen for the particular application.
  • Chelators or bonding moieties for diagnostic radiopharmaceuticals are selected to form stable complexes with the radioisotopes that have imageable gamma ray or positron emissions, such as 99m c 95 C lllm, 6 2 Cu, 60 Cu, 64 Cu, 67 Ga, 68 Ga, 86 Y .
  • Chelators for technetium, copper and gallium isotopes are selected from diaminedithiols, monoamine-monoamidedithiols , triamide-monothiols , monoamine-diamide-monothiols, diaminedioximes, and hydrazines.
  • the chelators are generally tetradentate with donor atoms selected from nitrogen, oxygen and sulfur.
  • Preferred reagents are comprised of chelators having amine nitrogen and thiol sulfur donor atoms and hydrazine bonding units.
  • the thiol sulfur atoms and the hydrazines may bear a protecting group which can be displaced either prior to using the reagent to synthesize a radiopharmaceutical or preferably in situ during the synthesis of the radiopharmaceutical.
  • Exemplary thiol protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1991), the disclosure of which is hereby incorporated 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 bonding units are hydrazones which can be aldehyde or ketone hydrazones having substituents selected from hydrogen, alkyl, aryl and heterocycle. Particularly preferred hydrazones are described in co-pending U.S.S.N. 08/476,296 the disclosure of which is herein incorporated by reference in its entirety.
  • the hydrazine bonding unit when bound to a metal radionuclide is termed a hydrazido, or diazenido group and serves as the point of attachment of the radionuclide to the remainder of the radiopharmaceutical .
  • a diazenido group can be either terminal (only one atom of the group is bound to the radionuclide) or chelating. In order to have a chelating diazenido group at least one other atom of the group must also be bound to the radionuclide.
  • the atoms bound to the metal are termed donor atoms .
  • Chelators for 11:L In and 86 Y are selected from cyclic and acyclic polyaminocarboxylates such as DTPA, DOTA, D03A, 2-benzyl-DOTA, alpha- (2-phenethyl) 1, 4, 7 , 10- tetraazazcyclododecane-l-acetic-4 , 7 , 10- tris (methylacetic) acid, 2-benzyl- cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl- 6-methyl-DTPA, and 6 , 6 " -bis [N,N,N" ,N"- tetra(carboxymethyl) aminomethyl) -4' - (3-amino-4- methoxyphenyl) -2 , 2 ' : 6 ' , 2 " -terpyridine .
  • the coordination sphere of metal ion includes all the ligands or groups bound to the metal .
  • a transition metal radionuclide to be stable it typically has a coordination number (number of donor atoms) comprised of an integer greater than or equal to 4 and less than or equal to 8; that is there are 4 to 8 atoms bound to the metal and it is said to have a complete coordination sphere.
  • the requisite coordination number for a stable radionuclide complex is determined by the identity of the radionuclide, its oxidation state, and the type of donor atoms .
  • the coordination sphere is completed by donor atoms from other ligands, termed ancillary or co-ligands, which can also be either terminal or chelating .
  • a large number of ligands can serve as ancillary or co-ligands, the choice of which is determined by a variety of considerations such as the ease of synthesis of the radiopharmaceutical, the chemical and physical properties of the ancillary ligand, the rate of formation, the yield, and the number of isomeric forms of the resulting radiopharmaceuticals, the ability to administer said ancillary or co-ligand to a patient without adverse physiological consequences to said patient, and the compatibility of the ligand in a lyophilized kit formulation.
  • the charge and lipophilicity of the ancillary ligand will effect the charge and lipophilicity of the radiopharmaceuticals .
  • Preferred technetium radiopharmaceuticals of the present invention are comprised of a hydrazido or diazenido bonding unit and an ancillary ligand, A L I, or a bonding unit and two types of ancillary A LI and A L2 , or a tetradentate chelator comprised of two nitrogen and two sulfur atoms.
  • Ancillary ligands A L ⁇ are comprised of two or more hard donor atoms such as oxygen and amine nitrogen (sp 3 hybridized) .
  • the donor atoms occupy at least two of the sites in the coordination sphere of the radionuclide metal; the ancillary ligand A L I serves as one of the three ligands in the ternary ligand system.
  • ancillary ligands A L I include but are not limited to dioxygen ligands and functionalized aminocarboxylates . A large number of such ligands are available from commercial sources .
  • Ancillary dioxygen ligands include ligands that coordinate to 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, altol, Kojic acid, 2, 2-bis (hydroxymethyl)propionic acid, 4, 5-dihydroxy-l, 3-benzene disulfonate, or substituted or unsubstituted 1,2 or 3,4 hydroxypyridinones .
  • 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' -ethylenediamine diacetic acid, N,N,N' -ethylenediamine triacetic acid, hydroxyethylethylenediamine triacetic acid, and
  • N,N' -ethylenediamine bis-hydroxyphenylglycine (The names for the ligands in these examples refer to either the protonated or non-protonated forms of the ligands.)
  • a series of functionalized aminocarboxylates are disclosed by Bridger et . al . in U.S. Patent 5,350,837, herein incorporated by reference, that result in improved rates of formation of technetium labeled hydrazino modified proteins. We have determined that certain of these aminocarboxylates result in improved yields of the radiopharmaceuticals of the present invention.
  • the preferred ancillary ligands ALI functionalized aminocarboxylates that are derivatives of glycine; the most preferred is tricine (tris (hydroxymethyl)methylglycine) .
  • the most preferred technetium radiopharmaceuticals of the present invention are comprised of a hydrazido or diazenido bonding unit and two types of ancillary designated A L ⁇ and A L2 , or a diaminedithiol chelator.
  • the second type of ancillary ligands A L are comprised of one or more soft donor atoms selected from the group: phosphine phosphorus, arsine arsenic, imine nitrogen
  • Ligands A L2 can be monodentate, bidentate or tridentate, the denticity 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.
  • radiopharmaceuticals comprised of one or more ancillary or co-ligands A L2 are more stable compared to radiopharmaceuticals that are not comprised of one or more ancillary ligands, A L2 ; that is, they have a minimal number of isomeric forms, the relative ratios of which do not change significantly with time, and that remain substantially intact upon dilution.
  • the ligands A L2 that are comprised of phosphine or arsine donor atoms are trisubstituted phosphines, trisubstituted arsines, tetrasubstituted diphosphines and tetrasubstituted diarsines.
  • the ligands A 2 that are comprised of imine nitrogen are unsaturated or aromatic nitrogen-containing, 5 or 6-membered heterocycles.
  • the ligands comprised of carbon (sp hybridized) donor atoms are isonitriles, comprised of the moiety CNR, where R is an organic radical.
  • Isonitriles can be synthesized as described in European Patent 0107734 and in U.S. Patent 4,988,827, herein incorporated by reference.
  • Preferred ancillary ligands A L2 are trisubstituted phosphines and unsaturated or aromatic 5 or 6 membered heterocycles.
  • the most preferred ancillary ligands A L2 are trisubstituted phosphines and unsaturated 5 membered heterocycles.
  • the ancillary ligands A L2 may be substituted with alkyl, aryl, alkoxy, heterocycle, aralkyl, alkaryl and arylalkaryl groups and may or may not bear functional groups comprised of heteroatoms such as oxygen, nitrogen, phosphorus or sulfur.
  • functional groups include but are not limited to: hydroxyl, carboxyl, carboxamide, nitro, ether, ketone, amino, ammonium, sulfonate, sulfonamide, phosphonate, and phosphonamide .
  • the functional groups may be chosen to alter the lipophilicity and water solubility of the ligands which may affect the biological properties of the radiopharmaceuticals, such as altering the distribution into non-target tissues, cells or fluids, and the mechanism and rate of elimination from the body.
  • Chelators or bonding moieties for therapeutic radiopharmaceuticals are selected to form stable complexes with the radioisotopes that have alpha particle, beta particle, Auger or Coster-Kronig electron emissions, such as 186 Re, 188 Re, 153 Sm, 166 Ho, 177 Lu,
  • Chelators for rhenium, copper, palladium, platinum, iridium, rhodium, silver and gold isotopes are selected from diaminedithiols , monoamine-monoamidedithiols, triamide-monothiols, monoamine-diamide-monothiols, diaminedioximes, and hydrazines.
  • Chelators for yttrium, bismuth, and the lanthanide isotopes are selected from cyclic and acyclic polyammocarboxylates such as DTPA, DOTA, D03A, 2-benzyl-DOTA, alpha- (2-phenethyl) 1, 4, 7 , 10- tetraazacyclododecane-l-acetic-4 , 7 , 10- tris (methylacetic) acid, 2-benzyl- cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl- 6-methyl-DTPA, and 6 , 6" -bis [N,N,N" ,N"- tetra (carboxymethyl) aminomethyl) -4 ' - (3-amino-4- methoxyphenyl) -2 , 2 ' : 6 ' , 2 "-terpyridine.
  • DTPA cyclic and acyclic polyammocarboxylates
  • DOTA DOTA
  • Chelators for magnetic resonance imaging contrast agents are selected to form stable complexes with paramagnetic metal ions, such as Gd(III) , Dy(III) , Fe(III), and Mn(II), are selected from cyclic and acyclic polyammocarboxylates such as DTPA, DOTA, D03A, 2-benzyl-DOTA, alpha- (2-phenethyl) 1,4,7,10- tetraazacyclododecane-l-acetic-4, 7 , 10- tris (methylacetic) acid, 2-benzyl- cyclohexyldiethylenetriaminepentaacetic acid, 2-benzyl- 6-methyl-DTPA, and 6, 6"-bis [N,N,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 hydrazido or diazenido bonding unit can be easily prepared by admixing a salt of a radionuclide, a reagent of the present invention, an ancillary ligand A L I, an ancillary ligand A L2 , and a reducing agent, in an aqueous solution at temperatures from 0 to 100 °C.
  • the technetium and rhenium radiopharmaceuticals of the present invention comprised of a tetradentate chelator having two nitrogen and two sulfur atoms can be easily prepared by admixing a salt of a radionuclide, a reagent of the present invention, and a reducing agent, in an aqueous solution at temperatures from 0 to 100 °C.
  • a salt of a radionuclide a reagent of the present invention
  • a reducing agent in an aqueous solution at temperatures from 0 to 100 °C.
  • the conversion of the hydrazone group to the hydrazine can occur either prior to reaction with the radionuclide, in which case the radionuclide and the ancillary or co-ligand or ligands are combined not with the reagent but with a hydrolyzed form of the reagent bearing the chelator or bonding unit, or in the presence of the radionuclide in which case the reagent itself is combined with the radionuclide and the ancillary or co-ligand or ligands. In the latter case, the pH of the reaction mixture must be neutral or acidic.
  • the radiopharmaceuticals of the present invention comprised of a hydrazido or diazenido bonding unit can be prepared by first admixing a salt of a radionuclide, an ancillary ligand A L I, and a reducing agent in an aqueous solution at temperatures from 0 to 100 °C to form an intermediate radionuclide complex with the ancillary ligand A L I then adding a reagent of the present invention and an ancillary ligand A L2 and reacting further at temperatures from 0 to 100 °C.
  • the radiopharmaceuticals of the present invention comprised of a hydrazido or diazenido bonding unit can be prepared by first admixing a salt of a radionuclide, an ancillary ligand A L I, a reagent of the present invention, and a reducing agent in an aqueous solution at temperatures from 0 to 100 °C to form an intermediate radionuclide complex, and then adding an ancillary ligand A L2 and reacting further at temperatures from 0 to 100 °C.
  • the technetium and rhenium radionuclides are preferably in the chemical form of pertechnetate or perrhenate and a pharmaceutically acceptable cation.
  • the pertechnetate salt form is preferably sodium pertechnetate such as obtained from commercial Tc-99m generators.
  • the amount of pertechnetate used to prepare the radiopharmaceuticals of the present invention can range 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 range from 0.01 ⁇ g to 10 mg, or more preferably from 0.5 ⁇ g to 200 ⁇ g. The amount used will be dictated by the amounts of the other reactants and the identity of the radiopharmaceuticals of the present invention to be prepared.
  • the amounts of the ancillary ligands L I used can range from 0.1 mg to 1 g, or more preferably from 1 mg to 100 mg.
  • the exact amount for a particular radiopharmaceutical is a function of identity of the radiopharmaceuticals of the present invention to be prepared, the procedure used and the amounts and identities of the other reactants.
  • Too large an amount of A L I will result in the formation of by-products comprised of technetium labeled A L I without a biologically active molecule or by-products comprised of technetium labeled biologically active molecules with the ancillary ligand A I but without the ancillary ligand A L2 • Too small an amount of A L ⁇ will result in other by-products such as technetium labeled biologically active molecules with the ancillary ligand A L2 but without the ancillary ligand A L ⁇ , or reduced hydrolyzed technetium, or technetium colloid.
  • the amounts of the ancillary ligands A 2 used can range from 0.001 mg to 1 g, or 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 procedure used and the amounts and identities of the other reactants .
  • a L2 Too large an amount of A L2 will result in the formation of by-products comprised of technetium labeled A L2 without a biologically active molecule or by-products comprised of technetium labeled biologically active molecules with the ancillary ligand A 2 but without the ancillary ligand A L I- If the reagent bears one or more substituents that are comprised of a soft donor atom, as defined above, at least a ten-fold molar excess of the ancillary ligand A L to the reagent of formula 2 is required to prevent the substituent from interfering with the coordination of the ancillary ligand A 2 to the metal radionuclide.
  • Suitable reducing agents for the synthesis of the radiopharmaceuticals of the present invention include stannous salts, dithionite. or bisulfite salts, borohydride salts, and formamidinesulfinic acid, wherein the salts are of any pharmaceutically acceptable form.
  • the preferred reducing agent is a stannous salt.
  • the amount of a reducing agent used can range from 0.001 mg to 10 mg, or more preferably from 0.005 mg to 1 mg.
  • Radiopharmaceuticals comprised of a hydrazido or diazenido bonding unit will depend on the identity of the reagent of the present invention used, the identity of any ancillary ligand A LI , the identity of any ancillary ligand A L2 , and the identity of the radionuclide.
  • Radiopharmaceuticals comprised of a hydrazido or diazenido bonding unit synthesized using concentrations of reagents of ⁇ 100 ⁇ g/mL, will be comprised of one hydrazido or diazenido group.
  • Those synthesized using >1 mg/mL concentrations will be comprised of two hydrazido or diazenido groups from two reagent molecules.
  • the biologically active molecule can be injected and not result in undesired side-effects, such as chemical toxicity, interference with a biological process or an altered biodistribution of the radiopharmaceutical. Therefore, the radiopharmaceuticals which require higher concentrations of the reagents comprised in part of the biologically active molecule, will have to be diluted or purified after synthesis to avoid such side-effects.
  • the identities and amounts used of the ancillary ligands A L I and A L2 will determine the values of the variables y and z.
  • the values of y and z can independently be 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 no more than seven donor atoms.
  • Z can be an integer from 1 to 2; for bidentate or tridentate ancillary ligands A L , z is 1.
  • the preferred combination for monodentate ligands is y equal to 1 or 2 and z equal to 1.
  • the preferred combination for bidentate or tridentate ligands is y equal to 1 and z equal to 1.
  • the indium, copper, gallium, silver, palladium, rhodium, gold, platinum, bismuth, yttrium and lanthanide radiopharmaceuticals of the present invention can be easily prepared by admixing a salt of a radionuclide and a reagent of the present invention, in an aqueous solution at temperatures from 0 to 100 °C.
  • These radionuclides are typically obtained as a dilute aqueous solution in a mineral acid, such as hydrochloric, nitric or sulfuric acid.
  • the radionuclides are combined with from one to about one thousand equivalents of the reagents of the present invention dissolved in aqueous solution.
  • a buffer is typically used to maintain the pH of the reaction mixture between 3 and 10.
  • the gadolinium, dysprosium, iron and manganese metallopharmaceuticals of the present invention can be easily prepared by admixing a salt of the paramagnetic metal ion and a reagent of the present invention, in an aqueous solution at temperatures from 0 to 100 °C.
  • These paramagnetic metal ions are typically obtained as a dilute aqueous solution in a mineral acid, such as hydrochloric, nitric or sulfuric acid.
  • the paramagnetic metal ions are combined with from one to about one thousand equivalents of the reagents of the present invention dissolved in aqueous solution.
  • a buffer is typically 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 reactants and the procedure used for the preparation.
  • the preparations may be complete, resulting in > 80% yield of the radiopharmaceutical, in 1 minute or may require more time. If higher purity metallopharmaceuticals are needed or desired, the products can be purified by any of a number of 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 metallopharmaceuticals and in diagnostic kits useful for the preparation of said radiopharmaceuticals include but are not limited to phosphate, citrate, sulfosalicylate, and acetate. A more complete list can be found in the United States Pharmacopeia.
  • Lyophilization aids useful in the preparation of diagnostic kits 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 metallopharmaceuticals and in diagnostic kits 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 metallopharmaceuticals and in diagnostic kits useful for the preparation of radiopharmaceuticals include but are not limited to ethanol, glycerin, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monoloeate, polysorbates , poly(oxyethylene) poly (oxypropylene) poly (oxyethylene) block copolymers (Pluronics) and lecithin.
  • Preferred solubilizing aids are polyethylene glycol, and Pluronics .
  • Bacteriostats useful in the preparation of metallopharmaceuticals and in diagnostic kits useful for the preparation of radiopharmaceuticals include but are not limited to benzyl alcohol, benzalkonium chloride, chlorbutanol, and methyl, propyl or butyl paraben.
  • a component in a diagnostic kit can also serve 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, ancillary or co-ligand and so forth.
  • the diagnostic radiopharmaceuticals are administered by intravenous injection, usually in saline solution, at a dose of 1 to 100 mCi per 70 kg body weight, or preferably at a dose of 5 to 50 mCi . Imaging is performed using known procedures.
  • the therapeutic radiopharmaceuticals are administered by intravenous injection, usually in saline solution, at a dose of 0.1 to 100 mCi per 70 kg body weight, or preferably at a dose of 0.5 to 5 mCi per 70 kg body weight .
  • the magnetic resonance imaging contrast agents of the present invention may be used in a similar manner as other MRI agents as described in U.S. Patent 5,155,215;
  • sterile aqueous solutions of the contrast agents are administered to a patient intravenously in dosages ranging from 0.01 to 1.0 mmoles per kg body weight.
  • compositions of the present invention should generally have a heavy atom concentration of 1 mM to 5 M, preferably 0.1 M to 2
  • Dosages, administered by intravenous injection, will typically range from 0.5 mmol/kg to 1.5 mmol/kg, preferably 0.8 mmol/kg to 1.2 mmol/kg. 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 ⁇ L of the echogenic gas per kg body weight or by infusion at a rate of approximately 3 ⁇ L/kg/min. Imaging is performed using known techniques of sonography.
  • N-methylmorpholine (NMM) N-methylmorpholine (NMM) , m-cresol, D-2-aminobutyric acid (Abu) , trimethylacetylchloride, diisopropylethylamine (DIEA), 1, 2 , 4-triazole, stannous chloride dihydrate, and tris (3-sulfonatophenyl) phosphine trisodium salt (TPPTS) were purchased from Aldrich Chemical Company.
  • Bis (3-sulfonatophenyl)phenylphosphine disodium salt (TPPDS) was prepared by the published procedure (Kuntz, E., U.S. Patent 4,248,802).
  • TPMS (3- Sulfonatophenyl)diphenylphosphine monosodium salt (TPPMS)wa ⁇ purchased from TCI America, Inc. Tricine was obtained from Research Organics, Inc. Technetium-99m- pertechnetate ( 99m Tc ⁇ 4 ⁇ ) was obtained from a DuPont Pharma 9j[o/99m r > c Technelite® generator. In-111- chloride (Indichlor®) was obtained from Amersham Medi- Physics, Inc. Sm-153-chloride and Lutetium-177-chloride were obtained from the University of Missouri Research Reactor (MURR) . Yttrium-90 chloride was obtained from the Pacific Northwest Research Laboratories.
  • DMF Dimethylformamide
  • CHCI3 chloroform
  • MeOH methanol
  • HC1 hydrochloric acid
  • Acetonitrile, dichloromethane (DCM) , acetic acid (HOAc) , trifluoroacetic acid (TFA) , ethyl ether, triethylamine, acetone, and magnesium sulfate were commercially obtained.
  • Absolute ethanol was obtained from Quantum Chemical Corporation.
  • Step 1A Synthesis of tert-butyl 3- ( ( (3- ( (tert-butoxy) carbonylamino) propyl) methylamino)methyl) -4- fluorobenzoate NT NHBOC
  • Step IB Synthesis of methyl (S) -3-N- (3- ( (tert- butoxyl) carbonyl amino) propyl ) -N- ( (5- ( (tert-butyl) oxycarbonyl) -2- fluorophenyl ) methyl) carbamoyl) -3- ( (phenylmethoxy) carbonylamino)propanoate
  • Step A The product of Step A (2 g, 5.3 mmol) was dissolved in 20 mL dry DMF, along with N-Cbz-L-aspartic acid ⁇ -methyl ester (1.65 g, 5.9 mmol), and 1-hydroxybenzotriazole hydrate (800 mg, 5.9 mmol) under a nitrogen atmosphere.
  • Dicyclohexylcarbodiimide (1M in CH 2 C1 2 , 5.9 mL, 5.9 mmol) was added via syringe, and the solution stirred 18 hr.
  • Ether 25 mL was added and the solids were filtered and rinsed with ether. The filtrate was concentrated, redissolved in ether, filtered, and the filtrate washed with sat.
  • Step IC Synthesis of methyl (S) -3-amino-3- (N- (3- ( (tert-butoxy) carbonylamino) propyl) -N- ( (5-( (tert- butyl) oxycarbonyl) -2- fluorophenyl ) methyl) carbamoyl) propanoate
  • step B The product of step B (2.8 g, 4.4 mmol) was dissolved in MeOH (50 mL) with 10% Pd/C (530 mg) and shaken under a hydrogen atmosphere (50 psi) in a Parr shaker for 2 hr.
  • the reaction mixture was filtered through Celite® and concentrated to a clear oil (2.14 g, 94%) under vacuum, which was not further purified.
  • Step ID Synthesis of methyl (S) -2- (2 , 5-diaza-9- ( (tert- butyl ) oxycarbonyl) -5- (3- ( (tert-butoxy) carbonylamino) propyl) -4- oxobicyclo [5.4.0] undeca-1 (7) , 8, 10-trien-3-yl) acetate
  • Step IE Synthesis of (S) -2 , 5-diaza-5- (3- ( (tert-butoxy) carbonylamino) propyl) -3- ( (methoxycarbonyl)methyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-9-carboxylic acid
  • the ester from D (880 mg, 1.8 mmol) was dissolved in dichloromethane (12 mL) and trifluoroacetic acid (6 mL) added with stirring under nitrogen. The reaction was stirred 2 hours, concentrated under vacuum, and redissolved in 7 mL dichloromethane. Acetonitrile (7mL) was added, followed by di- tert-butyldicarbonate (590 mg, 2.7 mmol) and diisopropylethylamine (1.4 mL, 7.6 mmol). The reaction was stirred overnight under nitrogen. EtOAc (15 mL) was added and the entire solution was washed with 5% citric acid and brine, dried (MgS04) , and concentrated to 1.12 g of oil.
  • step IE The product of step IE (476 mg, 1.09 mmol) was dissolved in dry dimethylformamide along with 2-
  • Step 1G Synthesis of (S, S) -7- ( (tert- butyl) oxycarbonyl) -2- (2- ( (tert-butyl) oxycarbonyl) ethyl) - 3-oxo-5- ( (phenylmethoxy) carbonyl amino) carbonyl) heptanoic acid
  • Step IH Synthesis of tert-butyl (S, S, S) -4- (N- (3- (3 , 6- diaza-5- ( (methoxycarbonyl)methyl) -10- (N- (benzimidazol-2- ylmethyl) -N-methylcarbamoyl) -4-oxobicyclo [5.4.0]undeca- 1 (7 ) , 8, 10-trien-3-y1) propyl) carbamoyl) -4- (4- ( (tert- butyl) oxycarbonyl) -2- ( (phenylmethoxycarbonylamino)butanoylamino)butanoate
  • Step II Synthesis of tert-butyl (S, S, S) -4-amino-4- (N- (3- (3 , 6-diaza-5- ( (methoxycarbonyl)methyl) -10- (N-
  • Step IH The product of Step IH (33 mg, 33 ⁇ mol) was hydrogenated with 10% palladium on carbon (15 mg) in methanol (6 mL) with acetic acid (0.1 mL) on a Parr shaker at 40 psi for 1.5 hr. The solution was filtered on Celite, rinsed with methanol and concentrated. The residue was dissolved in 20 L 1:1 acetonitrile/water, frozen, and lyophilized to afford the product as a white powder (21 mg, 75%).
  • step II (20 mg, 16.8 ⁇ mol) was dissolved in DMF (1 mL) along with DOTA(OtBu) 3-0H (26 mg, 25 ⁇ mol) , HBTU (20 mg, 53 ⁇ mol) , diisopropylethylamme (29.1 mg, 225 ⁇ mol) and HOBT hydrate (2.5 mg, 18 ⁇ mol). This was stirred for 18 hr under nitrogen, concentrated under vacuum, and purified by preparative HPLC (Vydac C- 18, 2.5 cm x 15 cm, 0. l%TFA/acetonitrile gradient). The product fractions were pooled and lyophilized to afford 17.5 mg of product as a white powder.
  • Step 2A Synthesis of tert-butyl 3- ( ( ( 6- ( (tert-butoxy) carbonylamino) hexyl) amino) methyl ) -4-f luorobenzoate NHBoc
  • tert-butyl-3 (alpha-bromomethyl)benzoate (5.4 g., 18 mmol) and 6-tert-butoxycarbonylamino-l-hexylamine hydrochloride (5.0 g., 19.8 mmol), affording 3.1 g (41%) of product as a yellow oil.
  • Step 2B Synthesis of methyl (S) -3-N- (6- ( (tert- butoxy1) carbonyl amino) hexyl) -N- ( (5- ( (tert-butyl) oxycarbonyl) -2- fluorophenyl) methyl ) carbamoyl) -3-
  • Step 2C Synthesis of methyl (S) -3-amino-3- (N- (6- ( (tert-butoxy) carbonylamino)hexyl) -N- ( (5- ( (tert- butyl) oxycarbonyl) -2- fluorophenyl)methyl) carbamoyl)propanoate
  • Step 2D Synthesis of methyl (S) -2- (2 , 5-diaza-9- ( (tert- butyl) oxycarbonyl) -5- (6- ( (tert-butoxy) carbonylamino) hexyl ) -4-
  • Step 2E Synthesis of (S) -2 , 5-diaza-5- (6- ( (tert-butoxy) carbonylamino) hexyl) -3- ( (methoxycarbonyl) methyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-9-carboxylic acid
  • Step 2F Synthesis of methyl (S) -2- (2 , 5-diaza-9- (N-
  • Step 2G Synthesis of (S) -2- (2 , 5-diaza-9- (N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl) -5- (6- ( (tert-butoxy) carbonylamino) hexyl) -4- oxobicyclo [5.4.0] undeca-1 (7) , 8, 10-trien-3-yl) acetic acid
  • step F The product of step F (152 mg, 245 ⁇ mol) was stirred with lithium hydroxide (21 mg, 500 ⁇ mol) in THF/H20 (3 mL/2 mL) for 22 hr. THF was removed under vacuum, the residue diluted with water and acidified with solid citric acid. The precipitated solid and solution was extracted with dichloromethane, washed with brine, dried (Na 2 S0 4 ) , and concentrated to afford the acid product
  • step G The product of step G (87 mg, 143 ⁇ mol) was dissolved in CHCl 2 (4 mL) and trifluoroacetic acid (2 mL) added with stirring under nitrogen. The solution was stirred for one hour, concentrated under vacuum, and the residue redissolved in dry DMF (2.5 mL) . To this was added sodium 2- [ [ [5- [ [ (2, 5-dioxo-l-pyrollidinyl) oxy] carbonyl] -2-pyridinyl] hydrazono] methyl] - benzenesulfonate (75 mg, 170 ⁇ mol) and diisopropylethylamine (500 ⁇ L, 2.87 mmol) with stirring under nitrogen.
  • Step 3A Synthesis of N- (6- ( (benzimidazol-2- ylmethyl) amino) hexyl) (phenylmethoxy) formamide dihydrochloride
  • Step 3B Synthesis of methyl (S) -2- (2 , 5-diaza-9- (N- (benzimidazol-2-ylmethyl) -N- (6-
  • Step 3C Synthesis of methyl ( S) -2- ( 9- (N- ( 6- aminohexyl ) -N- (benzimidazol-2 -ylmethyl ) carbamoyl ) -2 , 5- diaza-5-methyl-4-oxobicyclo [5 .4. 0 ] undeca-1 (7 ) , 8 , 10- trien-3-yl ) acetate
  • Step 3D Synthesis of (S) -2- (9- (N- (6-aminohexyl) -N-
  • Step 3C The product of Step 3C (100 mg, 192 ⁇ mol) was dissolved in methanol/tetrahydrofuran (2:1, 1 mL) and lithium hydroxide hydrate (23 mg, 550 ⁇ mol) dissolved in 0.5 mL water was added. The reaction was stirred for 4 hr, neutralized with 10% potassium hydrogen sulfate solution, and concentrated. The solids were dissolved in methanol, filtered, and the filtrate concentrated to an oil, which was dissolved in water/acetonitrile and lyophilized to afford 93 mg (96%) of the product as a white solid.
  • Step 3E Synthesis of 2- (2 , 5-diaza-9- (N- ( 6- ( (6- ( (1-aza-)
  • Step D The product of Step D (80 mg, 160 ⁇ mol) was dissolved in dry dimethylformamide, along with sodium 2- [ [ [5- [ [ (2 , 5- dioxo-1-pyrolidinyl) oxy] carbonyl] -2-pyridinyl] hydrazono] ethyl] -benzenesulfonate (88 mg, 250 ⁇ mol) and diisopropylethylamine (280 ⁇ L, 1.6 mmol) with stirring under nitrogen. The reaction was stirred overnight, concentrated, and the residue purified by preparative HPLC (Vydac C-18, 21.5 mm x 25 cm, 0.1% TFA/acetonitrile gradient) .
  • Step 4A Synthesis of (S) -2- (2 , 5-diaza-9- (N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl) -5- (6- aminohexyl) -4-oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3- yl) acetic acid
  • Step 4B Synthesis of (S, S) -2- (2, 5-diaza- (9- (N- benzimidazol-2-ylmethyl) ) -5- (6- (4- (N- (6- (3 , 6-diaza--5- (carboxymethyl) -4-oxobicyclo [5.4.0] undeca-1 (7) , 8, 10- trien-3-yl) hexyl) carbamoyl) -2- ( (tert- butoxy) carbonylamino)butanoylamino)hexyl) -4- oxobicyclo [5.4.0]undeca-l (11) ,7(8) , 9-trien-3-yl) acetic acid
  • Step 4C Synthesis of (S, S) -2- (2-aza-2- ( (5- (N- (1, 3- bis (N- (6- (aminohexyl-4-oxobicyclo [5.4.0]undeca- 1 (7) , 8, 10-trien-3-yl) acetic acid) (2- (2, 5-diaza-9- (N- (benzimidazol-2-ylmethyl)propyl) carbamoyl) (2- pyridyl) ) amino) vinyl) benzenesulfonic acid
  • Example 5 Preparation of (S, S, S) -4- (N- (3- (3 , 6-diaza-5- (carboxymethyl) -10- (N- (imidazol-2-ylmethyl) -N- benzylcarbamoyl) -4-oxobicyclo [5.4.0] undeca-1 (7) , 8, 10- trien-3-yl) propyl) carbamoyl) -4- (4-carboxy-2- (2- (1,4,7, 10-tetraaza-4, 7, 10-tris (carboxymethyl) cyclododecyl) acetylamino)butanoylamino) butanoic acid
  • Step 5A Synthesis of benzyl ((1- (triphenylmethyl) imidazol-2 -yl) methyl) amine
  • N-tritylimidazole-2-carboxaldehyde (338 mg, 1 mmol, prepared according to K.L.Kirk; J.Org.Chem., 1978, 43, 4381) was dissolved in dry toluene (7 mL) and anhydrous magnesium sulfate (602 mg, 5 mmol) added with stirring under nitrogen.
  • Benzylamine (131 ⁇ L, 1.2 mmol) was added and the solution stirred for 3.5 hr. The solids were filtered under nitrogen and the reaction concentrated. The residue is redissolved in 1,2- dichloroethane (25 mL) and cooled to 0°C.
  • Sodium triacetoxyborohydride (1.06 g, 5 mmol) was added slowly.
  • the solution was allowed to warm to room temperature over 2.5 hours .
  • the reaction mixture was added to water/ethyl acetate and the layers separated.
  • the aqueous layer was extracted with two portions of ethyl acetate and the combined organic layers washed with sat. bicarbonate, water, and brine.
  • the solution was concentrated to an oil and purified by flash chromatography on silica gel (99:1 EtOAc/EtOH with 0.1% triethylamine) to afford 330 mg (77%) of product as an oil which solidified on standing.
  • Step 5B Synthesis of methyl (S) -2- (2, 5-diaza-5- (3- ( (tert-butoxy) carbonylamino) propyl) -4-oxo-9- (N-benzyl-N- ( (2- (triphenylmethyl) imidazol-2- yl) methyl) carbamoyl)bicyclo [5.4.0] undeca-1 (7) ,8, 10- trien-3-yl) acetate
  • step 5E The product of step 5E (150 mg, 0.345 mmol) was treated in the same manner as step IF, affording the product (250 mg, 85%) as a thick oil.
  • LRMS (ES) 847.5 [M+H]+, 430.5, 243.2; 1 ⁇ NMR (600.1330 MHz, CDC1 3 ) This sample gave broad peaks with little fine splitting, even when refiltered, and was qualitatively similar to IE for the benzodiazepine nucleus .
  • Step 5C Synthesis of methyl (S) -2- (5- (3-aminopropyl) - 2, 5-diaza-9- (N- (imidazol-2-ylmethyl) -N-benzylcarbamoyl) - 4-oxobicyclo [5.4.0]undeca-l (7) ,8, 10-trien-3-yl) acetate
  • step 5B The product of step 5B (220 mg, 0.26 mmol) was added to neat trifluoroacetic acid (4 mL) containing triethylsilane (1 mL) under nitrogen and stirred for 1.5 hr. The solution was concentrated and residual acid removed by reconcentration with toluene. This product was not purified, but was used directly in the following step.
  • LRMS (ES) 505.4 [M+H] + , 253.4.
  • Step 5D Synthesis of tert-butyl (S, S, S) -4- (N- (3- (3 , 6- diaza-10- (N- (imidazol-2-ylmethyl) -N-benzylcarbamoyl) -5- ( (methoxycarbonyl) methyl-4-oxobicyclo [5.4.0]undeca- 1(7) , 8,10-trien-3-yl)propyl) carbamoyl) -4- (4- ( (tert- butyl) oxycarbonyl) -2- ( (phenylmethoxy) carbonylamino)butanoylamino) butanoate
  • step 5C A portion of the product of step 5C (65 mg, 130 ⁇ mol) was reacted with step IG as in Step IH to afford the product (64 mg, 49% from 5B) as an oil.
  • LRMS (ES) 1009.7 [M+H] + , 505.6 [M+2H] +2 ,;
  • Step 5E Synthesis of tert-butyl (S, S, S) ⁇ 4-amino-4- (N- (1- (N- (3- (3 , 6-diaza-10- (N- (imidazol-2-ylmethyl) -N- benzylcarbamoyl) -5- ( (methoxycarbonyl) methyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3- yl)propyl) carbamoyl) -3- ( (tert-butyl) oxycarbonyl) propyl) carbamoyl ) butanoate COgtBu
  • Step 5F Synthesis of tert-butyl (S, S, S) -4- (N- (1- (N- (3- (3 , 6-diaza-10- (N- (imidazol-2-ylmethyl) -N- benzylcarbamoyl) -5- ( (methoxycarbonyl)methyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3- yl)propyl) carbamoyl) -3- ( (tert-butyl) oxycarbonyl) propyl) carbamoyl) -4- (2- (1, 4, 7 , 10-tetraaza-4, 7 , 10- tris ( ( (tert- butyl) oxycarbonyl)methyl) cyclododecyl) acetylamino) butano ate
  • Step 5G Synthesis of (S, S, S) -4- (N- (3- (3 , 6-diaza-5- (carboxymethyl) -10- (N- (imidazol-2-ylmethyl) -N- benzylcarbamoyl) -4-oxobicyclo [5.4.0]undeca-1 (7) ,8, 10- trien-3-yl) propyl) carbamoyl) -4- (4-carboxy-2- (2- (1,4, 7, 10-tetraaza-4, 7, 10- tris (carboxymethyl) cyclododecyl) acetylamino) butanoylamin o) butanoic acid
  • Step 6A Synthesis of tert-butyl (S, S) -3- (N- (3- (3 , 6- diaza-10- (N- (imidazol-2-ylmethyl) -N-benzylcarbamoyl) -5- ( (methoxycarbonyl) methyl) -4-oxobicyclo [5.4.0]undeca- 1(7) ,8, 10-trien-3-yl)propyl) carbamoyl) -3- ( (phenylmethoxy) carbonylamino)propanoate
  • step 5D The product of step 5D (65 mg, 130 ⁇ mol) was reacted with N- (carbobenzyloxy) - ⁇ - (tert-butyl) -D- (N- hydroxysuccinimidyl) aspartate (66 mg, 156 ⁇ mol) and diisopropylethylamine (181 ⁇ L, 1.04 mmol) in dimethylformamide (1.5 mL) with stirring at room temperature under nitrogen for 20 hr. The reaction was concentrated, and the residue dissolved in ethyl acetate. The organics were washed with water, 10% potassium hydrogen sulfate, water, and brine, and then concentrated.
  • Step 6B Synthesis of tert-butyl (S, S) -3-amino-3- (N- (3- (3 , 6-diaza-10- (N- (imidazol-2-ylmethyl) -N- benzylcarbamoyl) -5- ( (methoxycarbonyl) methyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3-yl) propyl) carbamoyl) propanoate
  • Step 6C Synthesis of tert-butyl (S, S) -3- (N- (3- (3 , 6- diaza-10- (N- (imidazol-2-ylmethyl) -N-benzylcarbamoyl) -5- ( (methoxycarbonyl) methyl) -4-oxobicyclo [5.4.0] undeca- 1 (7) , 8, 10-trien-3-yl) ropyl) carbamoyl) -3- (2- (1, 4, 7, 10- tetraaza-4, 7, 10-tris ( ( (tert-butyl) oxycarbonyl)methyl) cyclododecyl) acetylamino)propanoate
  • Step 6D Synthesis of (S, S) -3- (N- (3- (3, 6-diaza-5- (carboxymethyl) -10- (N- (imidazol-2-ylmethyl) -N- benzylcarbamoyl) -4-oxobicyclo [5.4.0] undeca-1 (7) ,8, 10- trien-3-yl)propyl) carbamoyl) -3- (2- (1,4,7, 10-tetraaza- 4,7,10-tris(carboxymethyl) cyclododecyl) acetylamino)propanoic acid
  • Example 7 Synthesis of (S, S, S, S, S, S, S, S) -4- (N-l, 3- bis (N-3-carboxy-l- (N- (3- (3 , 6-diaza-10- (N- (benzimidazol- 2-ylmethyl) -N-methylcarbamoyl) -5- (carboxymethyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3- yl)propyl) carbamoyl) -4 , 4-dihydroxypentyl) carbamoyl) propyl) carbamoyl) -4- (5, 5-dihydroxy-2- (2- (1, 4,7, 10-tetraaza-4, 7, 10- tris (carboxymethyl) cyclodecyl) acetylamino) butanoic acid
  • Step 7A Synthesis of tert-butyl (S, S, S, S, S) 4- (N- (1-
  • step II The product of step II (65 g, 54.6 ⁇ mol) is dissolved in DMF (1 mL) along with HBTU (25 mg, 65 ⁇ mol) , N- carbobenzyloxy-L-glutamic acid (7.3 mg, 26 ⁇ mol), HOBT (7 mg, 52 ⁇ mol) , and diisopropylethylamine (40 ⁇ L, 225 ⁇ mol) under nitrogen. After stirring for 2 hrs, the reaction is concentrated and purified by preparative HPLC (0.1% TFA/acetonitrile gradient, Zorbax C8, 21.5 mm x 25 cm) . The product may be obtained as the trifluoroacetate salt after lyophilization.
  • Step 7B Synthesis of tert-butyl (S, S, S, S, S, S) -4- (2- amino-4- (N- (1- (N- (3- (3 , 6-diaza-10-10- (N- (benzimidazol-2- ylmethyl) -N-methylcarbamoyl) -5- ( (methoxycarbonyl)methyl) -4-oxobicyclo [5.4.0 ]undeca- 1(7) ,8, 10-trien-3-yl)propyl) carbamoyl) -3- ( (tert- butyl) oxycarbonyl) propyl) carbamoyl) -3- ( (tert- butyl) oxycarbonyl) propyl) carbamoyl) -3- ( (tert- butyl) oxycarbonyl) propyl) carbamoyl) butanoylamino) -4- (N- (1- (N- (3- (3 , 6-diaza-10-10- (N-
  • step 7A The product of step 7A is hydrogenated and isolated as in step II. This material is not further purified, but used directly in the following step.
  • Step 7C Synthesis of tert-butyl (S, S, S, S, S, S, S, S) -4- (N- (1, 3-bis (N- (3- ( (tert-butyl) oxycarbonyl) -1- (N-3-
  • step 7B The product of step 7B is reacted as in step 5D to afford the product, which is purified by preparative HPLC .
  • Step 7D Synthesis of tert-butyl (S, S, S, S, S, S, S, S) -4- amino-4- (N- (1- (N- (1, 3-bis (N- (3- ( (tert- butyl) oxycarbonyl) -1- (N-3- ( (tert-butyl) oxycarbonyl) -1- (N- (3- (3 , 6-diaza-10-10- (N- (benzimidazol-2-ylmethyl) -N- ethyl carbamoyl) -5- ( (methoxy carbonyl)methyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3- yl)propyl) carbamoyl) propyl) carbamoyl) propyl) carbamoyl) propyl) carbamoyl) propyl) carbamoyl) propyl) carbamoyl) -3- ( (tert-butyl)
  • step 7C is hydrogenated as in step II to afford the amine, which is not further purified but used directly in the next step.
  • Step 7E Synthesis of tert-butyl (S, S, S, S, S, S, S, S) -4- (N- (1- (N- (1 , 3-bis (N- (3- ( (tert-butyl) oxycarbonyl) -1- (N-3- ( (tert-butyl) oxycarbonyl) -1- (N- (3- (3 , 6-diaza-10-10- (N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl) -5- ( (methoxycarbonyl) methyl) -4-oxobicyclo [5.4.0]undeca-
  • step 7D is reacted with DOTA(OtBu) 3-OH as in step IJ to afford the product as a solid after preparative HPLC purification and lyophilization.
  • the product of 7B is reacted with the product of 71 in the presence of HBTU, HOBT, and diisopropylethylamine in dry dimethylformamide for 2 hours, after which the reaction is concentrated and the . residue purified by preparative HPLC to afford the product as a solid after lyophilization.
  • Step 7F Synthesis of (S, S, S, S, S, S, S, S) -4- (N-l, 3-bis (N- 3-carboxy-l- (N- (3- (3 , 6-diaza-10- (N- (benzimidazol-2- ylmethyl) -N-methylcarbamoyl) -5- (carboxymethyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3- yl)propyl) carbamoyl) -4 , 4-dihydroxypentyl) carbamoyl) propyl) carbamoyl) -4- (5, 5-dihydroxy-2- (2- (l,4,7,10-tetraaza-4,7,10- tris (carboxymethyl) cyclodecyl) acetylamino) butanoic acid
  • step 7D is deprotected as in step IK to afford the product as a solid after preparative HPLC purification and lyophilization.
  • Step 7G Synthesis of tert-butyl (S, S) -3 , 3-dimethyl-3- silabutyl 2- (4- ( (tert-butyl) oxycarbonyl) -2- ( (phenylmethoxy) carbonylamino) butanoylamino) pentane- 1,5-dioate
  • step IG The product of step IG (1.25 g, 2.4 mmol) was reacted with 2-trimethylsilylethanol (296 mg, 2.5 mmol) in the presence of ethyl [3- (N,N-dimethylaminopropyl] - carbodiimide hydrochloride (480 mg, 2.5 mmol) and dimethylaminopyridine (250 mg, 1.2 mmol) in dimethylformamide (10 mL) at 0°C. The reaction was allowed to warm slowly to room temperature and stirred overnight. It was concentrated and the residue partitioned between ethyl acetate and water.
  • Step 7H Synthesis of tert-butyl (S, S) -3 , 3-dimethyl-3- silabutyl 2- (2-amino-4- ( (tert-)
  • step 7G The product of step 7G (1.09 g) was dissolved in 2- propanol (75 mL) with 10% palladium on carbon (300 mg) and hydrogenated on a Parr shaker at 45 psi for one hour. The reaction mixture was filtered on a bed of Celite, washed with 2- propanol, and concentrated to yield the product (803 mg, 94%) as a clear oil.
  • LRMS (ES) 489.5 [M+H] + , 977.7 [2M+H] + . 1 ⁇ IMR (600.1343
  • Step 71 Synthesis of tert-butyl (S, S) -3 , 3-dimethyl-3- silabutyl 2- (4- ( (tert-butyl) oxycarbonyl) -2- (2- bromoacetylamino) butanoylamino)pentane-l, 5-dioate
  • step 7H The product of step 7H (397 mg, 0.813 mmol) was dissolved in dry tetrahydrofuran (5 mL) with diisopropylethylamine (180 ⁇ L, 1.05 mmol) and cooled to -10°C under nitrogen. Bromoacetyl bromide (85 ⁇ L, 0.98 0 mmol) , dissolved in 10 mL tetrahydrofuran, was added dropwise to the cold solution, keeping T ⁇ -5°C. The reaction was stirred in the cold for 1.5 hr, and 25 ⁇ L methanol added. The solids were filtered and rinsed and the combined filtrate concentrated to a brown oil, which 5 was purified by flash chromatography
  • Step 7J Synthesis of (S, S) -4- ( (tert- butyl) oxycarbonyl) -2- (4- ( (tert-butyl) oxycarbonyl) -2- (2- (l,4,7,10-tetraaza-4,7,10-tris( ( (tert- butyl) oxycarbonyl)methyl) cyclododecyl) acetylamino) butanoylamino)butanoic acid
  • step 7H The product of step 7H (214 mg, 0.416 mmol) was dissolved in dimethylformamide (3 mL) and added to a solution of triethylamine (250 ⁇ L) and D03A tri-tert- butyl ester in dimethylformamide (3mL) .
  • the reaction was stirred for 4 days at room temperature, concentrated, and the residue dissolved in ethyl acetate. This was washed with water and brine, dried, and concentrated to an oil which was not further purified but reacted directly with tetra-butylammonium fluoride (1.0M in tetrahydrofuran, 1.25 mL) in tetrahydrofuran (2.5 mL) .
  • Example 8 Synthesis of (S, S, S, S, S, S, S, S, S, S) -2- (4- (N- (1, 3-bis (N- (3- (N- (3- (3 , 6-diaza-10- (N- (benzimidazol-2- ylmethyl) -N-methylcarbamoyl) -5-
  • Step 8A Synthesis of ditert-butyl (S, S) -2- (4- ( (tert- butyl) oxycarbonyl) -2-
  • the product of 8a is dissolved in one volume of dichloromethane and treated with excess triethylsilane and one volume of trifluoroacetic acid.
  • the reaction is stirred under nitrogen for three hours and then concentrated to an oil.
  • the triacid residue is dissolved in dimethylformamide and treated with excess gamma-tert-butyl-alpha-methyl glutamate, HBTU, HOBT, and diisopropylethylamine with stirring under nitrogen for 4-5 hours.
  • the reaction is concentrated, partitioned into water/ethyl acetate and extracted with more ethyl acetate.
  • Step 8C Synthesis of methyl (S, S, S, S, S, S, S) -4- (N- (3-
  • the product of 8b is dissolved in one volume of dichloromethane and treated with excess triethylsilane and one volume of trifluoroacetic acid. The reaction is stirred under nitrogen for three hours and then concentrated to an oil.
  • step IF A threefold excess of the product of step IF is treated in the same fashion with trifluoroacetic acid and triethylsilane and concentrated to an oil.
  • the two residues are dissolved in dimethylformamide, combined, and treated with HBTU, HOBT, and diisopropylethylamine with stirring under nitrogen, following disappearance of starting material by HPLC.
  • the reaction is concentrated, partitioned into water/ethyl acetate and extracted with more ethyl acetate.
  • the combined organics are washed with water and brine and concentrated to an oil, which is purified by preparative HPLC. using a 0.1% trifluoroacetic acid/acetonitrile gradient to afford the product as a powder after lyophilization.
  • Step 8D Synthesis of methyl (S, S, S, S, S, S, S, S) -2- (4- amino-4- (N- (1, 3-bis (N- (3- (N- (3- (3 , 6-diaza-10- (N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl) -5- ( (methoxycarbonyl)methyl) -4-oxobicyclo [5.4.0]undeca- 1(7) ,8, 10-trien-3-yl)propyl) carbamoyl) -1- (methoxycarbonyl) propyl) carbamoyl)propyl) carbamoyl) butanoylamino) -4- (N- (3- (3 , 6-diaza-10- (N- (benzimidazol-2-ylmethyl) -N- methylcarbamoyl) -5- ( (methoxycarbonyl)methyl) -4- oxobicyclo [5.4.0]undeca-1
  • step 8C The product of step 8C is dissolved in methanol with 10% palladium on carbon and 2 equivalents of acetic acid in a Parr bottle.
  • the mixture is hydrogenated at 55 psi in a Parr shaker, following by HPLC until all the starting material has been reacted.
  • the reaction is filtered through Celite, concentrated, and the residual oil lyophilized from water/acetonitrile to yield the product as a powder, to be used directly in the next step.
  • Step 8E Conjugation of 8D with 71
  • step 8D is reacted with the product of step 71 as described in the alternate synthesis of 7E to " afford the product as a solid after preparative HPLC purification and lyophilization.
  • Step 8F Synthesis of (S, S, S, S, S, S, S, S, S, S) -2- (4- (N- (1, 3-bis (N- (3- (N- (3- (3 , 6-diaza-10- (N- (benzimidazol-2- ylmethyl) -N-methylcarbamoyl) -5-
  • step 8E The product of step 8E is dissolved in 2:1 methanol/ tetrahydrofuran and excess lithium hydroxide (3M solution) added. The solution is stirred, following by HPLC, until all the methyl esters have been hydrolyzed. The reaction is quenched with solid citric acid, concentrated, and redissolved in one volume of dichloromethane. The solids are filtered and the filtrate treated with excess triethylsilane and one volume of trifluoroacetic acid. The solution is stirred under nitrogen, following by HPLC, until all of the tert-butyl esters have been hydrolyzed.
  • 3M solution lithium hydroxide
  • Step 9A Synthesis of N- (3- (2- (2- (3- aminopropoxy) ethoxy) ethoxy)propyl) (tert- butoxy) formamide
  • a solution of at least three equivalents of 4,7,10- trioxa-1, 13-tridecanediamine in tetrahydrofuran is cooled to 0°C, and a solution of one equivalent of di- tert-butyl dicarbonate in acetonitrile is added dropwise with stirring.
  • the solution is stirred under nitrogen overnight and then concentrated.
  • the residue is dissolved in ether and washed with five portions of saturated sodium chloride .
  • the organic layer is dried over magnesium sulfate, filtered and concentrated to an oil, which is purified by flash chromatography to afford the monoamine.
  • Step 9B Synthesis of tert-butyl 3-(((3-(2-(2-(3- ( (tert- butoxy) carbonylamino) propoxy) ethoxy) ethoxy) propyl) amino) methyl) -4-fluorobenzoate
  • step 9A The product of step 9A is treated with crude terfc-butyl- 4-fluoro-3 (alpi ⁇ a-bromomethyl)benzoate, as described in step 1A, to afford the product after flash chromatography.
  • Step 9C Synthesis of methyl (S) -3- (N- (3- (2- (2- (3-)
  • step 9B The product of step 9B is treated with Z-aspartic acid- ⁇ -methyl ester as described in step IB, to afford the product after flash chromatography.
  • Step 9D Synthesis of methyl (S) -3-amino-3- (N- (3- (2- (2- (3-( (tert- butoxy) carbonylamino)propoxy) ethoxy) ethoxy) propyl) -N- ( (5-( (tert-butyl) oxycarbonyl) -2- fluoroph
  • step 9C The product of step 9C is treated as in step IC, and used directly in the following step.
  • Step 9E Synthesis of methyl (S) -2- (2 , 5-diaza-9- ( (tert- butyl) oxycarbonyl-5- (3- (2- (2- (3- ( (tert- butoxy) carbonylamino) propoxy) ethoxy) ethoxy)propyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3-yl) acetate
  • step 9D The product of step 9D is treated as in step ID, to afford the product after flash chromatography. •
  • Step 9F Synthesis of (S) -2 , 5-diaza-5- (3- (2- (2- (3- ( (tert- butoxy) carbonylamino) propoxy) ethoxy) ethoxy)propyl) -3- ( (methoxycarbonyl)methyl) -4-oxobicyclo [5.4.0] undeca- 1 (7) , 8, 10-trien-9-carboxylic acid
  • step 9G Synthesis of methyl (S) -2- (2 , 5-diaza-9- (N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl) -5- (3- (2- (2- (3- ( (tert-butoxy) carbonylamino)propoxy) ethoxy) ethoxy) propyl) -4-oxobicyclo
  • step 9F is treated as in step IF, to afford the product after flash chromatography.
  • Step 9H Synthesis of (S) -2- (2 , 5-diaza-5- (3- (2- (2- (3- ( (6- ( (l-aza-2- (2-sulfophenyl) vinyl) amino) (3- pyridyl) ) carbonylamino) propoxy) ethoxy) ethoxy)propyl) -9- (N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl) -4- oxobicyclo [5.4.0]undeca-1 (7) ,8, 10-trien-3-yl) acetic acid
  • step 9G The product of step 9G is treated as in step 2G, and the isolated residue then directly treated as in step 2H to afford the product after preparative HPLC and lyophilization.
  • Example 10 Preparation of (S, S, S, S, S) -4- (N- (1, 3-bis (N- (3- (2- (2- (3- (3 , 6-diaza-10- (N- (benzimidazol-2-ylmethyl) - N-methylcarbamoyl) -5- (carboxymethyl) -4- oxobicyclo [5.4.0]undeca-l (7) ,8, 10-trien-3- yl) propoxy) ethoxy) ethoxy)propyl) carbamoyl) propyl) carbamoyl) -4- (5, 5-dihydroxy-2- (2- (1, 4, 7, 10- tetraaza-4 , 7 , 10-tris (carboxy methyl) cyclododecyl) acetylamino) hex
  • Step 10A Synthesis of methyl (S) -2- (5- (3- (2- (2- (3- 15 aminopropoxy) ethoxy) ethoxy) propyl) -2 , 5-diaza-9- (N- (benzimidazol -2-ylmethyl) -N-methylcarbamoyl) -4- oxobicyclo [5.4.0] undeca-1 (7) , 8 , 10-trien-3-yl) acetate
  • step 9G The product of step 9G is treated with trifluoroacetic 20 acid and triethylsilane in dichloromethane for 30 minutes and the reaction then concentrated to an oil. Toluene is added and the solution reconcentrated to an oil, which is used directly in the next step.
  • Step 10B Synthesis of (S, S, S, S, S) -4- (N- (1, 3-bis (N- (3- (2- (2- (3- (3- (3 , 6-diaza-10- (N- (benzimidazol-2-ylmethyl) -N- methy1carbamoyl) -5- (carboxymethyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3- yl ) propoxy) ethoxy) ethoxy) propyl) carbamoyl)propyl) carbamo yl)-4-(5,5-dihydroxy-2-(2-(l,4,7,10-tetraaza-4,7,10- tris(carboxy methyl) cyclododecyl) acetylamino) hexanoylamino) butanoic acid
  • step 10A is treated in several steps as defined in example 7, steps 7A - 7F, substituting step 10A product for step II product as a starting material in step 7A.
  • the product is obtained as a solid after preparative HPLC purification and lyophilization.
  • Step 11A Synthesis of tert-butyl methyl (S,S)-2-(4- ( (tert-butyl) oxycarbonyl) -2-
  • step IG This process is carried out as in step IG, except starting with alpha-methyl-gamma-tert-butylglutamate.
  • Step 11B Synthesis of methyl (S, S) -4- (N- ( (R, S, S, S) - 2,3,4,5, 6-pentahydroxy hexyl) carbamoyl) -2- (4- (N- ( (R, S, S, S) -2, 3, 4, 5, 6-pentahydroxyhexyl) carbamoyl) - 2- ( (phenylmethoxy) carbonylamino) butanoylamino) butanoate
  • step 11A The product of step 11A is dissolved in dichloromethane, followed by addition of trifluoroacetic acid (to form a 35% solution) . This is stirred under nitrogen until the starting material and monoacid have disappeared by HPLC, and then the solution is concentrated. The residue is dissolved in dimethylformamide along with 2.5 equivalents of 1-amino-l-deoxysorbitol, 2.5 equivalents of HBTU, 2 equivalents of hydroxybenzotriazole hydrate, and 3 equivalents diisopropylethylamine. The solution is stirred for two hours, concentrated, and the residue purified by preparative HPLC.
  • Step 11C Synthesis of (S, S) -4- (N- ( (R, S, S, S) -2 , 3 , 4, 5, 6- pentahydroxyhexyl ) carbamoyl) -2- (4- (N- ( (R, S, S, S) - 2,3,4,5,6-pentahydroxyhexyl ) carbamoyl) -2- ( (phenylmethoxy) carbonylamino) butanoylamino) butanoic acid
  • step 11B The product of step 11B is dissolved in tetrahydrofuran/methanol (1:1) and treated with excess 3N aqueous lithium hydroxide .
  • the reaction is followed by HPLC for disappearance of starting material.
  • the reaction is concentrated, diluted with additional water, and purified by passage down an acidic ion exchange column.
  • the product fractions are lyophilized to afford the product as a solid.
  • Step 11D Synthesis of methyl (S, S, S) -2- (2 , 5-diaza-9- (N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl) ⁇ 4-oxo-5- (6-(4-(N-( (R,S,S,S)-2,3,4,5,6- pentahydroxyhexyl) carbamoyl) -2- (4- (N- ( (R, S, S, S) - 2,3,4,5,6-pentahydroxy hexyl) carbamoyl) -2- (phenylmethoxy) carbonylamino)butanoylamino)butanoylamino ) hexyl)bicyclo [5.4.0] undeca-1 (7) , 8, 10-trien-3- yl) acetate
  • step 2G The product of step 2G is dissolved in dichloromethane and stirred with trifluoroacetic acid and triethylsilane for 15 minutes.
  • the solution is concentrated, and the residue dissolved in dimethylformamide with the product of step 11C, HBTU, hydroxybenzotriazole hydrate, and diisopropylethylamine.
  • the reaction is stirred, following by HPLC for disappearance of starting materials. When complete, the solution is concentrated and the residue purified by preparative HPLC.
  • the product solutions are lyophilized to afford the product.
  • Step HE Synthesis of methyl (S, S, S) -2- (5- (6- (2- (2- amino-4(-(N-( (R, S, S, S) -2 , 3 , 4, 5 , 6- pentahydroxyhexyl) carbamoyl) butanoylamino) -4- (N- ( (R,S,S,S) -2, 3, 4, 5, 6-pentahydroxyhexyl) carbamoyl) butanoylamino) hexyl) -2 , 5-diaza-9- (N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl) -4-oxobicyclo [5.4.0] undeca-1 (7) , 8, 10-trien-3-yl) acetate
  • step 11D is treated as in step II, to afford the amine after concentration.
  • Step HF Synthesis of (S, S, S) -2- (2, 5-diaza-9- (N- (benzimidazol-2-ylmethyl) -N-methylcarbamoyl) -4-oxo-5- (6- (4-(N-( (R,S,S,S) -2 ,3, 4, 5, 6-pentahydroxyhexyl) carbamoyl) - 2-(4-(N-( (R,S,S,S)-2,3,4,5,6- pentahydroxyhexyl) carbamoyl) -2-(2-(l,4,7, 10-tetraaza- 4, 7, 10-tris ( ( (tert- butyl) oxycarbonyl) methyl) cyclododecyl) acetylamino)butanoylamino) butanoylamino) hexyl ) bicyclo [5.
  • step HE The product of step HE is reacted as in step IJ to afford the product after preparative HPLC purification.
  • Step 11G Synthesis of (S, S, S) -2- (2 , 5-diaza-9- (N-
  • step HF The product of step HF is treated as in step IK, to afford the product after preparative HPLC purification.
  • Step 12A Synthesis of H-Asp(OtBu) -D-Phe-Lys (Cbz) - Arg(Mtr)-Gly-OH
  • This peptide is prepared using an Advanced Chemtech Model 90 synthesizer using standard Fmoc protocols.
  • the starting resin is 4- [4-hydroxymethyl) -3-methoxy- phenoxy] butanoyl benzhydrylamine resin preloaded with Fmoc-glycine (Fmoc-Gly-HMPB-BHA) .
  • Synthesis of the protected linear peptide is achieved through sequential coupling (for 3 hrs) of the amino acids N-alpha-Fmoc-N 9 - 4-methoxy-2 , 3 , 6-trimethylbenzenesulfonyl-1-arginine, N- alpha-Fmoc-N-epsilon-benzyloxycarbonyl-L-lysine, Fmoc- phenylalanine, and Fmoc-gamma-tert-butyl aspartic acid, using HBTU and HOBT as coupling agents.
  • the couplings are carried out with five equivalents of amino acid, HBTU, HOBT, and diisopropylethylamine in dimethylformamide.
  • HBTU (0.7' mmol) and hydroxybenzotriazole (0.5 mmol) are dissolved in dimethylformamide (10 mL) .
  • the solution is warmed to 60°C under nitrogen and a solution of the product of step 12 A (0.4 g) and diisopropylethylamine (1.5 mmol) in dimethylformamide (10 mL) added slowly.
  • the solution is stirred at this temperature for 4 hours under nitrogen.
  • the solution is concentrated and the residue triturated with ethyl acetate.
  • the resulting solids are washed with ethyl acetate and dried under vacuum to afford the product, which is used directly in the next step.
  • Step 12C Synthesis of cyclo ⁇ Lys-Arg(Mtr) -Gly- Asp(OtBu)-D-Phe)
  • step 12 B The product of step 12 B is dissolved in 2-propanol and 10% palladium on carbon added with stirring. Hydrogen gas is gently bubbled into the reaction mixture until all of the starting material is consumed by HPLC analysis. The reaction mixture is filtered through a bed of Celite and the filtrate concentrated. The residue is not further purified but used directly in the following step.
  • Step 12D Synthesis of tert-butyl (S, S) -4- (N- (6- (3 , 6- diaza-10- (N- (benzimidazol-2-ylmethyl) -N- methy1carbamoyl) -5- ( (methoxycarbonyl)methyl) -4- oxobicyclo [5.4.0]undeca-l (7) ,8, 10-trien-3- yl) hexyl) carbamoyl) -4- ( (phenylmethoxy) carbonylamino) butanoate
  • step 2F The product of step 2F is dissolved in dichloromethane and trifluoroacetic acid added (30% solution) . The reaction is stirred 30 minutes and concentrated. The residue is dissolved in dimethylformamide and N- carbobenzyloxy-gamma-tert-butyl-alpha-N- hydroxysuccinimidylglutamate added, along with excess diisopropylethylamine. The reaction is stirred for four hours and concentrated. The residue is purified by preparative HPLC and the fractions lyophilized to afford the product as a solid.
  • Step 12E Synthesis of (S, S) -4- (N- ( 6- (3 , 6-diaza-10- (N-
  • step 12D The product of step 12D is dissolved in one volume of dichloromethane, followed by one volume of trifluoroacetic acid and 5 equivalents of triethylsilane. The solution is stirred for four hours and concentrated. The residue is dissolved in dimethylformamide containing the product of step 12C, HBTU, and hydroxybenzotriazole hydrate. Diisopropylethylamine is added to this mixture with stirring under nitrogen, following by HPLC for disappearance of the starting materials. When complete, the reaction is concentrated and the residue purified by preparative HPLC . The product fractions are combined and lyophilized.
  • Step 12F Synthesis of (S, S) -4- (N- (6- (3 , 6-diaza-10- (N-
  • step 12E The product of step 12E is treated as in step 8D.
  • the product is not further purified, but used directly in the next step.
  • Step 12G Synthesis of tert-butyl (S, S, S, S) -4- (N- (1-N- (1- (N- (6- (3 , 6-diaza-10- (N- (benzimidazol-2-ylmethyl) -N- methy1carbamoyl) -4-oxobicyclo [5.4.0] undeca-1 (7) ,8, 10- trien-3-yl) hexyl) carbamoyl) -3- (N-cyclo ⁇ Lys-Arg (Mtr) -Gly- Asp (OtBu) -D-Phe ⁇ carbamoyl)propyl) carbamoyl-3- ( (tert- butyl) oxycarbonyl)propyl) carbamoyl) -4-(2-(l,4,7,10- tetraaza-4, 7, 10-tris ( ( (tert-butyl) oxycarbonyl) methyl) cyclcododecyl) ace
  • step 12F is treated as in. step 8E to afford the product after preparative HPLC purification.
  • Step 12H Synthesis of (S, S, S, S) -2- (4- (N- (1- (N- (1- (N- (6- (3, 6-diaza-10- (N- (benzimidazol-2-ylmethyl) -N- methy1carbamoyl) -5- (carboxymethyl) -4- oxobicyclo [5.4.0] undeca-1 (7) ,8, 10-trien-3- yl) hexyl) carbamoyl) -3- (N-cyclo ⁇ Lys-Arg(Mtr) -Gly- Asp (OtBu) -D-Phe ⁇ [gamma-LysNH] carbamoyl) propyl) carbamoyl) -3-carboxypropyl) carbamoyl) - 4- (2- (1,4,7, 10-tetraaza-4, 7, 10- tris (carboxymethyl) cyclcododecyl) acetylamino) butanoic acid

Abstract

La présente invention concerne de nouveaux composés de la formule Qd-Ln-Cn, utiles pour le diagnostic et le traitement du cancer dans une thérapie combinée chez un patient. La présente invention permet d'obtenir de nouveaux composés utiles au traitement de la polyarthrite rhumatoïde. Les agents pharmaceutiques comprennent une fraction de ciblage se fixant à un récepteur lequel est régulé positivement pendant l'angiogénèse, un groupe de liaison facultatif ainsi qu'un radio-isotope thérapeutiquement efficace ou une fraction imageable efficace du point de vue du diagnostic.
PCT/US2001/020203 2000-06-21 2001-06-21 Agents pharmaceutiques antagonistes du recepteur de la vitronectine destines a etre utilises dans une therapie combinee WO2001097861A2 (fr)

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AU2001271435A AU2001271435A1 (en) 2000-06-21 2001-06-21 Vitronectin receptor antagonist pharmaceuticals
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EP01950446A EP1311292A2 (fr) 2000-06-21 2001-06-21 Agents pharmaceutiques antagonistes du recepteur de la vitronectine

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WO2001097848A2 (fr) * 2000-06-21 2001-12-27 Bristol-Myers Squibb Pharma Company Agents pharmaceutiques antagonistes du recepteur de vitronectine, a utiliser en polytherapie
US6683163B2 (en) 1998-12-18 2004-01-27 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US7018611B2 (en) 1998-12-18 2006-03-28 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
WO2010092114A1 (fr) 2009-02-13 2010-08-19 Guerbet Utilisation de tampons pour la complexation de radionucléides
WO2012084981A1 (fr) 2010-12-20 2012-06-28 Guerbet Nanoemulsion de chelate pour irm
WO2013045333A1 (fr) 2011-09-26 2013-04-04 Guerbet Nanoemulsions et leur utilisation comme agents de contraste
US8664252B2 (en) 2008-11-25 2014-03-04 Boehringer Ingelheim Vetmedica Gmbh Phosphodiesterase type III (PDE III) inhibitors or CA2+-sensitizing agents for the treatment of hypertrophic cardiomyopathy
WO2014114724A1 (fr) 2013-01-23 2014-07-31 Guerbet Magneto-emulsion vectorisee
US8846679B2 (en) 2004-03-08 2014-09-30 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical composition comprising pimobendan
US8926945B2 (en) 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
US8980894B2 (en) 2004-03-25 2015-03-17 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure
US8986650B2 (en) 2005-10-07 2015-03-24 Guerbet Complex folate-NOTA-Ga68
US9107952B2 (en) * 2006-11-07 2015-08-18 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US9463199B2 (en) 2004-03-25 2016-10-11 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure
US10071162B2 (en) 2013-07-19 2018-09-11 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
US10172804B2 (en) 2013-12-04 2019-01-08 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical compositions of pimobendan
US10398705B2 (en) 2012-03-15 2019-09-03 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof
US10537570B2 (en) 2016-04-06 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease
US11103483B2 (en) 2010-01-28 2021-08-31 Eagle Pharmaceuticals, Inc. Formulations of bendamustine

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US6683163B2 (en) 1998-12-18 2004-01-27 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6689337B2 (en) 1998-12-18 2004-02-10 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6743412B2 (en) 1998-12-18 2004-06-01 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US7018611B2 (en) 1998-12-18 2006-03-28 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
WO2001097848A3 (fr) * 2000-06-21 2003-03-13 Bristol Myers Squibb Pharma Co Agents pharmaceutiques antagonistes du recepteur de vitronectine, a utiliser en polytherapie
WO2001097848A2 (fr) * 2000-06-21 2001-12-27 Bristol-Myers Squibb Pharma Company Agents pharmaceutiques antagonistes du recepteur de vitronectine, a utiliser en polytherapie
US8846679B2 (en) 2004-03-08 2014-09-30 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical composition comprising pimobendan
US8859554B2 (en) 2004-03-08 2014-10-14 Boehringer Ingelheim Vetmedica Gmbh Packaging assembly for pharmaceutical composition including pimobendan
US8846680B2 (en) 2004-03-08 2014-09-30 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical composition comprising pimobendan
US9463199B2 (en) 2004-03-25 2016-10-11 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure
US9889148B2 (en) 2004-03-25 2018-02-13 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size in mammals suffering from heart failure
US10537588B2 (en) 2004-03-25 2020-01-21 Boehringer Ingelheim Vetmedica Gmbh Use of pimobendan for the reduction of heart size in mammals suffering from heart failure
US11413285B2 (en) 2004-03-25 2022-08-16 Boehringer Ingelheim Vetmedica Gmbh PDE III inhibitors for treatment of asymptomatic heart failure
US10117869B2 (en) 2004-03-25 2018-11-06 Boehringer Ingelheim Vetmedica Gmbh PDE III inhibitors for treatment of asymptomatic heart failure
US8980894B2 (en) 2004-03-25 2015-03-17 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure
US8926945B2 (en) 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
US8986650B2 (en) 2005-10-07 2015-03-24 Guerbet Complex folate-NOTA-Ga68
US10639305B2 (en) 2006-11-07 2020-05-05 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US9616134B2 (en) 2006-11-07 2017-04-11 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US9107952B2 (en) * 2006-11-07 2015-08-18 Boehringer Ingelheim Vetmedica Gmbh Liquid preparation comprising pimobendan
US8664252B2 (en) 2008-11-25 2014-03-04 Boehringer Ingelheim Vetmedica Gmbh Phosphodiesterase type III (PDE III) inhibitors or CA2+-sensitizing agents for the treatment of hypertrophic cardiomyopathy
WO2010092114A1 (fr) 2009-02-13 2010-08-19 Guerbet Utilisation de tampons pour la complexation de radionucléides
US11872214B2 (en) 2010-01-28 2024-01-16 Eagle Pharmaceuticals, Inc. Formulations of Bendamustine
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WO2013045333A1 (fr) 2011-09-26 2013-04-04 Guerbet Nanoemulsions et leur utilisation comme agents de contraste
US10398705B2 (en) 2012-03-15 2019-09-03 Boehringer Ingelheim Vetmedica Gmbh Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof
WO2014114724A1 (fr) 2013-01-23 2014-07-31 Guerbet Magneto-emulsion vectorisee
US11185590B2 (en) 2013-07-19 2021-11-30 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
US10071162B2 (en) 2013-07-19 2018-09-11 Boehringer Ingelheim Vetmedica Gmbh Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition
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