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WO2004032911A2 - Inhibition du facteur de croissance endothelial vasculaire - Google Patents

Inhibition du facteur de croissance endothelial vasculaire Download PDF

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Publication number
WO2004032911A2
WO2004032911A2 PCT/CA2003/001558 CA0301558W WO2004032911A2 WO 2004032911 A2 WO2004032911 A2 WO 2004032911A2 CA 0301558 W CA0301558 W CA 0301558W WO 2004032911 A2 WO2004032911 A2 WO 2004032911A2
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Prior art keywords
ealkyl
alkyl
ealkoxy
halo
compound
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PCT/CA2003/001558
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English (en)
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WO2004032911A3 (fr
Inventor
Chaim M. Roifman
Amos J. Simon
Peter M. Demin
Olga B. Rounova
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The Hospital For Sick Children
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Priority claimed from CA002407755A external-priority patent/CA2407755A1/fr
Application filed by The Hospital For Sick Children filed Critical The Hospital For Sick Children
Priority to CA002500385A priority Critical patent/CA2500385A1/fr
Priority to US10/530,800 priority patent/US20060241084A1/en
Priority to AU2003273702A priority patent/AU2003273702A1/en
Priority to EP03757609A priority patent/EP1551381A2/fr
Publication of WO2004032911A2 publication Critical patent/WO2004032911A2/fr
Publication of WO2004032911A3 publication Critical patent/WO2004032911A3/fr

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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • This invention relates to therapeutic organic compounds and inhibition of secretion of vascular endothelial growth factor (VEGF) and its effects, including angiogenesis.
  • VEGF vascular endothelial growth factor
  • VEGF is a disulfide-linked, dimeric glycoprotein with multifunctional properties. There are at least 5 isoforms derived from alternative splicing of a single gene, encoding proteins of 121, 145, 165, 189, and 206 amino acid residues. The isoforms differ in their degree of heparin-binding and sequestration in the extracellular matrix (ECM).
  • ECM extracellular matrix
  • VEGF also known as VEGF-A
  • VEGF-A belongs to a family of growth factors that includes placental growth factor (P1GF), VEGF-B, VEGF-C. VEGF-D, and VEGF-E.
  • VEGF is potent stimulator of angiogenesis, the formation of new capillaries from pre-existing blood vessels.
  • VEGF is an endothelial cell-specific mitogen and, further, VEGF induces non-proliferative endothelial cell activities involved in the angiogenic process, cell migration and invasion.
  • VEGF induces secretion of proteolytic enzymes which degrade the basement membrane and extracellular matrix, nitric oxide release, expression of adhesion molecules, and cell morphological changes.
  • VEGF acts as a survival factor for endothelial cells by inducing the expression of anti-apoptotic proteins.
  • VEGF is also a potent stimulator of vascular permeability.
  • VEGF vascular permeability factor
  • VEGF causes vascular leakage with a potency 50000 times that of histamine.
  • Excessive vascular peimeability may contribute to angiogenesis by enhancing protein extravasation, or it may represent a distinct factor in disease processes by leading to edema and swelling.
  • VEGF exerts its effects primarily via two endothelial receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).
  • VEGFR-1 and -2 are thought to mediate different signal transduction functions.
  • VEGFR-1 binds VEGF, VEGF-B, and PlGF;
  • VEGFR-2 binds VEGF, VEGF-C, VEGF-D, and VEGF-E.
  • VEGFR-1 shows higher affinity to VEGF. It is hypothesized that VEGFR-2, which is expressed almost exclusively in proliferating vessels, is responsible for driving endothelial cell angiogenic processes.
  • VEGFR-1 which is expressed in hematopoietic stem cells and inflammatory cells such as monocytes and macrophages in addition to endothelial cells, is believed to mediate the activation and recmitment of these cells in response to VEGF and P1GF.
  • VEGF vascular endothelial growth factor
  • tumour angiogenesis The critical role of tumour angiogenesis in the progression of cancer is well known. Neovascularization is necessary for the development of solid tumours beyond a few cubic millimetres in size as new blood vessels are required to provide oxygen and nutrients to the tumour cells; the new blood supply also allows tumour cells to enter the circulation and metastasize.
  • VEGF expression is markedly upregulated in tumours and VEGF receptors are upregulated on the tumour endothelium. Numerous studies have demonstrated a correlation between tumour vascularity and metastasis or patient prognosis.
  • angiogenesis has been reported to play a role in hematological disorders such as leukemias, lymphomas and myeloproliferative disorders, in which there is increased bone marrow vascularity and elevated levels of angiogenic factors.
  • VEGF vascular endothelial growth factor
  • Ischemic retinopathies such as diabetic retinopathy and retinopathy of prematurity, are leading causes of blindness in adults and children, respectively, in the developed world. These diseases are marked by retinal neovascularization. Increased levels of VEGF are found in the vitreous and retina of patients with diabetic retinopathy. VEGF is also increased in diabetic retinal tissue without overt retinopathy and so may also play a role in the early development of the disease by mediating breakdown of the blood-retinal barrier and increased retinal vascular permeability, leading to vessel leakage and macular edema.
  • choroidal neovascularization occurs which has been shown to involve overexpression of VEGF by retinal pigment epithelial cells and choroidal fibroblasts.
  • VEGF expression in rheumatoid synovial cells such as fibroblasts or activated leukocytes is involved in the angiogenic process in rheumatoid arthritis, and may also act as a vascular permeability factor, thus increasing edema and joint swelling.
  • Endometriosis is characterized by significant vascularization within and surrounding ectopic endometrial tissue.
  • a new blood supply is thought to be essential for the survival of the ectopic endometrial implant and the development of the disease.
  • VEGF and VEGF receptors Downregulation of VEGF and VEGF receptors occurs in psoriasis and other skin diseases. Increased circulating VEGF, seen in increased plasma VEGF levels, may cause systemic vascular hyperpermeability. Upregulated VEGF and VEGF receptors in the blister fluids and the lesional epidermis of patients with bullous diseases (bullous pemphigoid, eiythema multiforme and dermatitis herptiformis) suggests that VEGF is a factor in the development hyperpermeable dermal micro vessels and papillary edema.
  • bullous diseases bullous pemphigoid, eiythema multiforme and dermatitis herptiformis
  • VEGF vascular endothelial growth factor
  • atherosclerotic plaques and may be required for plaque progression.
  • Raised levels of VEGF which are expressed by neovascular endothelial cells, smooth muscle cells and inflammatory cells, are found in patients with arterial disease.
  • VEGF has been shown to increase atherosclerotic plaque formation and the numbers of macrophages, while inhibition of VEGFR-1 has been described as reducing atherosclerotic plaque growth through inhibition of inflammatoiy cell infiltration.
  • VEGF inhibitors may provide an effective treatment for these diseases and other diseases related to VEGF.
  • VEGF inhibitors are capable of inhibiting the activity of VEGF. While not wishing to be bound by any particular theory, the subject VEGF inhibitors are believed to antagonize VEGF by reducing the level of secretion of the active protein.
  • the invention relates to inhibition of secretion of VEGF.
  • the invention provides a method of inhibiting secretion of VEGF, in an animal in need of such inhibition, comprising administeiing to the animal an effective amount of a compound as disclosed herein.
  • the invention provides a method of inhibiting effects of VEGF, including angiogenesis, and a method of treating a disorder related to VEGF in an animal in need of such inhibition or treatment.
  • VEGF including angiogenesis
  • the -inimal is a human patient and the disorder is cancer, rheumatoid arthritis, retinopathy and atherosclerosis.
  • the invention relates to use of compounds disclosed herein to inhibit VEGF secretion or effects of VEGF or to treat a disorder related to VEGF.
  • the invention also relates to use of compounds disclosed herein to prepare a medicament to inhibit VEGF secretion, or effects of VEGF or to treat a disorder related to VEGF.
  • Figure 1 is a graph showing inhibition of VEGF secretion from HTB-133 (KDR+) and HTB-131 (KDR-) breast cancer cell lines by CR-4.
  • Figure 2 is a graph showing inhibition of VEGF secretion from breast cancer MDA-231 cell line by CR4.
  • Figure 3 is a graph showing inhibition of VEGF secretion from HTB-72 melanoma cell line by CR4.
  • Figure 4 is a graph showing inhibition of VEGF secretion from CR2- 1730 HUNEC cell line by CR4.
  • Figure 5 is a graph showing inhibition of HUNEC growth by CR-4 induced VEGF depleted media of HTB-133 (KDR+) and HTB-131 (KDR-) breast cancer cell lines and rescue by recombinant human VEGF (10 ng/ml).
  • Figure 6 is a graph showing inhibition of VEGF secretion from breast cancer cell lines HTB-133 and MDA-231 by CR11.
  • Figure 7 is a graph showing inhibition of VEGF secretion from breast cancer cell lines HTB-133 and MDA-231 by CR19.
  • VEGF activity inhibits certain compounds inhibit VEGF activity. These compounds inhibit, in a dose dependent manner, VEGF secretion from breast cancer cell lines, melanoma cell line and human umbilical vascular endothelial cell line. These compounds therefore provide a new therapeutic approach that target expression and secretion of VEGF.
  • VEGF vascular endothelial growth factor
  • CR4 by inhibiting secretion of VEGF, was found to inhibit endothelial cell proliferation.
  • CR4 when CR4 is added to breast cancer cell lines which normally secrete VEGF, the secretion of VEGF to the medium is inhibited and the medium is unable to stimulate proliferation of human umbilical vascular endothelial primary cells (these cells do not secrete detectable amount of NEGF).
  • the inhibition of endothelial cell growth is however rescued if recombinant NEGF is added to the medium, confirming that inhibition results from inhibition of NEGF secretion.
  • the inhibition of cell growth is also CR4 dose dependent, with an IC50 value of about 20 -30 nM.
  • the effective dose is therefore similar to that required for inhibition of VEGF secretion and further confirms that inhibition of cell growth results from inhibition of VEGF secretion.
  • VEGF vascular endothelial growth factor
  • VEGF is an essential part of normal embryonic development, repair, tissue regeneration, female reproductive cycle and other physiological processes
  • the effects of VEGF is associated with variety of disorders. In many of these disorders, VEGF expression/levels are upregulated.
  • the compounds therefore may also be used to treat these disorders.
  • VEGF plays a central role in angiogenesis (and vasculogenesis during embryonic development), the formation of new blood vessels, and it is known that angiogenesis is critical to growth and metastasis of tumour cells in the progression of cancer.
  • the compounds therefore may be used to treat cancer, including, by inhibiting tumour growth.
  • the invention therefore provides a method of inhibiting VEGF secretion comprising administering to an animal in need of such inhibition an effective amount of a compound as disclosed herein.
  • the invention also provides a method of inhibiting effects of NEGF in an animal in need of such inhibition.
  • effects of VEGF is used to refer to effects resulting from, or mediated by VEGF activity, including via its receptor(s), and include angiogenesis, vasculogenesis, aileriogenesis, vascular permeability, and inflammation.
  • inhibition or inhibiting or like terms are used to broadly refer to any reduction of targeted characteristic which is statistically significant when compared to a control (i.e., no administration of the compounds) as can be measured using techniques known in the art.
  • the animal may be a human patient suffering from disorders related to NEGF. It is meant by such disorders any disorder in which NEGF is believed to play a role in the progression or symptoms of the disorder or in which NEGF expression and/or levels are upregulated.
  • Cancers having VEGF-related components to the disease include: solid tumors cancers such as breast , pancreatic, colon and brain cancer, melanoma; hemangioma; Karposi's sarcoma; and hematological malignancy, including leukemia, lymphoproliferative disorders and myeloproliferative disorders.
  • the present invention may be used to treat animals and patients with aberrant angiogenesis, such as that contributing to a variety of diseases and disorders.
  • the most prevalent and/or clinically important of these, outside the field of cancer treatment, include arthritis (such as rheumatoid arthritis), psoriasis, atherosclerosis, disorders involving unwanted ocular vascularization, Grave's disease, vascular restenosis, including restenosis following angioplasty, arteriovenous malformations (AVM), renal vein occlusion, and neovascular glaucoma.
  • angiofibroma angiofibroma, atherosclerotic plaques, corneal graft neovascularization, hemophilic joints, hypeitrophic scars, osler-weber syndrome, pyogenic granuloma retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, various other inflammatory diseases and disorders, and even endometriosis.
  • Further diseases and disorders that are treatable by the invention, and the unifying basis of such angiogenic disorders, are set forth below.
  • VEGF vascular endothelial growth factor
  • BUC bucillamine
  • ocular neovascular disease is meant a disease characterized by ocular neovascularization, i.e. the development of abnormal blood vessels in the eye of a patient, and include comeal neovascularization.
  • diseases associated with ocular neovascularization that can be treated using the subject VEGF inhibitors include, but are not limited to, comeal neovascularization, retinal neovascularization, choroidal neovascularization, and include such disorders as retinopathy (such as diabetic, ischemic and/or retinopathy of prematurity), macular degeneration (such as age-related) , comeal graft rejection, neovascular glaucoma, retrolental fibroplasia, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical bums, bacterial ulcers, fungal ulcers, Herpes simplex infections
  • the subject VEGF inhibitors are used as part of a treatment for diseases associated with retinal/choroidal neovascularization, such as diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Pagets disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus eiythematosis, retinopathy of prematurity, Eales disease, Bechets disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Bests disease, myopia, optic pits, Stargarts disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications.
  • ocular disorders and diseases that can be treated according to the present invention include, but are not limited to, diseases associated with rubeosis or other iris neovascularization, and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy, whether or not associated with diabetes.
  • Other diseases include, but are not limited to, diseases associated with rubeosis (neovascularization of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy.
  • the subject VEGF inhibitors can be used alone or in combination with other therapeutic regimens directed to treating ocular diseases.
  • the present invention provides a method of treating an ocular neovascular disease which involves administering to a patient a NEGF inhibitor and treating the patient with phototherapy (e.g., PDT) or with other therapies, such as photocoagulation, that destroy abnormal blood vessels in the eye.
  • phototherapy e.g., PDT
  • other therapies such as photocoagulation
  • Chronic inflammation also involves pathological angiogenesis and can be treated with a program that includes the subject VEGF inhibitors.
  • Such disease states as ulcerative colitis and Crohn's disease show histological changes with the ingrowth of new blood vessels into the inflamed tissues.
  • Bartonellosis a bacterial infection found in South America, can result in a chronic stage that is characterized by proliferation of vascular- endothelial cells, and may be amenable to treatment including the subject VEGF inhibitors.
  • VEGF expression in human coronary atherosclerotic lesions has been demonstrated. This evidences the pathophysiological significance of VEGF in the progression of human coronary atherosclerosis, as well as in recanalization processes in obstructive coronary diseases.
  • the subject VEGF inhibitors can be used as part of an effective treatment for such conditions.
  • hemangioma One of the most frequent angiogenic diseases of childhood is the hemangioma. In most cases, the tumors are benign and regress without intervention. In more severe cases, the tumors progress to large cavernous and infiltrative forms and create clinical complications. Systemic forms of hemangiomas, the hemangiomatoses, have a high mortality rate. Therapy-resistant hemangiomas exist that cannot be treated with therapeutics cuirently in use. The subject VEGF inhibitors can be used in the treatment of hemangiomas.
  • Angiogenesis is also responsible for damage found in hereditary diseases such as Osier- Weber-Rendu disease, or hereditary hemo ⁇ agic telangiectasia. This is an inherited disease characterized by multiple small angiomas, tumors of blood or lymph vessels. The angiomas are found in the skin and mucous membranes, often accompanied by epistaxis (nosebleeds) or gastrointestinal bleeding and sometimes with pulmonary or hepatic arteriovenous fistula. The subject VEGF inhibitors can be used in the freatment of angiomas.
  • Angiogenesis is also involved in normal physiological processes such as reproduction and wound healing. Angiogenesis is an important step in ovulation and also in implantation of the blastula after fertilization. Prevention of angiogenesis with the subject NEGF inhibitors can be used to induce amenorrhea, to block ovulation or to prevent implantation by the blastula. [0051] In wound healing, excessive repair or fibroplasia can be a dehimental side effect of surgical procedures and may be caused or exacerbated by angiogenesis. Adhesions are a frequent complication of surgery and lead to problems such as small bowel obstruction. The subject VEGF inhibitors can be used post-operatively to influence wound healing processes.
  • Diseases and disorders characterized by undesirable vascular peimeability can also be freated by the present invention. These include edema associated with brain tumors, ascites associated with malignancies, Meigs' syndrome, lung inflammation, nephrotic syndrome, pericardial effusion and pleural effusion, as disclosed in WO 98/16551.
  • the invention provides a method of treating a disorder related to VEGF comprising administering an effective amount of a compound as disclosed herein to an animal in need of such treatment.
  • Compounds useful in the compositions and methods disclosed herein include compounds of Formula I, and salts, solvates or hydrates thereof:
  • R 1 and R 2 are each independently selected from H, OH, Ci- ⁇ alkyl, Ci- ⁇ alkoxy, NH ,
  • R' is selected from H, OH, C ⁇ - 6 alkyl, C ⁇ . 6 alkoxy, NH 2 , NH-C ⁇ - 6 alkyl, N(C ⁇ . 6 alkyl)(C : ealkyl), SH, S-C ⁇ - 6 alkyl, O-Si(C ⁇ .6alkyl)(C 1 - 6 alkyl)(C ⁇ . 6 alkyl), NO 2 , halo and CH 2 -S-(CH 2 ) n Ar;
  • X is selected from O, S, NH and N-C ⁇ . 6 alkyl;
  • R 5 is selected from NH 2 , OH, NH(CH 2 ) P Ar, NH(CH 2 ) P OH, (CH 2 ) p OC ⁇ . 6 alkyl, Ci-
  • Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents independently selected from OH, Ci- ⁇ alkyl, C ⁇ .6a_koxy, NH 2 , NH- Ci-ealkyl, N(C 1 - 6 a_kyl)(C ⁇ ;6 alkyl), SH, S-C ⁇ . 6 al yl, NO 2) CF 3 , OCF 3 and halo; n is 0 to 4; m is 1 to 4; and p is 1-4.
  • compounds of Formula I are those in which R 1 and R 2 are each independently selected from H, OH, Ci- ⁇ alkyl, C ⁇ . 6 alkoxy, NH 2 , NH-d-ealkyl, N(C ⁇ . 6 alkyl)(C 1 . 6 alkyl), SH, S-C ⁇ . 6 alkyl, O-Si(C ⁇ - 6 alkyl)(C ⁇ . 6 alkyl)(Ci.6alkyl), NO 2 , CF 3 , OCF 3 and halo.
  • R 1 and R 2 are each independently selected from H, OH, C ⁇ . alkyl, C ⁇ - alkoxy, NH 2 , NH-Ci.
  • R 1 and R 2 are each independently selected from H, OH, OCH 3 , 0-Si(CH 3 ) 2 ( t Bu), S-Me, SH, and NO 2 .
  • R 1 and R 2 are both OH or OCH 3 or R 1 is OCH 3 and R 2 is OH.
  • the compounds of Formula I include those in which R 3 is selected from H, OH, C ⁇ . 6 alkyl, Ci- ⁇ alkoxy, NH 2 , NH-Ci-ealkyl, N Ci-ealkylX -ealkyl), SH, S- -salkyl, O-Si(C ⁇ - 6 alkyl)(C ⁇ . 6 alkyl)(C ⁇ . 6 alkyl), NO 2 , halo and CH 2 -S-(CH 2 ) n Ar (where n is 0-4).
  • R 3 is selected from H, OH, C ⁇ - alkyl, C ⁇ . alkoxy, NH 2 , NH-C ⁇ .
  • R 3 is selected from H, OH, OCH , SH, SMe, NO 2 and halo. In the most preferred embodiment, R 3 is selected from H, OH and OCH 3 .
  • embodiments of the invention include compounds where X is selected from O,S, NH and N-Ci- ⁇ alkyl and R 5 is selected fromNHz, OH, NH(CH 2 ) p Ar, NH(CH 2 ) p OH, (CH 2 )pOC ⁇ . 6 alkyl, C ⁇ . 6 alkyl, C ⁇ . 6 alkoxy, NHNH 2 , NHC(O)NH 2 , NHC(O)C ⁇ - 6 alkoxy, N-moipholino and N-pyn-olidino (where p is 1-4).
  • X is O or S and R 5 is selected from NH 2 , OH, NH(CH 2 ) p Ar, (CH 2 ) p OH and C ⁇ . alkoxy, (where p is 1-3).
  • R 5 is selected from NH 2 , OH, NH(CH 2 ) p Ar, NH(CH 2 ) p OH and OCH 3 , (where p is 1-2).
  • Suitable compounds include compounds of Formula I wherein the term "Ar” means an unsubstituted or substituted aryl and/or heteroaryl group which, in the case of heteroaryl, may contain up to two heteroatoms, wherein the optional substituents are independently selected from OH, C ⁇ - 6 alkyl, Ci- ⁇ alkoxy, NH 2 , NH-Ci- 6 alkyl, N(C ⁇ . 6 alkyl)(C ⁇ . 6 alkyl), SH, S-C ⁇ .
  • Ar means an unsubstituted or substituted aryl and/or heteroaryl group which, in the case of heteroaryl, may contain up to two heteroatoms, wherein the optional substituents are independently selected from OH, C ⁇ - 6 alkyl, Ci- ⁇ alkoxy, NH 2 , NH-Ci- 6 alkyl, N(C ⁇ . 6 alkyl)(C ⁇ . 6 alkyl), SH, S-C ⁇ .
  • Ar is an unsubstituted phenyl group or a phenyl group substituted with 1-4 substituents optionally selected from OH, C ⁇ . 6 alkyl, C ⁇ . 6 al oxy, NH 2 , NH-C ⁇ . 6 alkyl, N(C ⁇ . 6 alkyl)(C ⁇ . 6 alkyl), SH, S-Ci. ⁇ alkyl, NO 2 , CF , OCF 3 and halo.
  • Ar is an unsubstituted phenyl group or phenyl group substituted with 1-2 substituents optionally selected from OH, C ⁇ . 4 alkyl, C ⁇ . 4 alkoxy, NH 2 , NH-C ⁇ . 4 alkyl, N(C ⁇ . 4 alkyl)(C ⁇ . 4 alkyl), SH, S- C ⁇ . 4 alkyl, NO 2 , CF 3 , OCF 3 and halo.
  • Ar is an unsubstituted phenyl group or phenyl group substituted with 1-2 substituents optionally selected from OH, OCH 3 , NH 2 , NHCH 3j N(CH 3 ) 2) SH, SCH 3 , CF 3 , OCF 3 and halo.
  • Ar is selected from phenyl and 3,4- dihydroxyphenyl.
  • compositions and methods disclosed herein include compounds of Formula II and salts, solvates and hydrates thereof: wherein
  • R 1 and R 2 are each independently selected from H, OH, Ci-ealkyl, Ci- ⁇ alkoxy, NH 2 ,
  • R 3 is selected from H, OH, Ci-ealkyl, Ci-ealkoxy, NH 2 , NH-Ci. 6 alkyl, N(C ⁇ -ealkyl)(C ⁇ . ealkyl), SH, S-C ⁇ . 6 alkyl, O-Si(C ⁇ .ealkyl)(C ⁇ . 6 alkyl)(C ⁇ .6alkyl), NO 2 , halo and
  • Ar is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from OH, Ci- ⁇ alkyl, Ci-ealkoxy, NH 2 ,
  • NH-C ⁇ . 6 alkyl N(C ⁇ - 6 alkyl)(C ⁇ . 6 alkyl), SH, S-C ⁇ . 6 allcyl, NO 2 , CF 3 , OCF 3 and halo;
  • R 6 is selected from Ar, OH and OCi- ⁇ alkyl;
  • X is selected from O and S;
  • n is 0-4; and
  • p is 1-4.
  • compounds of Formula II are those in wliich R 1 and R 2 are each independently selected from H, OH, Ci- ⁇ alkyl, C ⁇ -6alkoxy, NH 2j NH-C ⁇ . 6 alkyl, N(C ⁇ -6alkyl)(C ⁇ . 6 alkyl), SH, S-C ⁇ - 6 alkyl, O-Si(C ⁇ . 6 alkyl)(C ⁇ . 6 alkyl)(C ⁇ - 6 alkyl), NO 2 , CF 3 , OCF 3 and halo.
  • R 1 and R 2 are each independently selected from H, OH, C ⁇ . 4 alkyl, C ⁇ . alkoxy, NH 2 , NH-Ci.
  • R 1 and R 2 are each independently selected from H, OH, OCH 3 , 0-Si(CH 3 ) 2 ('Bu), S-Me, SH, and NO 2 .
  • R 1 and R 2 are both OH or OCH 3 or R 1 is OCH 3 and R 2 is OH.
  • the compounds of Formula II include those in which R 3 is selected from H, OH, Ci- ⁇ alkyl, Ci-ealkoxy, NH 2 , NH-Ci-ealkyl, N(C ⁇ . 6 alkyl)(C ⁇ . 6 alkyl), SH, S-C ⁇ _ 6 alkyl, O-Si(C ⁇ -ealkyl)(C ⁇ . ealkyl)(C ⁇ .6alkyl), NO 2 , halo and CH 2 -S-(CH 2 ) n Ar (where n is 0-4).
  • R 3 is selected from H, OH, C ⁇ . alkyl, C ⁇ .
  • R 3 is selected from H, OH, OCH , SH, SMe, NO 2 , and halo. In the most preferred embodiment, R 3 is selected from H, OH and OCH 3 .
  • Suitable compounds include compounds of Formula II wherein the term "Ar” means an unsubstituted or substituted aryl and heteroaryl group which, in the case of heteroaryl, may contain up to two heteroatoms, wherein the optional substituents are independently selected from OH, Ci- ⁇ alkyl, Ci-ealkoxy, NH 2 , NH-Cj.
  • eal yl N(C 1 .ealkyl)(C ⁇ .ealkyl), SH, S-C ⁇ - 6 alkyl, NO 2 , CF 3 , OCF 3 and halo, and includes unsubstituted or substituted phenyl, furyl, thienyl, indolyl, naphthyl, quinolyl and the like.
  • Ar is an unsubstituted phenyl group or a phenyl group substituted with 1-4 substituents optionally selected from OH, C ⁇ .
  • Ar is an unsubstituted phenyl group or phenyl group substituted with 1-2 substituents optionally selected from OH, C ⁇ - 4 alkyl, C ⁇ - 4 alkoxy, NH 2 , NH-C ⁇ - 4 alkyl, N(C ⁇ . alkyl)(C ⁇ .
  • Ar is an unsubstituted phenyl group or phenyl group substituted with 1-2 substituents optionally selected from OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2> SH, SCH 3 , CF 3 , OCF 3 and halo.
  • Ar is selected from phenyl and 3,4- dihydroxyphenyl.
  • the compounds of Formula II include those in which R 6 is selected from Ar, OH and OC ⁇ -6alkyl and p is 1-4.
  • R 6 is selected from Ar and OH and p is 1-2.
  • R 6 is Ar
  • p is 1 and when R 6 is OH, p is 2.
  • Ar means an unsubstituted or substituted aryl and/or heteroaryl group wliich, in the case of heteroaryl, may contain up to two heteroatoms, wherein the optional substituents are independently selected from OH, C ⁇ .
  • Ci-ealkoxy NH 2 , NH-Ci.ealkyl, N(C ⁇ - 6 alkyl)(C ⁇ .ealkyl), SH, S-Ci-ealkyl, NO 2 , CF 3 , OCF 3 and halo, and includes unsubstituted or substituted phenyl, furyl, thienyl, indolyl, naphthyl, quinolyl and the like.
  • Ar is an unsubstituted phenyl group or a phenyl group substituted with 1-4 substituents optionally selected from OH, Ci- ⁇ alkyl, Ci-ealkoxy, NH 2 , NH-C ⁇ _6_tlkyl, N(C ⁇ - 6 alkyl)(C ⁇ .ealkyl), SH, S-C ⁇ . 6 alkyl, NO 2 , CF 3 , OCF 3 and halo.
  • Ar is an unsubstituted phenyl group or phenyl group substituted with 1- 2 substituents optionally selected from OH, C ⁇ - 4 alkyl, C ⁇ . alkoxy, NH 2 , NH-C ⁇ .
  • Ar is an unsubstituted phenyl group or phenyl group substituted with 1- 2 substituents optionally selected from OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2( SH, SCH 3 , CF 3 , OCF 3 and halo.
  • Ar is selected from phenyl and 3,4-dihydroxyphenyl.
  • Compounds of Formula II further include those in which X is selected from O and S. In preferred embodiments, X is O.
  • Compounds useful in the compositions and methods disclosed herein include compounds of Formula III and salts, solvates and hydrates thereof:
  • R 1 and R 2 are each independently selected from H, OH, Ci- ⁇ alkyl, Ci-ealkoxy, NH 2 ,
  • R 3 is selected from H, OH, C ⁇ . 6 alkyl, Ci. 6 alkoxy, NH 2 , NH-Ci-ealJ yl, N(C ⁇ . 6 alkyl)(C ⁇ ealkyl), SH, S-Ci-ealkyl, O-Si(C ⁇ -6alkyl)(C ⁇ .6alkyl)(C ⁇ .ealkyl), NO 2) halo and
  • Ai is an aromatic or heteroaromatic group, unsubstituted or substituted with 1-4 substituents, independently selected from OH, Ci-ealkyl, Ci-ealkoxy, NH 2 , NH-Ci-ealkyl, N(C ⁇ - 6 alkyl)(C ⁇ .ealkyl), SH,
  • R 7 is selected from OH, NH 2 and OC ⁇ . 6 alkyl
  • X is selected from O and S; and n is 0-4.
  • compounds of Formula HI are those in which R 1 and R 2 are each independently selected from H, OH, Ci-ealkyl, Ci-ealkoxy, NH 2 , NH-C ⁇ .ealkyl, N(C ⁇ -6alkyl)(C ⁇ . 6 alkyl), SH, S-d. 6 alkyl, O-Si(C ⁇ . 6 alkyl)(C ⁇ . 6alkyl)(C ⁇ -6alkyl), NO 2 , CF 3 , OCF 3 and halo.
  • R 1 and R 2 are each independently selected from H, OH, C ⁇ . 4 alkyl, C ⁇ . alkoxy, NH 2 , NH-Ci.
  • R 1 and R 2 are each independently selected from H, OH, OCH 3 , O-Si(CH 3 ) 2 ( t Bu), S-Me, SH, andNO 2 .
  • R 1 and R 2 are both OH or OCH 3 or R 1 is OCH 3 and R 2 is OH.
  • the compounds of Formula DI include those in which R 3 is selected from H, OH, Ci- ⁇ alkyl, Ci-ealkoxy, NH 2 , NH-Ci. 6 a]_kyl, N(Ci. 6 alkyl)(Ci.ealkyl), SH, S-Ci-ealkyl, O-Si(C ⁇ -ealkyl)(C ⁇ . ealkyl)(C ⁇ . 6 alkyl), NO 2 , halo and CH 2 -S-(CH 2 ) a Ar (where n is 0-4).
  • R 3 is selected from H, OH, C ⁇ .
  • R 3 is selected from H, OH, OCH 3 , SH, SMe, NO 2 , and halo. In the most preferred embodiment, R 3 is selected from H, OH and OCH 3 .
  • the present invention further contemplates compounds of Formula in wherein the term "Ar” means an unsubstituted or substituted aryl and/or heteroaryl group which, in the case of heteroaryl, may contain up to two heteroatoms, wherein the optional substituents are independently selected from OH, Ci-ealkyl, Ci-ealkoxy, NH 2 , NH-d-ealkyl, N(C ⁇ . 6 alkyl)(C ⁇ .6alkyl), SH, S-C ⁇ .
  • Ar means an unsubstituted or substituted aryl and/or heteroaryl group which, in the case of heteroaryl, may contain up to two heteroatoms, wherein the optional substituents are independently selected from OH, Ci-ealkyl, Ci-ealkoxy, NH 2 , NH-d-ealkyl, N(C ⁇ . 6 alkyl)(C ⁇ .6alkyl), SH, S-C ⁇ .
  • Ar is an unsubstituted phenyl group or a phenyl group substituted with 1-4 substituents optionally selected from OH, Ci-ealkyl, Ci-ealkoxy, NH 2 , NH-Ci. 6 alkyl, N(C- ⁇ - 6alkyl)(C ⁇ . 6 alkyl). SH, S-C ⁇ . 6 alkyl, NO 2 , CF 3 , OCF 3 and halo.
  • Ar is an unsubstituted phenyl group or phenyl group substituted with 1- 2 substituents optionally selected from OH, C ⁇ - 4 alkyl, C ⁇ . 4 alkoxy, NH 2 , NH-C ⁇ . alkyl, N(C ⁇ - 4 alkyl)(C ⁇ . 4 alkyl), SH, S-C ⁇ . 4 alkyl, NO 2 , CF 3 , OCF 3 and halo.
  • Ar is an unsubstituted phenyl group or phenyl group substituted with 1- 2 substituents optionally selected from OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2) SH, SCH 3 , CF 3 , OCF 3 and halo.
  • Ar is selected from phenyl and 3,4-dihydroxyphenyl.
  • Compounds of Formula DI further include those in which R 7 is selected from OH, NH 2 and OCi- ⁇ alkyl. In prefeired embodiments, R 7 is selected from OH and NH 2 .
  • Compounds of Formula DI further include those in which X is selected from O and S. In preferred embodiments, X is O.
  • suitable compounds include:
  • Additional compounds useful in the compositions and methods disclosed herein include compounds of Formula IV, and salts, solvates or hydrates thereof:
  • R 1 , R 2 and R 3 are each independently selected from H, OH, Ci-ealkyl, Ci-ealkoxy,
  • R 4 is unsubstituted Ar, or Ar substituted with 1-4 substituents, independently selected from C ⁇ . 6 alkyl, Ci-ealkoxy and halo;
  • compounds of Formula IV are those in which R 1 , R 2 and R 3 are each independently selected from H, OH, C ⁇ -6alkyl, d. ealkoxy, NH 2 , NH-Ci-ealkyl, N(C ⁇ . 6 alkyl)(C ⁇ .ealkyl), SH, S-Ci-ealkyl, NO 2 , CF 3 , OCF 3 and halo.
  • R 1 , R 2 and R 3 are each independently selected from H, OH, C ⁇ . 4 alkyl, C ⁇ - alkoxy, NH 2 , NH-d. 4 alkyl, N(C ⁇ . 4 alkyl)(C ⁇ .
  • R 1 , R 2 and R 3 are each independently selected from H, OH, OCH 3 , NH 2 , N(CH 3 ) 2 , andNO 2 . In the most prefeired embodiments, R 1 , R 2 and R 3 are each independently selected from H, OH and OCH 3 .
  • R 4 is Ar.
  • R 4 is unsubstituted Ar.
  • R 4 is phenyl.
  • n is 1-3; most preferably n is 1.
  • compounds of Formula IN include those in which at least one of R 1 , R 2 and R 3 is OH, more preferably at least two of R 1 , R 2 and R 3 are OH, while R 4 is Ar and n is 1-3.
  • Compounds useful in the compositions and methods disclosed herein include compounds of Foimula N and salts, solvates and hydrates thereof:
  • R , R , R are each independently selected from H, OH, Ci. 6 alkyl, Ci-ealkoxy, ⁇ H 2 , NH-Ci-ealkyl, N(C ⁇ .6alkyl)(C ⁇ . 6 alkyl), SH, S-Ci-ealkyl, NO 2 , CF 3 , OCF 3 and halo;
  • compounds of Formula V are those in which R 1 , R 2 and R 3 are each independently selected from H, OH, C ⁇ . 6 alkyl, C ⁇ _ ealkoxy, NH 2 , NH-Ci-ealkyl, N(d.6alkyl)(C ⁇ . 6 allcyl), SH, S-Ci. 6 alkyl, NO 2 , CF 3 , OCF 3 and halo.
  • R 1 , R 2 and R 3 are each independently selected from H, OH, d. 4 alkyl, C ⁇ . 4 alkoxy, NH 2 , H-C ⁇ _4alkyl, N(C ⁇ - 4 alkyl)(C ⁇ .
  • R 1 , R 2 and R 3 are each independently selected from H, OH, OCH 3 , NH 2 , N(CH 3 ) 2 , andNO 2 . In the most preferred embodiments, R 1 , R 2 and R 3 are each independently selected from H, OH and OCH 3 .
  • R 4 is Ci- ⁇ alkyl.
  • R 4 is methyl or ethyl. Most preferably, R 4 is methyl.
  • n in 1-4 Preferably, n is 2-3; most preferably, n is 3.
  • compounds useful in the compositions and methods disclosed herein include compounds of Foimula VI, and salts, solvates or hydrates thereof:
  • R 1 , R 2 andR 3 are each independently selected from H, OH, Ci- ⁇ alkyl, Ci-ealkoxy,
  • R 4 is selected from Ci-ealkyl, phenyl and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with 1-4 substituents, independently selected from
  • Ci-ealkyl Ci-ealkoxy and halo.
  • compounds of Formula NI are those in which R 1 , R 2 and R 3 are each independently selected from H, OH, Ci- ⁇ alkyl, Ci. ealkoxy, ⁇ H 2 , NH-Ci-ealkyl, N(C ⁇ - 6 alkyl)(C ⁇ .ealkyl), SH, S-Ci-ealkyl, NO 2 , CF 3 , OCF 3 and halo.
  • R 1 , R 2 and R 3 are each independently selected from H, OH, d. 4 alkyl, C ⁇ . 4 alkoxy, NH 2 , NH-C ⁇ - 4 alkyl, N(C ⁇ .
  • R 1 , R 2 and R 3 are each independently selected from H, OH, OCH 3 , NH 2 , N(CH 3 ) 2 , N(CH 3 ) 2 andNO 2 .
  • R 1 , R 2 and R 3 are each independently selected fiOm H, OH and OCH .
  • R 4 is selected from Ci- ⁇ alkyl, phenyl and pyiidyl, wherein phenyl and pyridyl are unsubstituted or substituted with 1-4 substituents, independently selected from Ci- ⁇ alkyl, Ci-ealkoxy and halo.
  • R 4 is selected from C ⁇ -4alkyl, phenyl and pyridyl, wherein phenyl and pyridyl are unsubstituted or substituted with 1-3 substituents, independently selected from Ci. 4 alkyl, C ⁇ - 4 alkoxy and halo.
  • R 4 is selected from CH 3 and phenyl, wherein phenyl is unsubstituted or substituted with 1-2 substituents, independently selected from C ⁇ _ 4 alkyl, d ⁇ alkoxy and halo. In the most preferred embodiment, R 4 is unsubstituted phenyl.
  • compounds of Foimula IV include those in which at least one of R 1 , R 2 and R 3 is OH, more preferably at least two of R 1 , R 2 and R 3 are OH, while R 4 is selected from unsubstituted phenyl and phenyl substituted with 1-4 substituents, independently selected from d. 6 alkyl, C ⁇ .6alkoxy and halo.
  • contemplated compounds include:
  • the present invention also contemplates the use of prodrugs of the compounds described above.
  • prodmgs will be functional derivatives of a compound of the invention which are readily convertible in vivo into the compound from which it is notionally derived.
  • Conventional procedures for the selection and preparation of suitable prodmgs are described, for example, in "Design of Prodmgs" ed. H. Bundgaard, Elsevier, 1985.
  • the present invention also contemplates using radiolabeled forms of compounds of the invention, for example, compounds of the invention labeled by incorporation within the structure 3 H or 14 C or a radioactive halogen such as 125 I.
  • the compounds may be used in the foim of the free base, or in other forms such as salts, prodrugs, solvates, and hydrates, and reference to the formulae provided herein, and CR4, CR11, and CR19 specifically, are intended to encompass all such forms of the compound.
  • the acids which can be used to prepare acid addition salts are those which produce, when combined with the compound, pharmaceutically acceptable salts; that is, salts whose anions are non-toxic to the animal in pharmaceutical doses of the salts, so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions.
  • Pharmaceutically acceptable salts include those derived from the following acids; mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexy sulfamic acid, quinic acid, and the like.
  • basic addition salt may be prepared using an inorganic base such as lithium, sodium, potassium, calcium, magnesium or barium hydroxide.
  • inorganic base such as lithium, sodium, potassium, calcium, magnesium or barium hydroxide.
  • organic bases which foim suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia.
  • Prodmgs of the compounds may be conventional esters formed with available hydroxy, amino or carboxyl group on the compound.
  • an OH group may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. and acid chloride in pyridine).
  • Some common esters which have been utilized as prodmgs are phenyl esters, aliphatic (C 8 -C 2 4) esters, acyloxymethyl esters, carbamates and amino acid esters. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodmgs" ed. H. Bundagaard, Elsevier, 1985.
  • a "solvate” is formed when a suitable solvent are incorporated in the crystal lattice of the compound or salt thereof.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a "hydrate”.
  • Methods to prepare a solvate are known in the art. In general, solvates are prepared by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvent is typically dried or azeotroped under ambient conditions.
  • the compounds may be administered alone or in combination with a phaimaceutically acceptable carrier, the proportion of which is deteimined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
  • the compounds are formulated into pharmaceutical compositions in a biologically compatible foim suitable for administration in vivo. Accordingly, in one embodiment, one or more compounds as described above are administered to a human patient in combination with a phaimaceutically acceptable carrier.
  • compositions containing the compounds can be prepared by known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of the active substance is combined in a mixture with a phaimaceutically acceptable vehicle.
  • Suitable vehicles are described, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985).
  • the compositions include, albeit not exclusively, solutions of the substances in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffer solutions with a suitable pH and iso-osmotic with the physiological fluids.
  • compositions of the invention may be administered orally or parenterally.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonaiy, intrathecal, rectal and topical modes of administration.
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • the compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the compound of the invention may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.
  • the compounds may also be administered parenterally or intraperitoneally .
  • Solutions of a compound can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • a person skilled in the art would know how to prepare suitable formulations. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (1990 - 18 th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • the pharmaceutical foims suitable for injectable use include sterile aqueous solutions or dispersion and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringeability exists.
  • An effective amount of the compounds refers to the amount sufficient to inhibit secretion or effects of VEGF, or in the case of treatment of a disorder related to VEGF, the amount sufficient to alleviate, improve, mitigate, ameliorate or cure the disorder or one or more symptoms of the disorder.
  • the clinical effects resulting from inhibition of VEGF secretion or effects of VEGF or treatment of a disorder related to VEGF may be assessed in the known manner, for example, in the case of effect on tumour growth, by tumour shrinkage.
  • the effective amount can vary depending on many factors such as the phaimacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the animal to be treated.
  • One of skill in the ait can deteimine the appropriate dosage based on the above factors.
  • the compounds may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.
  • the compounds may be packaged as a kit and the invention in one aspect provides a kit or packaged pharmaceutical comprising one or more compounds as disclosed above and instructions or label for use of the compound, including to inhibit secretion or effects of VEGF or to treat a disorder related to VEGF.
  • the VEGF inhibitors may be provided in sustained release compositions, such as those described in, for example, U.S. Patent Nos. 5,672,659 and 5,595,760.
  • sustained release compositions such as those described in, for example, U.S. Patent Nos. 5,672,659 and 5,595,760.
  • immediate or sustained release compositions depends on the nature of the condition being treated. If the condition consists of an acute or over- acute disorder, treatment with an immediate release foim will be preferred over a prolonged release composition. Alternatively, for certain preventative or long-term treatments, a sustained released composition may be appropriate.
  • the VEGF inhibitor may also be delivered using an intraocular implant.
  • Such implants may be biodegradable and/or biocompatible implants, or may be non-biodegradable implants.
  • the implants may be permeable or impermeable to the active agent, and may be inserted into a chamber of the eye, such as the anterior or posterior chambers or may be implanted in the sclera, transchoroidal space, or an avascularized region exterior to the vitreous.
  • the implant may be positioned over an avascular region, such as on the sclera, so as to allow for transcleral diffusion of the drug to the desired site of treatment, e.g. the intraocular space and macula of the eye.
  • the site of transcleral diffusion is preferably in proximity to the macula.
  • implants for delivery of a VEGF inhibitor include, but are not limited to, the devices described in U.S. Patent Nos. 3,416,530; 3,828,777; 4,014,335; 4,300,557; 4,327,725; 4,853,224; 4,946,450; 4,997,652; 5,147,647; 5,164,188; 5,178,635; 5,300,114; 5,322,691; 5,403,901; 5,443,505; 5,466,466; 5,476,511; 5,516,522; 5,632,984; 5,679,666; 5,710,165; 5,725,493; 5,743,274; 5,766,242; 5,766,619; 5,770,592; 5,773,019; 5,824,072; 5,824,073; 5,830,173; 5,836,935; 5,869,079, 5,902,598; 5,904,144; 5,916,584; 6,001,386; 6,074,661
  • the present invention provides a system comprising a coated medical device, the coating of which is suitable for sustained release of the subject NEGF inhibitor in the locality of the implanted device.
  • a coated medical device the coating of which is suitable for sustained release of the subject NEGF inhibitor in the locality of the implanted device.
  • Exemplary embodiments are described using an intraluminal medical device, particularly a stent, but the inventive system is also readily applicable to and advantageous in other forms of medical devices.
  • the system remains in the body and serves as a continuous source of the NEGF inhibitor to the affected area.
  • the system according to the present invention permits prolonged release of VEGF inhibitor(s) over a specific period of days, weeks, months (e.g., about 3 months to about 6 months) or years (e.g., about 1 year to about 20 years, such as from about 5 years to about 10 years) until the drug reservoir is used up.
  • the present invention provides an intraluminal medical device for implantation into a lumen of a blood vessel, in particular adjacent an intraluminal lesion such as an atherosclerotic lesion, for maintaining patency of the vessel.
  • the present invention provides an elongate radially expandable tubular stent having an interior luminal surface and an opposite exterior surface extending along a longitudinal stent axis, the stent having a coating on at least a portion of the interior or exterior surface thereof.
  • the local delivery of VEGF inhibitor from a stent has the following advantages; namely, the prevention of vessel recoil and remodeling through the scaffolding action of the stent and the prevention of multiple components of neointimal hyperplasia or restenosis as well as a reduction in inflammation and thrombosis.
  • This local administration of VEGF inhibitors to stented coronary arteries may also have additional therapeutic benefit.
  • higher tissue concentrations of the NEGF inhibitor may be achieved utilizing local delivery, rather than systemic administration.
  • reduced systemic toxicity may be achieved utilizing local delivery rather than systemic administration while maintaining higher tissue concentrations.
  • a single procedure may suffice with better patient compliance.
  • the polymer in which a sustained release VEGF inhibitor formulation is suspended or dispersed is coated onto a surgical implement such as surgical tubing (such as colostomy, peritoneal lavage, catheter, and intravenous tubing).
  • a surgical implement such as surgical tubing (such as colostomy, peritoneal lavage, catheter, and intravenous tubing).
  • the device is an intravenous needle having the polymer and a corticosteroid (or codmg or prodrug thereof) coated thereon.
  • a stent is commonly used as a tubular structure left inside the lumen of a duct to relieve an obstruction.
  • stents are inserted into the lumen in a non-expanded form and are then expanded autonomously, or with the aid of a second device in situ.
  • a typical method of expansion occurs through the use of a catheter- mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen.
  • the stents of the present invention may be fabricated utilizing any number of methods.
  • the stent may be fabricated from a hollow or formed stainless steel tube that may be machined using lasers, electric discharge milling, chemical etching or other means.
  • the stent is inserted into the body and placed at the desired site in an unexpanded form.
  • expansion may be effected in a blood vessel by a balloon catheter, where the final diameter of the stent is a function of the diameter of the balloon catheter used.
  • a stent in accordance with the present invention may be embodied in a shape-memory material, including, for example, an appropriate alloy of nickel and titanium or stainless steel.
  • Structures formed from stainless steel may be made self-expanding by configuring the stainless steel in a predetermined manner, for example, by twisting it into a braided configuration.
  • the stent after the stent has been formed it may be compressed so as to occupy a space sufficiently small as to permit its insertion in a blood vessel or other tissue by insertion means, wherein the insertion means include a suitable catheter, or flexible rod.
  • the stent On emerging from the catheter, the stent may be configured to expand into the desired configuration where the expansion is automatic or triggered by a change in pressure, temperature or electrical stimulation.
  • the sustained releaseNEGF inhibitor formulation applied with enough specificity and a sufficient concentration to provide an effective dosage in the lesion area.
  • the "reservoir size" in the coating is preferably sized to adequately apply the VEGF inhibitor formulation at the desired location and in the desired amount and for a sustained period of time.
  • Various embodiments of this invention comprise polymers with varied physical characteristics.
  • the system comprises a polymer that is relatively rigid.
  • the system comprises a polymer that is soft and malleable.
  • the system includes a polymer that has an adhesive character. Hardness, elasticity, adhesive, and other characteristics of the polymer may be varied as necessary.
  • Any number of bioerodible or non-erodible polymers may be utilized in conjunction with the VEGF inhibitors. Polymers may be advantageously selected from among those which reduce the rate of diffusion of the VEGF inhibitor. Polymers that can be used for coatings in this application can be absorbable or non- absorbable and must be biocompatible to minimize irritation to the vessel wall.
  • the polymer may be either biostable or bioabsorbable depending on the desired rate of release or the desired degree of polymer stability, but a bioabsorbable polymer may be prefen-ed since, unlike biostable polymer, it will not be present long after implantation to cause any adverse, chronic local response.
  • the polymer coating is permeable to water in the surrounding tissue, e.g. in blood plasma.
  • water solution may permeate the polymer, thereby contacting the VEGF inhibitor.
  • the rate of dissolution may be governed by a complex set of variables, such as the polymer's permeability, the solubility of the VEGF inhibitor, the pH, ionic strength, and protein composition, etc. of the physiologic fluid. In certain embodiments, however the peimeability may be adjusted so that the rate of dissolution is governed primarily, or in some cases practically entirely, by the solubility of the VEGF inhibitor in the ambient liquid phase.
  • the NEGF inhibitor may have a high solubility in the surrounding fluid.
  • the matrix peimeability may be adjusted so that the rate of dissolution is governed primarily, or in some cases practically entirely, by the peimeability of the polymer.
  • Suitable bioerodible and bioabsorbable polymers that could be used include polymers selected from the group consisting of aliphatic polyesters, poly(amino acids), copoly (ether-esters), polyalkylenes oxalates, polyamides, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amido groups, poly(anhydrides), polyphosphazenes, biomolecules and blends thereof.
  • aliphatic polyesters include homopolymers and copolymers of lactide (which includes lactic acid d-,1- and meso lactide), E-caprolactone, glycolide (including glycolic acid), hydroxybutyrate, hydroxy valerate, para-dioxanone, trimethylene carbonate (and its alkyl derivatives), 1 ,4-dioxepan-2-one, l,5-dioxepan-2-one, 6,6-dimethyl-l,4-dioxan- 2-one and polymer blends thereof.
  • lactide which includes lactic acid d-,1- and meso lactide
  • E-caprolactone glycolide (including glycolic acid)
  • glycolide including glycolic acid
  • hydroxybutyrate hydroxy valerate
  • para-dioxanone trimethylene carbonate (and its alkyl derivatives)
  • 1 ,4-dioxepan-2-one l,5-dio
  • Poly(iminocarbonate) for the purpose of this invention include as described by Kemnitzer and Kohn, in the Handbook of Biodegradable Polymers, edited by Domb, Kost and Wisemen, Hardwood Academic Press, 1997, pages 251-272.
  • Copoly(ether-esters) for the purpose of this invention include those copolyester-ethers described in Journal of Biomaterials Research, Vol. 22, pages 993-1009, 1988 by Cohn and Younes and Cohn, Polymer Preprints (ACS Division of Polymer Chemistry) Vol. 30(1), page 498, 1989 (e.g. PEO/PLA).
  • Polyalkylene oxalates for the purpose of this invention include U.S. Pat. Nos.
  • Polyoxaesters polyoxaamides and polyoxaesters containing amines and/or amido groups are described in one or more of the following U.S. Pat. ⁇ os. 5,464,929; 5,595,751; 5,597,579; 5,607,687; 5,618,552; 5,620,698; 5,645,850; 5,648,088; 5,698,213 and 5,700,583; (which are incorporated herein by reference).
  • Polyorthoesters such as those described by Heller in Handbook of Biodegradable Polymers, edited by Domb, Kost and Wisemen, Hardwood Academic Press, 1997, pages 99-118 (hereby incorporated herein by reference).
  • suitable polymers include naturally occurring or synthetic materials that are biologically compatible with bodily fluid and mammalian tissues.
  • Polymeric biomolecules for the purpose of this invention include naturally occurring materials that may be enzymatically degraded in the human body or are hydiOlytically unstable in the human body such as fibrin, fibrinogen, collagen, elastin, and absorbable biocompatible polys accharides such as chitosan, starch, fatty acids (and esters thereof), glucoso-glycans and hyaluronic acid.
  • the NEGF inhibitor can also be administered in combination with any other method of freatment of the paiticular disorder.
  • the NEGF inhibitor can be administered in combination with one or more suitable adjuvants, such as, e.g., cytokines or other immune stimulators.
  • the NEGF inhibitor is administered with an anti-inflammatory drug, such as an ⁇ SAIDs or other agent that exerts anti-inflammatory, analgesic and antipyretic activity.
  • salicylates such as aspirin, sodium salicylate, choline salicylate, salicylsalicylic acid, diflunisal, aloxiprine, lysine-acetyl salicylate, benorilate, calcium carcasalate, and salsalate
  • indoleacetic acids such as indomethacin and proglumethacin
  • aryl-acetic acids such as bufexamac, diclofenac, tolmetin and sulindac
  • pyrazoles such as phenylbutazone, oxyphenbutazone
  • pyrrolealkanoic acids such as tolmetin
  • phenylacetic acids such as ibuprofen, feroprofen, flurbiprofen, and ketoprofen
  • fenamates such as nifluminic acid, mefanamic acid, and meclofenainate
  • oxicams such as piroxicarn and tenoxicarn
  • Adrenal corticosteroids are alternatives to ⁇ SAIDs for treating inflammatory diseases. These steroids include hydrocoitisone, prednisolone, methylprednisolone, triamicinolone, dexamethasone and betaroethasone.
  • the compounds CR4, CR11 and CR19 may be prepared as described in Examples 1 to 14.
  • Vacuum distillations were done using Kugelrohr apparatus (Aldrich, USA) at stated temperatures of an oven. 3,5-Dimethoxy-4-hydroxycinnamaldehyde, 3,4- dimethoxycinnamic acid, 3,4-dihydroxycinnamic acid, 3,4-dimethoxybenzylamine, benzylamine, methyl cyanoacetate, were purchased from Aldrich (USA) and were used as received. The reagents were from Aldrich (USA). Solvents were purchased from Caledon (Canada).
  • Example 3 (E,E)-2-(3,4-Dihydroxybenzylaminocarbonyl)-3-(3,5- dimethoxy-4-hydiOxysty ⁇ -yl)acrylonit ⁇ ile (CR11)
  • Example 8 (E,E)-2-(Benzylaminocarbonyl)-3-(3,4- dihydroxystyryl)acrylonitrile (CR4) - Method A
  • Example 10 3,4-Bis(t-butyldimethylsilyloxy)cinnamyl alcohol (A 9 )
  • Example 12 (E,E)-2-(Benzylaminocarbonyl)-3-(3,4-bis(t- butyldimethylsilyloxystyryl))ac ⁇ ylonitrile (CR18)
  • Example 15 NEGF secretion from the breast cancer cell lines HTB-
  • HTB- 133 KDR+
  • HTB-131 KDR-
  • MDA-231 HTB-181 prostate cancer cell line
  • HTB-72 melanoma cell line HTB-72 melanoma cell line
  • CR2-1730 human umbilical vascular endothelial (HUN- EC-C) cell line and normal HUVEC primary cells was measured as follows.
  • Results All cell lines tested secreted to the medium 2-3 ng/ml of VEGF. No VEGF secretion was detected in normal HUVEC primary cells.
  • Example 16 CR-4 dependent inhibition of VEGF secretion from breast, prostate, melanoma and HUVEC cell lines.
  • Example 17 CR-4 dependent inhibition of VEGF secretion results in the inhibition of HUVEC growth.
  • HUVEC medium which does not contain VEGF (Ml 99 containing 10% FCS, heparin, antibiotics and endothelial cell growth supplement). After an incubation for 5 brs. with various concenfrations of CR-4 the wells were washed twice and fresh HUVEC medium was added for 24 hrs. This medium with or without 10 ng/ml of recombinant VEGF was then fransferred to parallel wells containing 10 s cells/ml of HUVEC that were plated and grown in HUNEC medium for 24 hrs. Radioactive labelled [ 3 H]-Thymidine was added to HUNEC wells over night. Cells were harvested and their [ 3 H]-Thymidine incorporation was measured.
  • VEGF Ml 99 containing 10% FCS, heparin, antibiotics and endothelial cell growth supplement
  • Figure 5 shows CR-4 dose dependent inhibition, with an IC50 of 20-30 nM, of HUNEC growth is shown. This inhibition is rescued by recombinant NEGF.
  • Example 18 CR11 and CR19 dependent inhibition of NEGF secretion from breast cancer cell lines.
  • Procedure 10 6 cells/ml of each of HTB-133 and MDA-231 cells were incubated for 5 hours with various concentrations of CRl 1 or CR19. Cells were washed twice in PBS to remove CRl 1 and CRl 9 and fresh medium was added for 24 hours. Medium was collected and analysed for the presence of NEGF using VEGF- 165 ELISA kit (R&D Systems).

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Abstract

La présente invention concerne des composés organiques thérapeutiques ainsi que l'inhibition de la sécrétion du facteur de croissance endothélial vasculaire (VEGF), et de ses effets, notamment de l'angiogenèse.
PCT/CA2003/001558 2002-10-11 2003-10-10 Inhibition du facteur de croissance endothelial vasculaire WO2004032911A2 (fr)

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CA002500385A CA2500385A1 (fr) 2002-10-11 2003-10-10 Inhibition du facteur de croissance endothelial vasculaire
US10/530,800 US20060241084A1 (en) 2002-10-11 2003-10-10 Inhibition of vascular endothelial growth factor
AU2003273702A AU2003273702A1 (en) 2002-10-11 2003-10-10 Styrylacrylonitrile compounds for inhibition of vascular endothelial growth factor
EP03757609A EP1551381A2 (fr) 2002-10-11 2003-10-10 Inhibition du facteur de croissance endothelial vasculaire

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US41764202P 2002-10-11 2002-10-11
US60/417,642 2002-10-11
CA002407755A CA2407755A1 (fr) 2002-10-11 2002-10-11 Inhibition de la secretion de facteur de croissance vegf
CA2,407,755 2002-10-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1858542A2 (fr) * 2005-02-24 2007-11-28 Joslin Diabetes Center, Inc. Compositions et methodes permettant de traiter la permeabilite vasculaire
US20120309744A1 (en) * 2011-06-01 2012-12-06 NBI Pharmaceuticals, Inc. Dosing regimens and methods for treating or preventing hepatocellular carcinoma

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001079158A2 (fr) * 2000-04-13 2001-10-25 Hsc Research And Development Limited Partnership Nouveaux composes destines a la modulation de la proliferation cellulaire
WO2003030895A1 (fr) * 2001-10-11 2003-04-17 The Hospital For Sick Children Composes styryl acrylonitrile et utilisation desdits composes pour favoriser la myelopoiese
WO2003062190A1 (fr) * 2002-01-18 2003-07-31 The Hospital For Sick Children Composes destines a moduler la proliferation cellulaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001079158A2 (fr) * 2000-04-13 2001-10-25 Hsc Research And Development Limited Partnership Nouveaux composes destines a la modulation de la proliferation cellulaire
WO2003030895A1 (fr) * 2001-10-11 2003-04-17 The Hospital For Sick Children Composes styryl acrylonitrile et utilisation desdits composes pour favoriser la myelopoiese
WO2003062190A1 (fr) * 2002-01-18 2003-07-31 The Hospital For Sick Children Composes destines a moduler la proliferation cellulaire

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1858542A2 (fr) * 2005-02-24 2007-11-28 Joslin Diabetes Center, Inc. Compositions et methodes permettant de traiter la permeabilite vasculaire
EP1858542A4 (fr) * 2005-02-24 2009-08-19 Joslin Diabetes Center Inc Compositions et methodes permettant de traiter la permeabilite vasculaire
EP2500031A3 (fr) * 2005-02-24 2012-12-26 Joslin Diabetes Center, Inc. Compositions et procédés de traitement de la perméabilité vasculaire
US8841259B2 (en) 2005-02-24 2014-09-23 Joslin Diabetes Center Compositions and methods for treating vascular permeability
US20120309744A1 (en) * 2011-06-01 2012-12-06 NBI Pharmaceuticals, Inc. Dosing regimens and methods for treating or preventing hepatocellular carcinoma

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