WO1994020085A1 - Methods and compositions for inhibition of angiogenesis - Google Patents

Methods and compositions for inhibition of angiogenesis Download PDF

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Publication number
WO1994020085A1
WO1994020085A1 PCT/US1994/001971 US9401971W WO9420085A1 WO 1994020085 A1 WO1994020085 A1 WO 1994020085A1 US 9401971 W US9401971 W US 9401971W WO 9420085 A1 WO9420085 A1 WO 9420085A1
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Prior art keywords
angiogenesis
human
animal
group
compound
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PCT/US1994/001971
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English (en)
French (fr)
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Robert D'amato
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The Children's Medical Center Corporation
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26699202&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1994020085(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to DE69430796T priority Critical patent/DE69430796T2/de
Priority to DK94909773T priority patent/DK0688211T3/da
Priority to KR1019950703700A priority patent/KR100506043B1/ko
Priority to CA002157288A priority patent/CA2157288C/en
Priority to AU62486/94A priority patent/AU676722B2/en
Priority to AT94909773T priority patent/ATE218865T1/de
Priority to DE122008000044C priority patent/DE122008000044I2/de
Application filed by The Children's Medical Center Corporation filed Critical The Children's Medical Center Corporation
Priority to NZ262676A priority patent/NZ262676A/xx
Priority to JP6520046A priority patent/JPH08507767A/ja
Priority to EP94909773A priority patent/EP0688211B1/en
Publication of WO1994020085A1 publication Critical patent/WO1994020085A1/en
Priority to FR08C0036C priority patent/FR08C0036I2/fr
Priority to LU91471C priority patent/LU91471I2/fr
Priority to NL300358C priority patent/NL300358I2/nl

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Definitions

  • the present invention relates to methods and compositions for preventing unwanted angiogenesis in a human or animal. More particularly, the present invention relates to a method for preventing unwanted angiogenesis, particularly in angiogenesis dependent or associated diseases, by administration of compounds such as thalidomide and related compounds.
  • angiogenesis means the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans or animals only undergo angiogenesis in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. The control of angiogenesis is a highly regulated system of angiogenic stimulators and inhibitors.
  • the control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to the uncontrolled angiogenesis.
  • Endothelial cells and pericytes surrounded by a basement membrane, form capillary blood vessels.
  • Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. The endothelial cells, which line the lumen of blood vessels, then protrude through the basement membrane.
  • Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane.
  • the migrating cells form a "sprout" off the parent blood vessel, where the endothelial cells undergo mitosis and proliferate.
  • the endothelial sprouts merge with each other to form capillary loops, creating the new blood vessel.
  • prevention of angiogenesis could avert the damage caused by the invasion of the new microvascular system.
  • Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions.
  • the diverse pathological states created due to unregulated angiogenesis have been grouped together as angiogenic dependent or angiogenic associated diseases. Therapies directed at control of the angiogenic processes could lead to the abrogation or mitigation of these diseases.
  • ocular neovascular disease This disease is characterized by invasion of new blood vessels into the structures of the eye such as the retina or cornea. It is the most common cause of blindness and is involved in approximately twenty eye diseases. In age- related macular degeneration, the associated visual problems are caused by an ingrowth of chorioidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia.
  • corneal neovascularization include, but are not limited to, 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 burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegeners sarcoidosis, Scleritis, Steven's Johnson disease, periphigoid radial keratotomy, and corneal graph rejection.
  • Diseases associated with retinal/choroidal neovascularization include, but are not limited to, 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 erythematosis, 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.
  • Other diseases include, but are not limited to, diseases associated with rubeosis (n
  • angiogenesis Another disease in which angiogenesis is believed to be involved is rheumatoid arthritis.
  • the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction.
  • the factors involved in angiogenesis may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis.
  • Factors associated with angiogenesis may also have a role in osteoarthritis.
  • the activation of the chondrocytes by angiogenic-related factors contributes to the destruction of the joint. At a later stage, the angiogenic factors would promote new bone formation.
  • Therapeutic intervention that prevents the bone destruction could halt the progress of the disease and provide relief for persons suffering with arthritis.
  • Chronic inflammation may also involve pathological angiogenesis.
  • pathological angiogenesis 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.
  • Another pathological role associated with angiogenesis is found in atherosclerosis.
  • the plaques formed within the lumen of blood vessels have been shown to have angiogenic stimulatory activity.
  • 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.
  • Angiogenesis is also responsible for damage found in hereditary diseases such as Osier- Weber-Rendu disease, or hereditary hemorrhagic 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. Angiogenesis is prominent in solid tumor formation and metastasis.
  • Angiogenic factors have been found associated with several solid tumors such as rhabdomyosarcomas, retinoblastoma, Ewing sarcoma, neuroblastoma, and osteosarcoma.
  • a tumor cannot expand without a blood supply to provide nutrients and remove cellular wastes.
  • Tumors in which angiogenesis is important include solid tumors, and benign tumors such as acoustic neuroma, neurofibroma, trachoma and pyogenic granulomas.
  • Prevention of angiogenesis could halt the growth of these tumors and the resultant damage to the animal due to the presence of the tumor.
  • angiogenesis has been associated with blood-born tumors such as leukemias, any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen. It is believed that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia-like tumors. Angiogenesis is important in two stages of tumor metastasis. The first stage where angiogenesis stimulation is important is in the vascularization of the tumor which allows tumor cells to enter the blood stream and to circulate throughout the body.
  • angiogenesis must occur before the new tumor can grow and expand. Therefore, prevention of angiogenesis could lead to the prevention of metastasis of tumors and possibly contain the neoplastic growth at the primary site.
  • Knowledge of the role of angiogenesis in the maintenance and metastasis of tumors has led to a prognostic indicator for breast cancer.
  • the amount of neovascularization found in the primary tumor was determined by counting the microvessel density in the area of the most intense neovascularization in invasive breast carcinoma. A high level of microvessel density was found to correlate with tumor recurrence. Control of angiogenesis by therapeutic means could possibly lead to cessation of the recurrence of the tumors.
  • 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 could be used to induce amenorrhea, to block ovulation or to prevent implantation by the blastula. In wound healing, excessive repair or fibroplasia can be a detrimental 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. Several kinds of compounds have been used to prevent angiogenesis. Taylor et al. have used protamine to inhibit angiogenesis, see Taylor et al., Nature 297:307 (1982).
  • interferon inhibits angiogenesis.
  • interferon ⁇ or human interferon ⁇ has been shown to inhibit tumor-induced angiogenesis in mouse dermis stimulated by human neoplastic cells.
  • Interferon ⁇ is also a potent inhibitor of angiogenesis induced by allogeneic spleen cells. See Sidky et al., Cancer Research 47:5155-5161 (1987).
  • a fungal product, fumagillin is a potent angiostatic agent in vitro.
  • the compound is toxic in vivo, but a synthetic derivative, AGM 12470, has been used in vivo to treat collagen II arthritis. Fumagillin and O- substituted fumagillin derivatives are disclosed in EPO Publication Nos. 0325199 A2 and 0357061 Al.
  • PCT Application No. WO 92/14455 to Kaplan et al. is directed to a method for controlling abnormal concentration of TNF- ⁇ by administering thalidomide or thalidomide derivatives to a patient with toxic concentrations of TNF- ⁇ .
  • the above compounds are either topical or injectable therapeutics. Therefore, there are drawbacks to their use as a general angiogenic inhibitor and lack adequate potency. For example, in prevention of excessive wound healing, surgery on internal body organs involves incisions in various structures contained within the body cavities. These wounds are not accessible to local applications of angiogenic inhibitors. Local delivery systems also involve frequent dressings which are impracticable for internal wounds, and increase the risk of infection or damage to delicate granulation tissue for surface wounds.
  • compositions and methods are provided that are effective in inhibiting unwanted angiogenesis. These compositions are easily administered by different routes including oral and can be given in dosages that are safe and provide angiogenic inhibition at internal sites.
  • the present invention provides a method of treating mammalian diseases mediated by undesired and uncontrolled angiogenesis by administering a composition comprising an anti-angiogenic compound in a dosage sufficient to inhibit angiogenesis.
  • the present invention also includes angiogenic inhibiting compounds that contain an epoxide group. These angiogenic inhibiting compounds can be administered to a human or animal alone or with epoxide hydrolase inhibiting compounds.
  • the present invention is especially useful for treating certain ocular neovascular diseases such as macular degeneration.
  • the compounds which are contemplated as part of the present invention preferably can be given orally to the patient and thereby halt the progression of the disease.
  • Other disease that can be treated using the present invention are diabetic retinopathy, neovascular glaucoma and retrolental fibroplasia.
  • Figures 1 through 3 are a listing of representative compounds in the genus represented by the following general formulas:
  • Figure 4 is a listing of representative compounds in the genus represented by the following general formula:
  • Figure 5 is a listing of representative compounds in the genus represented by the following general formula:
  • Figure 6 shows the effect of thalidomide and EM 12 on angiogenesis in a rabbit cornea model of angiogenesis.
  • Figure 7 shows the effect of thalidomide on the area of corneal vascularization in a rabbit cornea model of angiogenesis.
  • the present invention includes compositions and methods for the treatment of diseases that are mediated by angiogenesis.
  • One embodiment of the present invention is the use of thalidomide or the metabolites of thalidomide as disclosed herein to inhibit unwanted angiogenesis.
  • the present invention also includes compounds which cause dysmelia is the developing fetus and have anti-angiogenic activity.
  • the present invention comprises a method of treating undesired angiogenesis in a human or animal comprising the steps of administering to the human or animal with the undesired angiogenesis a composition comprising an effective amount of a teratogenic compound that is anti- angiogenic.
  • Compounds that can be used in accordance with the present invention include compounds included in the following general formulae. Examples of compounds that have anti-angiogenic properties having one of the following three formulae (A), (B), or (C):
  • R 20 where Ri8, Rl9 and R20 are, independently selected from
  • another aspect of the present invention features inhibiting angiogenesis in a mammal by administering a therapeutic composition comprising one of the above-described compounds in a dosage sufficient to inhibit angiogenesis
  • the compound has formula B), where R5 and R6 are selected from the group consisting of:
  • R9 has formula F) or H); and R14 and R16 are selected from the group consisting of:
  • R 15 and is -0-, or -N- ,
  • R 21 is -H, -CH 3 , or -OH.
  • Specific preferred compounds according to this aspect of the present invention include thalidomide, its precursors, metabolites and analogs. Particular analogs include EM- 12, N-phthaloyl-DL-glutamic acid (PGA) or N-phthaloyl-DL-glutamine anhydride. Examples of compounds that are members of this genus are listed in Figures 1 through 3. It is to be understood that the compounds included as part of the present invention are not to be limited to those compounds shown in Figures 1 through 3 and include all other compounds that are members of the genus described by the general formulas herein.
  • R22 and R23 are (independently), -H, -F, -Cl, -Br, -I, -CH3, or -CH2 -CH3; and R24 is -H, -CH3, or -CH2 -CH3.
  • the present invention also features inhibiting angiogenesis in a mammal by administering a compound according to the above formulae in a dosage sufficient to inhibit angiogenesis.
  • a compound according to the above formulae examples of specific compounds that are members of this genus are listed in Figure 4.
  • Angiogenesis inhibition hydrolysis products of thalidomide having the following general formula can be used in practicing the present invention:
  • X is R 25 -C— C— (CH 2 ) n -C— R 26
  • Angiogenesis inhibition compounds having the following general formula can be used in practicing the present invention:
  • Another set of compounds that are considered part of the present invention are the epoxides of thalidomide, EM- 12 and EM- 138. Representative epoxide compounds are shown as follows:
  • epoxide can be attached at the 6,1 site on the benzene ring, the 1,2 site, the 2,3 site 3,4 or the 4,5 site. All of these compounds are contemplated as part of the present invention.
  • the epoxides of the thalidomide, EM- 12, and EM 138 can be hydrolized to the following compounds:
  • the hydroxyl group can be on carbons 1, 2, 3, 4, 5 and 6 of the benzene ring. Also contemplated as part of the present invention are dihydroxyl compounds wherein the two hydroxyl groups are located bis to each other on carbons 1, 2, 3, 5 and 6 of the above compounds.
  • the epoxides, the hydrolysis products of the epoxides, and the hydrolysis products of the thalidomide are all contemplated to be part of the present invention.
  • epoxides are hydrolized by a group of enzymes known as epoxide hydrolases.
  • epoxide hydrolases There is a class of compounds which are epoxide hydrolase inhibitors. Examples of these compounds are valpromide (2-propylpentanamide) and valproic acid (2-propylpentanoic acid).
  • epoxides are important angiogenesis inhibitors, it is contemplated as part of the present invention, compositions comprising any of the angiogenesis inhibitors compounds recited herein in combination with epoxide hydrolase inhibitors.
  • the epoxide hydrolase inhibitors can be administered to a human or animal together or sequentially.
  • the expoxide group appears to be an important substituent common to several angiogenesis inhibitors.
  • epoxide hydrolase inhibitors to potentiate the activity of any ' angiogenesis inhibitor containing an epoxide is contemplated as part of the present invention.
  • the epoxide hydrolase inhibitors can be administered with the following epoxide-containing anti-angiogenesis compounds: AGM 1470, Eponimycin, microbial metabolites of Scolecobasidium arenarium designated f/2015, fr/1 1 1 142 and fr/18487. See Oikawa, Biochem Biophys. Res. Comm, Vol. 81 :1070 (1971) and Otsuka,
  • TNF- ⁇ has been recognized as manifesting a dose dependent toxicity. if present at low levels for a long period of time, TNF- ⁇ can result in cachexia. Cachexia is a general weight loss and wasting occurring in the course of some chronic diseases such as cancer, opportunistic infections of AIDS, inflammatory diseases, parasitic diseases, tuberculosis, and high dose IL-2 therapy.
  • the epoxide containing angiogenesis inhibitors, with or without epoxide hydrolase inhibitors are also effective in treating diseases such as septic shock, leprosy and graph vs. host disease. Other embodiments are within the present invention.
  • teratogens such as valproic acid (2-propylpentanoic acid), the retinoids, such as cis-retinoic acid, and rifampin may also be used in accordance with the invention.
  • the preferred compounds are thalidomide, as well as analogs, hydrolysis products, metabolites and precursors of thalidomide that are teratogenic, and, more specifically, that cause dismelia.
  • Dysmelia-causing compounds can be identified by the general procedures of Helm, Arzneimittle- aba, 31(i/6):941-949 (1981 ), in which rabbit pups are examined after exposure to the compound in utero.
  • the compounds can generally be purchased, e.g., from Andrulis
  • the compounds described above can be provided as pharmaceutically acceptable formulations using formulation methods known to those of ordinary skill in the art. These formulations can be administered by standard routes. In general, the combinations may be administered by the topical, transdermal, oral, rectal or parenteral (e.g., intravenous, subcutaneous or intramuscular) route. In addition, the combinations may be incorporated into biodegradable polymers allowing for sustained release of the compound, the polymers being implanted in the vicinity of where drug delivery is desired, for example, at the site of a tumor. The biodegradable polymers and their use are described, for example, in detail in Brem et al., J. Neurosurg. 74:441-446 (1991).
  • the dosage of the compound will depend on the condition being treated, the particular compound, and other clinical factors such as weight and condition of the human or animal and the route of administration of the compound. It is to be understood that the present invention has application for both human and veterinary use.
  • the formulations include those suitable for oral, rectal, ophthalmic, (including intravitreal or intracameral) nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratracheal, and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques. Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into associate the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, etc.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally coated or scored and may be formulated so as to provide a slow or controlled release of the active ingredient therein.
  • a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may be optionally coated or scored
  • Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
  • Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in a pharmaceutical acceptable carrier.
  • a preferred topical delivery system is a transdermal patch containing the ingredient to be administered.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for vaginal administration may be presented as pessaries, tamports, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) conditions requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered ingredient.
  • formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
  • corneal neovascularization Diseases associated with corneal neovascularization that can be treated according to the present invention include but are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and 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 burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginal keratolysis, trauma, rheumatoid arthritis, systemic
  • Diseases associated with retinal/choroidal neovascularization that can be treated according to the present invention include, but are not limited to, 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 erythematosis, 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.
  • diseases include, but are not limited to, diseases associated with rubeosis (neovasculariation of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy, whether or not associated with diabetes.
  • Another disease which can be treated according to the present invention is rheumatoid arthritis. It is believed that the blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks, the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction. The factors involved in angiogenesis may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis.
  • Another disease that can be treated according to the present invention are hemangiomas, Osier- Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.
  • Pellets for implantation into rabbit corneas were made by mixing 110 ⁇ l of saline containing 12 ⁇ g of recombinant bFGF (Takeda Pharmaceuticals-Japan) with 40 mg of sucralfate
  • Example III Various mathematical models were utilized to determine the amount of vascularized cornea and this formula was found to provide the most accurate approximation of the area of the band of neovascularization that grows towards the pellet. It is important to note that the rabbit cornea assay is preferable because it will generally recognize compounds that are inactive per se but are metabolized to yield active compounds. Thalidomide related compounds, as shown below in Example III, are known to be teratogens and are candidates for use in the present invention. Example III
  • Pellets containing bFGF and sucralfate were implanted into micropockets of both corneas of rabbits according to Example II. Vessel ingrowth into clear cornea from the limbus was first noted on day 2 and treatments (200 mg/kg orally) were begun on this day. The area of corneal neovascularization was measured from day 4 through day 12. Day 8 measurements were used for comparison between groups. No regression of vessels and near maximal neovascularization was seen at this time point. Statistical analysis was performed with ANOVA with ranked data to account for interexperimental variation and to guard against a non-normal distribution of data (i.e. outliers) by utilizing a nonparametric method.
  • Other analogs, PGA and PG acid displayed weaker inhibitory effects than thalidomide (data not shown). The density of vessel ingrowth in tha idomide-treated animals was also markedly reduced.
  • EM- 12 was tested in the rabbit cornea assay described in Example II at 100 mg/kg/day and showed 21 % inhibition, and at 200mg/kg/day the assay showed 43% inhibition.
  • Phthaloyl glutamic acid in CAM Phthaloyl glutamic acid in CAM
  • Phthaloyl glutamic acid was tested in the above described CAM assay and exhibit an avascular zone with a mild scar, Example VI
  • Phthaloyl glutamic anhydride was test in the CAM assay described above and exhibited an avascular zone.
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EP94909773A EP0688211B1 (en) 1993-03-01 1994-02-24 Thalidomide for inhibition of angiogenesis
DE122008000044C DE122008000044I2 (US20020061911A1-20020523-C00014.png) 1993-03-01 1994-02-24
KR1019950703700A KR100506043B1 (ko) 1993-03-01 1994-02-24 맥관형성을억제하기위한조성물
CA002157288A CA2157288C (en) 1993-03-01 1994-02-24 Methods and compositions for inhibition of angiogenesis
AU62486/94A AU676722B2 (en) 1993-03-01 1994-02-24 Methods and compositions for inhibition of angiogenesis
AT94909773T ATE218865T1 (de) 1993-03-01 1994-02-24 Thalidomid zur hemmung der angiogenese
NZ262676A NZ262676A (en) 1993-03-01 1994-02-24 Method of inhibiting angiogenesis in a non-human animal using thalidomide and analogues thereof
DE69430796T DE69430796T2 (de) 1993-03-01 1994-02-24 Thalidomid zur hemmung der angiogenese
DK94909773T DK0688211T3 (da) 1993-03-01 1994-02-24 Thalidomid til inhibering af angiogenese
JP6520046A JPH08507767A (ja) 1993-03-01 1994-02-24 管脈形成を抑制する方法および組成物
FR08C0036C FR08C0036I2 (US20020061911A1-20020523-C00014.png) 1993-03-01 2008-08-01
LU91471C LU91471I2 (fr) 1993-03-01 2008-08-20 Thalidomide pour inhiber l'angiogenese
NL300358C NL300358I2 (nl) 1993-03-01 2008-09-01 Thalidomide voor remming van angiogenese.

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Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0688771A1 (de) * 1994-06-24 1995-12-27 Grünenthal GmbH Verwendung von Lactamverbindungen als pharmazeutische Wirkstoffe
EP0770390A1 (en) * 1995-11-01 1997-05-02 Dott Research Laboratory Nasally administrable compositions containing physiologically active peptides
WO1998003502A1 (en) * 1996-07-24 1998-01-29 Celgene Corporation Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels
WO1998019649A2 (en) * 1996-11-05 1998-05-14 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
WO1998054170A1 (en) * 1997-05-30 1998-12-03 Celgene Corporation SUBSTITUTED 2-(2,6-DIOXOPIPERIDIN-3-YL)-PHTHALIMIDES AND 1-OXOISOINDOLINES AND METHOD OF REDUCING TNFα LEVELS
US5858991A (en) * 1997-01-29 1999-01-12 Vanderbilt University Facilitation of wound healing with CM101/GBS toxin
WO1999046258A1 (en) * 1998-03-13 1999-09-16 Celgene Corporation SUBSTITUTED 2-(2,6-DIOXO-3-FLUOROPIPERIDIN-3-YL)-ISOINDOLINES AND THEIR USE TO REDUCE TNFα LEVELS
US5981508A (en) * 1997-01-29 1999-11-09 Vanderbilt University Facilitation of repair of neural injury with CM101/GBS toxin
WO1999058096A2 (en) 1998-05-11 1999-11-18 Entremed, Inc. Analogs of 2-phthalimidinoglutaric acid and their use as inhibitors of angiogenesis
US6028060A (en) * 1997-01-29 2000-02-22 Vanderbilt University Treatment of chronic inflammatory diseases with CM101/GBS toxin
WO2000041547A2 (en) * 1999-01-13 2000-07-20 The Rockefeller University Methods of promoting or enhancing interleukin-12 production through administration of thalidomide
US6114355A (en) * 1993-03-01 2000-09-05 D'amato; Robert Methods and compositions for inhibition of angiogenesis
EP1040838A1 (de) * 1999-03-31 2000-10-04 Grünenthal GmbH Stabile wässrige Lösung von EM 12
US6228879B1 (en) 1997-10-16 2001-05-08 The Children's Medical Center Methods and compositions for inhibition of angiogenesis
US6380239B1 (en) 1999-03-18 2002-04-30 Celgene Corporation Substituted 1-oxo- and 1,3-dioxoisoindoline and method of reducing inflammatory cytokine levels
US6420414B1 (en) 1993-03-01 2002-07-16 The Children's Medical Center Corporation Amino derivatives of EM-138 and methods of treating angiogenesis with same
EP1226824A1 (en) * 2001-01-24 2002-07-31 TTY Biopharm Company Limited Use of thalidomide for the treatment of hepatocellular carcinoma
EP1308444A1 (en) * 1997-11-18 2003-05-07 Celgene Corporation Substituted 2-(2,6-Dioxo-3-Fluoropiperidine-3-YL)-Isoindolines and their use to reduce TNF-alpha Levels
US6670337B1 (en) 1998-01-29 2003-12-30 Yeda Reaearch And Development Co., Ltd. Facilitation of wound healing with CM101/GBS toxin
US6673828B1 (en) 1998-05-11 2004-01-06 Children's Medical Center Corporation Analogs of 2-Phthalimidinoglutaric acid
WO2005016326A2 (en) * 2003-07-11 2005-02-24 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors
US6914067B2 (en) 2000-05-15 2005-07-05 Celgene Corporation Compositions and methods for the treatment of colorectal cancer
US7041680B2 (en) 1996-07-24 2006-05-09 Celgene Corporation (R) and (S) isomers of substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and 1-oxoisoindolines and methods of using the same
US7081464B2 (en) 1995-08-29 2006-07-25 Celgene Corporation Topical compositions of cyclic amides as immunotherapeutic agents
US7119106B2 (en) 1996-07-24 2006-10-10 Celgene Corporation Pharmaceutical compositions of 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline
US7320991B2 (en) 2001-02-27 2008-01-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Analogs of thalidomide as potential angiogenesis inhibitors
US7435726B2 (en) 2000-05-15 2008-10-14 Celgene Corporation Compositions and methods for the treatment of cancer
US7482005B2 (en) 1991-03-29 2009-01-27 Genentech, Inc. Methods of treating diseases with anti-VEGF antibodies
US7629360B2 (en) 1999-05-07 2009-12-08 Celgene Corporation Methods for the treatment of cachexia and graft v. host disease
EP2177517A1 (en) * 1996-07-24 2010-04-21 Celgene Corporation Amino substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimide for reducing TNF alpha levels
US7834033B2 (en) 2000-11-14 2010-11-16 Celgene Corporation Methods for treating cancer using 3-[1,3dioxo-4-benzamidoisoindolin-2-yl]-2,6-dioxo-5-hydroxypiperidine
US7968569B2 (en) 2002-05-17 2011-06-28 Celgene Corporation Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
US7973057B2 (en) 2003-09-17 2011-07-05 The United States Of America As Represented By The Department Of Health And Human Services Thalidomide analogs
US8609614B2 (en) 1998-07-22 2013-12-17 Vanderbilt University GBS toxin receptor compositions and methods of use
US8853253B2 (en) 2003-09-17 2014-10-07 P2D, Inc. Thalidomide analogs
US9056103B2 (en) 2002-05-17 2015-06-16 Celgene Corporation Methods using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of certain leukemias
US9084783B2 (en) 2011-12-02 2015-07-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
US9198898B2 (en) 2013-06-24 2015-12-01 Tigercat Pharma, Inc. Use of NK-1 receptor antagonists in pruritus
US9486439B2 (en) 2013-06-24 2016-11-08 Menlo Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
WO2017059062A1 (en) * 2015-09-30 2017-04-06 Theunited States Of America, As Represented By The Secretary, Department Of Health And Human Service Thalidomide analogs and methods of use
US10001483B2 (en) 2015-06-26 2018-06-19 Celgene Corporation Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers
US10017492B2 (en) 2014-10-30 2018-07-10 Kangpu Biopharmaceuticals, Ltd. Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
US10034872B2 (en) 2014-08-22 2018-07-31 Celgene Corporation Methods of treating multiple myeloma with immunomodulatory compounds in combination with antibodies
US10457669B2 (en) 2015-10-21 2019-10-29 Otsuka Pharmaceutical Co., Ltd. Benzolactam compounds as protein kinase inhibitors
US11116782B2 (en) 2002-10-15 2021-09-14 Celgene Corporation Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine
US11142518B2 (en) 2017-04-20 2021-10-12 Otsuka Pharmaceutical Co., Ltd. 6-pyrimidin-isoindole derivative as ERK1/2 inhibitor
USRE48890E1 (en) 2002-05-17 2022-01-11 Celgene Corporation Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation

Families Citing this family (244)

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Publication number Priority date Publication date Assignee Title
US8143283B1 (en) * 1993-03-01 2012-03-27 The Children's Medical Center Corporation Methods for treating blood-born tumors with thalidomide
US6805865B1 (en) 1993-05-27 2004-10-19 Entremed, Inc. Compositions and methods for treating cancer and hyperproliferative disorders
US20040248799A1 (en) * 1993-05-27 2004-12-09 Holaday John W. Compositions and methods for treating cancer and hyperproliferative disorders
US6429221B1 (en) * 1994-12-30 2002-08-06 Celgene Corporation Substituted imides
US6440729B1 (en) * 1995-06-30 2002-08-27 University Of Kansas Medical Center Treating angiogenesis-mediated diseases with the α2 monomer of type IV collagen
US6358735B1 (en) 1995-06-30 2002-03-19 University Of Kansas Medical Center Method for inhibiting angiogenesis and tumors with the isolated NC1 α3 chain monomer of type IV collagen
US6346510B1 (en) 1995-10-23 2002-02-12 The Children's Medical Center Corporation Therapeutic antiangiogenic endostatin compositions
US5798368A (en) * 1996-08-22 1998-08-25 Celgene Corporation Tetrasubstituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and method of reducing TNFα levels
US5955496A (en) * 1996-08-13 1999-09-21 The Regents Of The University Of California Dihydroxy-oxy-eicosadienoates
US6593291B1 (en) 1997-02-06 2003-07-15 Entremed, Inc. Compositions and methods of use of ligands that bind components of the blood coagulation/clotting pathway for the treatment of cancer and angiogenic-based disease
US5994388A (en) * 1997-03-18 1999-11-30 The Children's Medical Center Corporation Cytochalasin and isoindolinone derivatives as inhibitors of angiogenesis
WO1998042722A1 (en) 1997-03-21 1998-10-01 President And Fellows Of Harvard College Antisense inhibition of angiogenin expression
US6174695B1 (en) 1997-08-12 2001-01-16 The Regents Of The University Of California Epoxide hydrolase inhibitor methods
CA2302017C (en) 1997-08-25 2007-01-30 Harold Brem Prevention of adhesions and excessive scar formation using angiogenesis inhibitors
TR200101503T2 (tr) * 1998-03-16 2002-06-21 Celgene Corporation 2-(2,6-dioksopiperidin-3-il) izoindolin türevleri, bunların hazırlanması ve enflamatuar sitokinlerin inhibitörleri olarak kullanımı
WO1999058126A1 (en) 1998-05-11 1999-11-18 The Endowment For Research In Human Biology, Inc. Use of neomycin for treating angiogenesis-related diseases
US6620382B1 (en) 1998-05-22 2003-09-16 Biopheresis Technologies, Llc. Method and compositions for treatment of cancers
US8197430B1 (en) * 1998-05-22 2012-06-12 Biopheresis Technologies, Inc. Method and system to remove cytokine inhibitor in patients
US6576613B1 (en) * 1998-07-24 2003-06-10 Corvas International, Inc. Title inhibitors of urokinase
US6703050B1 (en) * 1998-09-04 2004-03-09 The Regents Of The University Of Michigan Methods and compositions for the prevention or treatment of cancer
US6537554B1 (en) 1998-09-10 2003-03-25 Curagen Corporation Nucleotide sequences and amino acid sequences of secreted proteins involved in angiogenesis
AU5991699A (en) 1998-09-21 2000-04-10 Biochem Pharma Inc. Quinolizinones as integrin inhibitors
US6231889B1 (en) 1998-09-21 2001-05-15 Chronorx, Llc Unit dosage forms for the treatment of herpes simplex
US6596690B2 (en) * 1998-10-06 2003-07-22 The United States Of America As Represented By The Department Of Health And Human Services Vasostatin as marrow protectant
FR2784580B1 (fr) 1998-10-16 2004-06-25 Biosepra Inc Microspheres de polyvinyl-alcool et procedes de fabrication de celles-ci
US20030013739A1 (en) * 1998-12-23 2003-01-16 Pharmacia Corporation Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia
US7238711B1 (en) * 1999-03-17 2007-07-03 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
US6468990B1 (en) * 1999-05-17 2002-10-22 Queen's University At Kingston Method of inhibiting binding of nerve growth factor to p75 NTR receptor
US6673843B2 (en) 1999-06-30 2004-01-06 Emory University Curcumin and curcuminoid inhibition of angiogenesis
US6916843B1 (en) * 1999-08-11 2005-07-12 The United States Of America As Represented By The Department Of Health And Human Services Anti-inflammatory actions of cytochrome P450 expoxygenase-derived eicosanoids
US7087592B1 (en) 1999-08-23 2006-08-08 Entre Med, Inc. Compositions comprising purified 2-methoxyestradiol and methods of producing same
US20040214783A1 (en) 2002-05-08 2004-10-28 Terman David S. Compositions and methods for treatment of neoplastic disease
WO2001037873A2 (en) 1999-11-10 2001-05-31 Lentz M Rigdon Method and system to remove cytokine inhibitor in patients
US6204270B1 (en) * 1999-11-12 2001-03-20 Eyal S. Ron Ophthalmic and mucosal preparations
WO2001036604A2 (en) 1999-11-18 2001-05-25 Corvas International, Inc. Nucleic acids encoding endotheliases, endotheliases and uses thereof
US6379708B1 (en) * 1999-11-20 2002-04-30 Cytologic, Llc Method for enhancing immune responses in mammals
WO2001041755A2 (en) * 1999-12-02 2001-06-14 The Regents Of The University Of Michigan Topical compositions comprising thalidomide for the treatment of inflammatory diseases
US7182953B2 (en) * 1999-12-15 2007-02-27 Celgene Corporation Methods and compositions for the prevention and treatment of atherosclerosis restenosis and related disorders
US6699899B1 (en) * 1999-12-21 2004-03-02 Celgene Corporation Substituted acylhydroxamic acids and method of reducing TNFα levels
US7700341B2 (en) 2000-02-03 2010-04-20 Dendreon Corporation Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon
CN1121218C (zh) * 2000-03-08 2003-09-17 台湾东洋药品工业股份有限公司 酞胺哌啶酮在治疗肝细胞癌的药物组合物中的应用
US8697137B2 (en) 2000-03-24 2014-04-15 Biosphere Medical, Inc. Methods of using microspheres for active embolization
US20030212022A1 (en) * 2001-03-23 2003-11-13 Jean-Marie Vogel Compositions and methods for gene therapy
WO2001074362A1 (en) * 2000-03-31 2001-10-11 Celgene Corporation Inhibition of cyclooxygenase-2 activity
US20030104573A1 (en) * 2000-09-11 2003-06-05 Shimkets Richard A. Nucleotide sequences and amino acid sequences of secreted proteins involved in angiogenesis
JP4242651B2 (ja) * 2000-11-30 2009-03-25 ザ チルドレンズ メディカル センター コーポレイション ４−アミノ−サリドマイドエナンチオマーの合成法
US20040121945A1 (en) * 2000-12-15 2004-06-24 Hong Liang Compositions and methods for inhibiting endothelial cell proliferation
US6632835B2 (en) 2001-02-22 2003-10-14 Nanodesign Inc. Dibenzo[c]chromen-6-one derivatives as anti-cancer agents
CA2444704C (en) * 2001-04-23 2012-07-10 University Of Virginia Patent Foundation Synthesis and evaluation of phthalimide mimics as anti-angiogenic agents
JP2005504037A (ja) * 2001-07-27 2005-02-10 ユニヴァースティ オブ カンザス メディカル センター Ｉｖ型コラーゲンｎｃ１ドメイン六量体の結晶化構造
US7153867B2 (en) * 2001-08-06 2006-12-26 Celgene Corporation Use of nitrogen substituted thalidomide analogs for the treatment of macular degenerator
GB0125659D0 (en) * 2001-10-25 2001-12-19 Ssl Int Plc Spermicides
AU2002357004A1 (en) * 2001-11-20 2003-06-10 Dendreon San Diego Llc Nucleic acid molecules encoding serine protease 17, the encoded polypeptides and methods based thereon
US20030139469A1 (en) * 2002-01-23 2003-07-24 The Regents Of The University Of California Use of inhibitors of soluble epoxide hydrolase to inhibit vascular smooth muscle cell proliferation
DK1572169T3 (da) * 2002-03-08 2013-10-21 Shanghai Inst Biol Sciences Påvisning og modulering af Slit- og Robo-medieret angiogenese og anvendelser deraf
US20060229239A9 (en) * 2002-03-08 2006-10-12 Mamoru Shoji Novel curcuminoid-factor VIIa constructs as suppressors of tumor growth and angiogenesis
WO2003086283A2 (en) * 2002-04-09 2003-10-23 Greenville Hospital System Metastasis modulating activity of highly sulfated oligosaccharides
US20100129363A1 (en) * 2002-05-17 2010-05-27 Zeldis Jerome B Methods and compositions using pde4 inhibitors for the treatment and management of cancers
WO2003097052A2 (en) 2002-05-17 2003-11-27 Celgene Corporation Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases
US7323479B2 (en) * 2002-05-17 2008-01-29 Celgene Corporation Methods for treatment and management of brain cancer using 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline
EP1556033A4 (en) 2002-05-17 2006-05-31 Celgene Corp METHODS AND COMPOSITIONS USING CYTOKINE INHIBITOR SELECTIVE MEDICAMENTS FOR THE TREATMENT AND MANAGEMENT OF CANCERS AND OTHER DISEASES
US20040001801A1 (en) * 2002-05-23 2004-01-01 Corvas International, Inc. Conjugates activated by cell surface proteases and therapeutic uses thereof
US20060142203A1 (en) * 2002-06-26 2006-06-29 Todd Hembrough Compositions and methods comprising protein activated receptor antagonists
ES2358730T3 (es) 2002-07-15 2011-05-13 Board Of Regents, The University Of Texas System Anticuerpos seleccionados y péptidos de duramicina que se enlazan a fosfolípidos aniónicos y aminofosfolípidos y sus usos en el tratamiento de infecciones virales y del cáncer.
CA2493544A1 (en) * 2002-07-22 2004-01-29 Chemgenex Pharmaceuticals, Inc. Angiogenesis inhibition by cephalotaxine alkaloids, derivatives, compositions and uses thereof
EA008683B1 (ru) * 2002-07-23 2007-06-29 Дзе Риджентс Оф Дзе Юниверсити Оф Мичиган Тетрапропиламмония тетратиомолибдат и родственные соединения для антиангиогенной терапии
US7189740B2 (en) * 2002-10-15 2007-03-13 Celgene Corporation Methods of using 3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myelodysplastic syndromes
US8404716B2 (en) * 2002-10-15 2013-03-26 Celgene Corporation Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine
US8404717B2 (en) * 2002-10-15 2013-03-26 Celgene Corporation Methods of treating myelodysplastic syndromes using lenalidomide
ZA200503024B (en) * 2002-10-15 2006-11-29 Celgene Corp Selective cytokine inhibitory drugs for treating myelodysplastic syndrome
EP1900369A1 (en) 2002-10-15 2008-03-19 Celgene Corporation Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of myelodysplastic syndromes
US20040087558A1 (en) * 2002-10-24 2004-05-06 Zeldis Jerome B. Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment, modification and management of pain
US20050203142A1 (en) * 2002-10-24 2005-09-15 Zeldis Jerome B. Methods of using and compositions comprising immunomodulatory compounds for treatment, modification and management of pain
CA2504024A1 (en) * 2002-10-31 2004-05-21 Celgene Corporation Composition for the treatment of macular degeneration
US20040091455A1 (en) * 2002-10-31 2004-05-13 Zeldis Jerome B. Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration
US7776907B2 (en) * 2002-10-31 2010-08-17 Celgene Corporation Methods for the treatment and management of macular degeneration using cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindoline-4-yl}carboxamide
NZ564480A (en) 2002-11-06 2008-12-24 Celgene Corp Use of selective cytokine inhibitory drugs for the treatment of Behcet's disease
US8034831B2 (en) * 2002-11-06 2011-10-11 Celgene Corporation Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-Dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies
US7563810B2 (en) * 2002-11-06 2009-07-21 Celgene Corporation Methods of using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myeloproliferative diseases
BR0316206A (pt) * 2002-11-12 2005-09-27 Alcon Inc Uso inibidores de histona desacetilase para o tratamento de distúrbios e de doenças oculares neovasculares ou edematosos
US7230012B2 (en) 2002-11-14 2007-06-12 Celgene Corporation Pharmaceutical compositions and dosage forms of thalidomide
US9006267B2 (en) * 2002-11-14 2015-04-14 Celgene Corporation Pharmaceutical compositions and dosage forms of thalidomide
US7517887B2 (en) * 2003-04-09 2009-04-14 General Atomics Reversible inhibitors of S-adenosyl-L-homocysteine hydrolase and uses thereof
US7868011B2 (en) * 2003-04-09 2011-01-11 General Atomics Use of reversible inhibitors of S-adenosyl-L-homocysteine hydrolase for treating lupus
US7196093B2 (en) * 2003-04-09 2007-03-27 General Atomics Reversible inhibitors of SAH hydrolase and uses thereof
DE10323898A1 (de) 2003-05-26 2004-12-23 Wilex Ag Hydroxyamidin- und Hydroxyguanidin-Verbindungen als Urokinase-Hemmstoffe
AU2004275693A1 (en) * 2003-05-28 2005-04-07 Entremed, Inc. Antiangiogenic agents
RS53476B (en) 2003-07-18 2014-12-31 Amgen Fremont Inc. Hepatocyte Growth Factor Binders
UA83504C2 (en) 2003-09-04 2008-07-25 Селджин Корпорейшн Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
US20080027113A1 (en) * 2003-09-23 2008-01-31 Zeldis Jerome B Methods of Using and Compositions Comprising Immunomodulatory Compounds for Treatment and Management of Macular Degeneration
US7612096B2 (en) * 2003-10-23 2009-11-03 Celgene Corporation Methods for treatment, modification and management of radiculopathy using 1-oxo-2-(2,6-dioxopiperidin-3yl)-4-aminoisoindoline
AU2003286931A1 (en) * 2003-11-06 2004-06-06 Celgene Corporation Methods and compositions using thalidomide for the treatment and management of cancers and other diseases
US20050100529A1 (en) * 2003-11-06 2005-05-12 Zeldis Jerome B. Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of asbestos-related diseases and disorders
JP2007510670A (ja) * 2003-11-06 2007-04-26 セルジーン・コーポレーション サリドマイドを用いた、癌、及び他の疾患を治療、及び管理する方法ならびに組成物
CN1913896B (zh) * 2003-12-02 2010-12-01 细胞基因公司 用于治疗和控制血红蛋白病和贫血病的方法和组合物
US20050143344A1 (en) * 2003-12-30 2005-06-30 Zeldis Jerome B. Methods and compositions using immunomodulatory compounds for the treatment and management of central nervous system disorders or diseases
US7430276B2 (en) * 2004-02-25 2008-09-30 Nanodynamics-88 Low dose X-ray mammography method
AU2005222934B2 (en) * 2004-03-12 2010-06-17 Entremed, Inc. Antiangiogenic agents
CN1956718A (zh) * 2004-03-22 2007-05-02 细胞基因公司 用于治疗和控制皮肤疾病和病症的含免疫调节化合物的组合物和使用方法
US20050222209A1 (en) * 2004-04-01 2005-10-06 Zeldis Jerome B Methods and compositions for the treatment, prevention or management of dysfunctional sleep and dysfunctional sleep associated with disease
MXPA06011798A (es) * 2004-04-14 2007-01-16 Celgene Corp Metodos de uso y composiciones que comprenden compuestos inmunomoduladores para el tratamiento y manejo de sindromes mielodisplasticos.
CA2563207A1 (en) * 2004-04-14 2005-11-24 Celgene Corporation Use of selective cytokine inhibitory drugs in myelodysplastic syndromes
BRPI0510110A (pt) * 2004-04-23 2007-09-25 Celgene Corp método para tratar, prevenir ou controlar hipertensão pulmonar, e, composição farmacêutica
ZA200609227B (en) * 2004-04-23 2008-06-25 Celgene Corp Methods of using and compositions comprising thalidomide for the treatment and management of pulmonary hypertension
JP2008511340A (ja) * 2004-04-30 2008-04-17 バイオフェレシス テクノロジーズ， インコーポレイテッド 患者において可溶性ｔｎｆｒ１、可溶性ｔｎｆｒ２、および可溶性ｉｌ２を除去する方法およびシステム
US7273890B1 (en) * 2004-06-08 2007-09-25 Sagittarius Life Science Corp. ST104P, an anti-angiogenic agent
EP1778652A2 (en) * 2004-08-20 2007-05-02 EntreMed, Inc. Compositions and methods comprising proteinase activated receptor antagonists
WO2006028964A1 (en) * 2004-09-03 2006-03-16 Celgene Corporation Processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines
AU2005302523A1 (en) * 2004-10-28 2006-05-11 Celgene Corporation Methods and compositions using PDE4 modulators for treatment and management of central nervous system injury
BRPI0518282A2 (pt) * 2004-11-23 2008-11-11 Celgene Corp uso de uma quantidade terapeuticamente ou profilaticamente efetiva de um composto imunomodulatàrio
ES2568782T3 (es) 2005-05-09 2016-05-04 Biosphere Medical, S.A. Composiciones y métodos de uso de microesferas y agentes de contraste no iónicos
US20060270707A1 (en) * 2005-05-24 2006-11-30 Zeldis Jerome B Methods and compositions using 4-[(cyclopropanecarbonylamino)methyl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione for the treatment or prevention of cutaneous lupus
US20080167272A1 (en) * 2005-06-16 2008-07-10 Auckland Uniservices Limited Thalidomide metabolites and methods of use
PT2380887E (pt) * 2005-06-30 2013-09-18 Celgene Corp Processos para a preparação de compostos de 4-amino-2-(2,6-dioxopiperidin-3-il)isoindolina-1,3-diona
US20080279912A1 (en) * 2005-07-12 2008-11-13 Regents Of The University Of California Office Of Technology Transfer Use of Cis-Epoxyeicosatrienoic Acids And Inhibitors of Soluble Epoxide Hydrolase to Alleviate Eye Disorders
US20080138295A1 (en) * 2005-09-12 2008-06-12 Celgene Coporation Bechet's disease using cyclopropyl-N-carboxamide
US20070065514A1 (en) * 2005-09-22 2007-03-22 Howell Mark D Method for enhancing immune responses in mammals
CN1939922B (zh) * 2005-09-27 2010-10-13 天津和美生物技术有限公司 可抑制细胞释放肿瘤坏死因子的5H-噻吩[3，4-c]吡咯-4，6-二酮衍生物
AU2006301292A1 (en) * 2005-10-14 2007-04-19 F. Hoffmann-La Roche Ag Regimen of administration for 5-(2-chlorophenyl)-1 ,2-dihydro-7-fluoro-8-methoxy-3-methyl-pyrazolo (3, 4.-b) (1, 4) benzodiazepine
US20070155791A1 (en) * 2005-12-29 2007-07-05 Zeldis Jerome B Methods for treating cutaneous lupus using aminoisoindoline compounds
EP1986707A2 (en) 2006-01-30 2008-11-05 Surgica Corporation Compressible intravascular embolization particles and related methods and delivery systems
WO2007090130A2 (en) * 2006-01-30 2007-08-09 Surgica Corporation Porous intravascular embolization particles and related methods
WO2007109312A2 (en) * 2006-03-20 2007-09-27 Entremed, Inc. Disease modifying anti-arthritic activity of 2-methoxyestradiol
US20070226632A1 (en) * 2006-03-21 2007-09-27 Nokia Corporation Method, electronic device and computer program product for enhancing contact list functionality
AU2007238785B2 (en) * 2006-04-13 2013-02-07 Agnieszka Ambrozak Tetrahalogenated compounds useful as inhibitors of angiogenesis
WO2007136640A2 (en) * 2006-05-16 2007-11-29 Celgene Corporation Processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
US20080051431A1 (en) * 2006-05-26 2008-02-28 Dominique Verhelle Methods and compositions using immunomodulatory compounds in combination therapy
KR20090014393A (ko) * 2006-05-26 2009-02-10 셀진 코포레이션 조합 요법에서 면역조절 화합물을 사용하는 방법 및 조성물
WO2008007979A1 (en) * 2006-07-12 2008-01-17 Auckland Uniservices Limited (2,6-dioxo-3-piperinyl)amidobenzoic immunomodulatory and anti-cancer derivatives
PE20080403A1 (es) 2006-07-14 2008-04-25 Amgen Inc Derivados heterociclicos fusionados y metodos de uso
US8217177B2 (en) 2006-07-14 2012-07-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
WO2008011513A2 (en) 2006-07-19 2008-01-24 The Cleveland Clinic Foundation Compounds and methods of modulating angiogenesis
CL2007002218A1 (es) * 2006-08-03 2008-03-14 Celgene Corp Soc Organizada Ba Uso de 3-(4-amino-1-oxo-1,3-dihidro-isoindol-2-il)-piperidina 2,6-diona para la preparacion de un medicamento util para el tratamiento de linfoma de celula de capa.
CN101138634A (zh) 2006-09-07 2008-03-12 于保法 用于治疗肿瘤的组合物
US20080075690A1 (en) * 2006-09-22 2008-03-27 Mark Douglas Howell Method for enhancing immune responses in mammals
EP2114898A2 (en) 2007-02-16 2009-11-11 Amgen Inc. Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
EP2136831B1 (en) 2007-03-02 2012-09-12 The Cleveland Clinic Foundation Anti-angiogenic peptides
US20090068236A1 (en) * 2007-04-13 2009-03-12 Chemgenex Pharmaceuticals, Inc. Oral Cephalotaxine Dosage Forms
WO2009020590A1 (en) 2007-08-07 2009-02-12 Celgene Corporation Methods for treating lymphomas in certain patient populations and screening patients for said therapy
BRPI0815368A2 (pt) 2007-08-21 2015-02-10 Amgen Inc "proteinas c-fms humanas a antigeno"
JP2010539245A (ja) 2007-09-14 2010-12-16 日東電工株式会社 薬物担体
US11331294B2 (en) 2007-09-26 2022-05-17 Indiana University Research And Technology Corporation Benzoquinone derivative E3330 in combination with chemotherapeutic agents for the treatment of bladder cancer
WO2009042542A1 (en) * 2007-09-26 2009-04-02 Indiana University Research And Technology Corporation Benzoquinone derivative e3330 in combination with chemotherapeutic agents for the treatment of cancer and angiogenesis
WO2009060198A1 (en) 2007-11-09 2009-05-14 Peregrine Pharmaceuticals, Inc. Anti-vegf antibody compositions and methods
US20090137631A1 (en) * 2007-11-22 2009-05-28 National Yang-Ming University Methods and pharmaceutical compositions for regulation of g- and/or gc-rich nucleic acid expression
US20110200612A1 (en) 2008-06-30 2011-08-18 Michael Schuster Treatment of eye diseases and excessive neovascularization using combined therapy
AU2009274512A1 (en) 2008-07-25 2010-01-28 The Regents Of The University Of Colorado Clip inhibitors and methods of modulating immune function
JP2012507562A (ja) * 2008-10-30 2012-03-29 ダビド リウ 微小球性多孔質生体適合性足場並びにその製造方法及び装置
PT2391355T (pt) 2009-05-19 2017-02-21 Celgene Corp Formulações de 4-amino-2-(2,6-dioxopiperidin-3-il)isoindolino-1,3-diona
WO2010137547A1 (ja) 2009-05-25 2010-12-02 国立大学法人東京工業大学 中枢神経細胞の増殖及び分化に係る中核因子を含む医薬組成物
GB0914330D0 (en) 2009-08-17 2009-09-30 Univ Dublin City A method of predicting response to thalidomide in multiple myeloma patients
WO2011038139A1 (en) 2009-09-23 2011-03-31 Amgen Inc. Treatment of ovarian cancer using a specific binding agent of human angiopoietin-2 in combination with a taxane
WO2012078492A1 (en) 2010-12-06 2012-06-14 Celgene Corporation A combination therapy with lenalidomide and a cdk inhibitor for treating multiple myeloma
EP2649095B1 (en) 2010-12-10 2021-10-06 Aleksander S. Popel Mimetic peptides derived from collagen type iv and their use for treating angiogenesis- and lymphangiogenesis- dependent diseases
KR20160035613A (ko) 2011-03-23 2016-03-31 암젠 인크 Cdk 4/6 및 flt3의 융합된 트리사이클릭 이중 저해제
AU2012249491B2 (en) 2011-04-29 2016-12-15 Celgene Corporation Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor
JP6069312B2 (ja) 2011-06-29 2017-02-01 アムジェン インコーポレイテッド 腎細胞癌の治療における生存の予測バイオマーカー
US9745288B2 (en) 2011-08-16 2017-08-29 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
US20130058926A1 (en) * 2011-08-30 2013-03-07 Shiseido Company, Ltd. Method for alleviating and/or preventing skin reddening
ES2671608T3 (es) 2012-02-21 2018-06-07 Celgene Corporation Formas sólidas de 3-(4-nitro-1-oxoisoindolin-2-il)piperidina-2,6-diona
AR090263A1 (es) 2012-03-08 2014-10-29 Hoffmann La Roche Terapia combinada de anticuerpos contra el csf-1r humano y las utilizaciones de la misma
WO2014004990A2 (en) * 2012-06-29 2014-01-03 Celgene Corporation Methods for determining drug efficacy using cereblon-associated proteins
US9587281B2 (en) 2012-08-14 2017-03-07 Celgene Corporation Cereblon isoforms and their use as biomarkers for therapeutic treatment
AU2013204922B2 (en) 2012-12-20 2015-05-14 Celgene Corporation Chimeric antigen receptors
EP2954330A4 (en) 2013-02-08 2016-08-31 Inst Myeloma & Bone Cancer Res IMPROVED DIAGNOSTIC, PROGNOSTIC AND MONITORING METHODS FOR MULTIPLE MYELOMA, CHRONIC LYMPHOCYTIC LEUKEMIA AND NON-HODGKIN LYMPHOMA B-CELL LYMPHOMA
AU2014217485B2 (en) 2013-02-13 2017-02-16 Cartiheal (2009) Ltd Solid substrates for mitigating or preventing cell and tissue adhesion and vascularization
US10238690B2 (en) 2013-03-15 2019-03-26 Celgene Corporation Modified T lymphocytes comprising an inducible caspase and methods of apoptosis
EP2815749A1 (en) 2013-06-20 2014-12-24 IP Gesellschaft für Management mbH Solid form of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione having specified X-ray diffraction pattern
AU2015210999A1 (en) 2014-01-29 2016-07-21 Otsuka Pharmaceutical Co., Ltd. Device-based risk management of a therapeutic
EP4233870A3 (en) 2014-05-28 2024-01-24 Onco Tracker, Inc. Anti-cancer effects of jak2 inhibitors in combination with thalidomide derivatives and glucocorticoids
JP6640126B2 (ja) 2014-06-27 2020-02-05 セルジーン コーポレイション セレブロン及び他のｅ３ユビキチンリガーゼの立体構造の変化を誘導するための組成物及び方法
SG11201704175WA (en) 2014-11-26 2017-06-29 Baofa Yu Hapten-enhanced chemoimmunotherapy by ultra-minimum incision personalized intratumoral chemoimmunotherapy
US20190004048A1 (en) 2015-06-26 2019-01-03 Amgen Inc. Biomarker of Survival in the Treatment of Renal Cell Carcinoma with a VEGFR Inhibitor and an Ang2 Inhibitor
EP3324965A4 (en) 2015-07-24 2019-07-03 Oncotracker, Inc. MODULATORS OF GAMMA-SECRETASE FOR THE TREATMENT OF MALFUNCTIONS OF THE IMMUNE SYSTEM
WO2017117118A1 (en) 2015-12-28 2017-07-06 Celgene Corporation Compositions and methods for inducing conformational changes in cereblon and other e3 ubiquitin ligases
ES2898329T3 (es) 2016-01-12 2022-03-07 Oncotracker Inc Métodos mejorados para supervisar el estado inmunitario de un sujeto
WO2017173290A1 (en) * 2016-03-31 2017-10-05 Omeros Corporation Methods for inhibiting angiogenesis in a subject in need thereof
BR112019011065A2 (pt) 2016-12-03 2019-10-01 Juno Therapeutics Inc métodos para determinação da dosagem de células t car
WO2018102786A1 (en) 2016-12-03 2018-06-07 Juno Therapeutics, Inc. Methods for modulation of car-t cells
CR20190338A (es) 2016-12-22 2019-09-09 Amgen Inc Inhibidores de kras g12c y métodos para su uso
EP3576726A1 (en) 2017-02-06 2019-12-11 Massachusetts Institute Of Technology Methods and products related to glutaminase inhibitors
IL310031A (en) 2017-05-01 2024-03-01 Juno Therapeutics Inc A combination of cellular therapy and an immune modulatory compound
JOP20190272A1 (ar) 2017-05-22 2019-11-21 Amgen Inc مثبطات kras g12c وطرق لاستخدامها
US10093647B1 (en) 2017-05-26 2018-10-09 Celgene Corporation Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione dihydrate, compositions and methods of use thereof
AU2018275894A1 (en) 2017-06-02 2019-12-12 Juno Therapeutics, Inc. Articles of manufacture and methods for treatment using adoptive cell therapy
EP3639028A4 (en) 2017-06-13 2021-04-14 Inc. Onco Tracker DIAGNOSTIC, PROGNOSTIC AND MONITORING PROCEDURES FOR MALIGNE SOLID TUMORS
CA3067602A1 (en) 2017-06-29 2019-01-03 Juno Therapeutics, Inc. Mouse model for assessing toxicities associated with immunotherapies
US10513515B2 (en) 2017-08-25 2019-12-24 Biotheryx, Inc. Ether compounds and uses thereof
ES2928576T3 (es) 2017-09-08 2022-11-21 Amgen Inc Inhibidores de KRAS G12C y métodos de uso de los mismos
US10093649B1 (en) 2017-09-22 2018-10-09 Celgene Corporation Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione monohydrate, compositions and methods of use thereof
US10093648B1 (en) 2017-09-22 2018-10-09 Celgene Corporation Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione hemihydrate, compositions and methods of use thereof
WO2019089858A2 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Methods of assessing or monitoring a response to a cell therapy
US11623961B2 (en) 2017-11-01 2023-04-11 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for B-cell maturation antigen
JP2021508317A (ja) 2017-12-01 2021-03-04 ジュノー セラピューティクス インコーポレイテッド 遺伝子操作された細胞の投与および調節のための方法
WO2019118937A1 (en) 2017-12-15 2019-06-20 Juno Therapeutics, Inc. Anti-cct5 binding molecules and methods of use thereof
US10537585B2 (en) 2017-12-18 2020-01-21 Dexcel Pharma Technologies Ltd. Compositions comprising dexamethasone
WO2019210080A1 (en) * 2018-04-25 2019-10-31 The Regents Of The University Of California Methods and compositions for skeletal and neurological disorders
US11045484B2 (en) 2018-05-04 2021-06-29 Amgen Inc. KRAS G12C inhibitors and methods of using the same
AU2019262589B2 (en) 2018-05-04 2022-07-07 Amgen Inc. KRAS G12C inhibitors and methods of using the same
EP3790886A1 (en) 2018-05-10 2021-03-17 Amgen Inc. Kras g12c inhibitors for the treatment of cancer
MA52765A (fr) 2018-06-01 2021-04-14 Amgen Inc Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019241157A1 (en) 2018-06-11 2019-12-19 Amgen Inc. Kras g12c inhibitors for treating cancer
MX2020012261A (es) 2018-06-12 2021-03-31 Amgen Inc Inhibidores de kras g12c que comprenden un anillo de piperazina y uso de estos en el tratamiento del cancer.
EP3830093A1 (en) 2018-07-27 2021-06-09 Biotheryx, Inc. Bifunctional compounds as cdk modulators
US20220008477A1 (en) 2018-11-08 2022-01-13 Juno Therapeutics, Inc. Methods and combinations for treatment and t cell modulation
JP2020090482A (ja) 2018-11-16 2020-06-11 アムジエン・インコーポレーテツド Ｋｒａｓ ｇ１２ｃ阻害剤化合物の重要な中間体の改良合成法
SG11202105084VA (en) 2018-11-16 2021-06-29 Juno Therapeutics Inc Methods of dosing engineered t cells for the treatment of b cell malignancies
AU2019384118A1 (en) 2018-11-19 2021-05-27 Amgen Inc. KRAS G12C inhibitors and methods of using the same
JP7377679B2 (ja) 2018-11-19 2023-11-10 アムジエン・インコーポレーテツド がん治療のためのｋｒａｓｇ１２ｃ阻害剤及び１種以上の薬学的に活性な追加の薬剤を含む併用療法
JP2022513685A (ja) 2018-11-30 2022-02-09 ジュノー セラピューティクス インコーポレイテッド 養子細胞療法を用いた処置のための方法
CR20210387A (es) 2018-12-20 2021-08-19 Amgen Inc Inhibidores de kif18a
US20220056015A1 (en) 2018-12-20 2022-02-24 Amgen Inc. Kif18a inhibitors
CA3123044A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
JP2022514268A (ja) 2018-12-20 2022-02-10 アムジエン・インコーポレーテツド Ｋｉｆ１８ａ阻害剤
US20220096651A1 (en) 2019-01-29 2022-03-31 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for receptor tyrosine kinase like orphan receptor 1 (ror1)
SG11202109036WA (en) 2019-03-01 2021-09-29 Revolution Medicines Inc Bicyclic heteroaryl compounds and uses thereof
MX2021010323A (es) 2019-03-01 2021-12-10 Revolution Medicines Inc Compuestos bicíclicos de heterociclilo y usos de este.
EP3738593A1 (en) 2019-05-14 2020-11-18 Amgen, Inc Dosing of kras inhibitor for treatment of cancers
SG11202112855WA (en) 2019-05-21 2021-12-30 Amgen Inc Solid state forms
US20220372018A1 (en) 2019-08-02 2022-11-24 Amgen Inc. Kif18a inhibitors
WO2021026098A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
CA3147451A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
MX2022004656A (es) 2019-10-24 2022-05-25 Amgen Inc Derivados de piridopirimidina utiles como inhibidores de kras g12c y kras g12d en el tratamiento del cancer.
CA3160142A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
CN115873020A (zh) 2019-11-04 2023-03-31 锐新医药公司 Ras抑制剂
MX2022005525A (es) 2019-11-08 2022-06-08 Revolution Medicines Inc Compuestos de heteroarilo bicíclicos y usos de estos.
AU2020383535A1 (en) 2019-11-14 2022-05-05 Amgen Inc. Improved synthesis of KRAS G12C inhibitor compound
AU2020381492A1 (en) 2019-11-14 2022-05-26 Amgen Inc. Improved synthesis of KRAS G12C inhibitor compound
WO2021108683A1 (en) 2019-11-27 2021-06-03 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
EP4087611A1 (en) 2020-01-07 2022-11-16 Revolution Medicines, Inc. Shp2 inhibitor dosing and methods of treating cancer
US11897930B2 (en) 2020-04-28 2024-02-13 Anwita Biosciences, Inc. Interleukin-2 polypeptides and fusion proteins thereof, and their pharmaceutical compositions and therapeutic applications
CN115916194A (zh) 2020-06-18 2023-04-04 锐新医药公司 用于延迟、预防和治疗针对ras抑制剂的获得性抗性的方法
EP4208261A1 (en) 2020-09-03 2023-07-12 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
PE20231207A1 (es) 2020-09-15 2023-08-17 Revolution Medicines Inc Derivados indolicos como inhibidores de ras en el tratamiento del cancer
CA3203111A1 (en) 2020-12-22 2022-06-30 Kailiang Wang Sos1 inhibitors and uses thereof
KR20240004960A (ko) 2021-05-05 2024-01-11 레볼루션 메디슨즈, 인크. Ras 억제제
JP2024516450A (ja) 2021-05-05 2024-04-15 レボリューション メディシンズ インコーポレイテッド 共有結合性ｒａｓ阻害剤及びその使用
IL308195A (en) 2021-05-05 2024-01-01 Revolution Medicines Inc RAS inhibitors for cancer treatment
AR127308A1 (es) 2021-10-08 2024-01-10 Revolution Medicines Inc Inhibidores ras
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2023250400A1 (en) 2022-06-22 2023-12-28 Juno Therapeutics, Inc. Treatment methods for second line therapy of cd19-targeted car t cells
WO2024081916A1 (en) 2022-10-14 2024-04-18 Black Diamond Therapeutics, Inc. Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4552888A (en) * 1982-01-15 1985-11-12 Eli Lilly And Company Ascorbic acid ethers in angiogene
US5021404A (en) * 1988-04-20 1991-06-04 The Children's Medical Center Corporation Angiostatic collagen modulators

Family Cites Families (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB768821A (en) 1954-05-17 1957-02-20 Gruenenthal Chemie Novel products of the amino-piperidine-2, 6-dione series
US2830991A (en) * 1954-05-17 1958-04-15 Gruenenthal Chemie Products of the amino-piperidine-2-6-dione series
US3142672A (en) * 1957-09-03 1964-07-28 Takeda Pharmaceutical Derivatives of nu-alpha-phenyl-and nu-alpha-biphenylylbutyric acids and amino sugars
US3560495A (en) * 1965-05-08 1971-02-02 Ernst Frankus 1-heterocyclic amino methyl or 1-heterocyclic hydrazino methyl-3-phthalimido or (3',6'-dithia-3',4',5',6'-tetrahydrophthalimido)-pyrrolidinediones-2,5 or piperidinediones-2,6
US3563986A (en) * 1965-10-12 1971-02-16 Ernst Frankus 4 - phthalimido - n - heterocyclic amino methyl or piperidino hydrazino piperidine diones 2,6
DE1670551B2 (de) * 1965-10-30 1973-01-25 Salze trisubstituierter s-triazine
AT278739B (de) * 1966-11-08 1970-02-10 Kwizda Fa F Johann Verfahren zur Herstellung von neuen Anhydriden und Imiden substituierter Dicarbonsäuren
US3705162A (en) * 1967-07-01 1972-12-05 Gruenenthal Chemie 4-phthalimidine glutarimides
FI830078L (fi) * 1982-01-15 1983-07-16 Lilly Co Eli Askorbinsyraetrar och liknande foereningar
US4994443A (en) * 1982-12-20 1991-02-19 The Children's Medical Center Corporation Inhibition of angiogenesis
US5001116A (en) * 1982-12-20 1991-03-19 The Children's Medical Center Corporation Inhibition of angiogenesis
JP2544136B2 (ja) * 1986-05-23 1996-10-16 第一製薬株式会社 硫酸化多糖体ｄｓ４１５２を含有する血管新生抑制剤及び抗腫瘍剤
US4808402A (en) * 1987-05-29 1989-02-28 Northwestern University Method and compositions for modulating neovascularization
DE68910138T2 (de) * 1988-01-19 1994-04-28 Takeda Chemical Industries Ltd Fumagillin als angiostatisches Mittel.
AT393221B (de) * 1988-02-03 1991-09-10 Leopold Pharma Gmbh Mittel mit zerstoerender wirkung auf maligne tumore, verfahren zu dessen herstellung und praeparation zur anwendung in der therapie von krebskranken
ES2053890T3 (es) * 1988-09-01 1994-08-01 Takeda Chemical Industries Ltd Agente inhibidor de la angiogenesis.
US5049154A (en) * 1989-08-07 1991-09-17 Berkshire Research & Development, Inc. Adjustable intra-luminal valvulotome
JPH03109324A (ja) * 1989-09-22 1991-05-09 Microbial Chem Res Found 血管新生阻害剤
GB9000644D0 (en) * 1990-01-11 1990-03-14 Erba Carlo Spa New ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds
US5192744A (en) 1990-01-12 1993-03-09 Northwestern University Method of inhibiting angiogenesis of tumors
KR0166088B1 (ko) * 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도
US5405851A (en) * 1990-06-19 1995-04-11 Burroughs Wellcome Co. Pharmaceutical compounds
US5399363A (en) 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
WO1992014455A1 (en) * 1991-02-14 1992-09-03 The Rockefeller University METHOD FOR CONTROLLING ABNORMAL CONCENTRATION TNF α IN HUMAN TISSUES
ES2098505T3 (es) * 1991-04-17 1997-05-01 Gruenenthal Chemie Nuevos derivados de la talidomida, su procedimiento de preparacion y composiciones farmaceuticas que los contienen.
US5679696A (en) 1992-07-28 1997-10-21 Rhone-Poulenc Rorer Limited Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group
US6228879B1 (en) * 1997-10-16 2001-05-08 The Children's Medical Center Methods and compositions for inhibition of angiogenesis
US6114355A (en) * 1993-03-01 2000-09-05 D'amato; Robert Methods and compositions for inhibition of angiogenesis
US5629327A (en) * 1993-03-01 1997-05-13 Childrens Hospital Medical Center Corp. Methods and compositions for inhibition of angiogenesis
DE4320157A1 (de) 1993-06-18 1994-12-22 Bayer Ag Verwendung von 1,2,4-Dithiazolium-Salzen als Chemotherapeutica
US5605914A (en) 1993-07-02 1997-02-25 Celgene Corporation Imides
AU7376494A (en) 1993-08-04 1995-02-28 Andrulis Pharmaceuticals Corporation Treatment of rheumatoid arthritis with thalidomide alone or in combination with other anti-inflammatory agents
US5405855A (en) 1993-12-23 1995-04-11 Andrulis Pharmaceuticals Corp. Treatment of insulin resistant diabetes with thalidomine
US5434170A (en) 1993-12-23 1995-07-18 Andrulis Pharmaceuticals Corp. Method for treating neurocognitive disorders
US5443824A (en) 1994-03-14 1995-08-22 Piacquadio; Daniel J. Topical thalidomide compositions for surface or mucosal wounds, ulcerations, and lesions
DE69633040T2 (de) * 1995-03-17 2004-12-09 Toray Industries, Inc. Inhibitor der hornhaut-vaskularisation
US5643915A (en) 1995-06-06 1997-07-01 Andrulis Pharmaceuticals Corp. Treatment of ischemia/reperfusion injury with thalidomide alone or in combination with other therapies
US5731325A (en) * 1995-06-06 1998-03-24 Andrulis Pharmaceuticals Corp. Treatment of melanomas with thalidomide alone or in combination with other anti-melanoma agents
US5654312A (en) 1995-06-07 1997-08-05 Andrulis Pharmaceuticals Treatment of inflammatory and/or autoimmune dermatoses with thalidomide alone or in combination with other agents
US5798368A (en) * 1996-08-22 1998-08-25 Celgene Corporation Tetrasubstituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and method of reducing TNFα levels
US5635517B1 (en) * 1996-07-24 1999-06-29 Celgene Corp Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines
US6281230B1 (en) * 1996-07-24 2001-08-28 Celgene Corporation Isoindolines, method of use, and pharmaceutical compositions
AU771015B2 (en) 1999-03-18 2004-03-11 Celgene Corporation Substituted 1-oxo- and 1,3-dioxoisoindolines and their use in pharmaceutical compositions for reducing inflammatory cytokine levels

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4552888A (en) * 1982-01-15 1985-11-12 Eli Lilly And Company Ascorbic acid ethers in angiogene
US5021404A (en) * 1988-04-20 1991-06-04 The Children's Medical Center Corporation Angiostatic collagen modulators

Cited By (128)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7482005B2 (en) 1991-03-29 2009-01-27 Genentech, Inc. Methods of treating diseases with anti-VEGF antibodies
US6114355A (en) * 1993-03-01 2000-09-05 D'amato; Robert Methods and compositions for inhibition of angiogenesis
US6469045B1 (en) 1993-03-01 2002-10-22 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis with EM-138
US6977268B2 (en) 1993-03-01 2005-12-20 Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis with EM-138
US6420414B1 (en) 1993-03-01 2002-07-16 The Children's Medical Center Corporation Amino derivatives of EM-138 and methods of treating angiogenesis with same
US7524865B2 (en) 1993-03-01 2009-04-28 Celgene Corporation Methods and compositions for treating an ocular neovascular disease
EP0688771A1 (de) * 1994-06-24 1995-12-27 Grünenthal GmbH Verwendung von Lactamverbindungen als pharmazeutische Wirkstoffe
US6500845B1 (en) 1994-06-24 2002-12-31 Gruenenthal Gmbh Lactam derivatives as immunomodulating agents
US7081464B2 (en) 1995-08-29 2006-07-25 Celgene Corporation Topical compositions of cyclic amides as immunotherapeutic agents
EP0770390A1 (en) * 1995-11-01 1997-05-02 Dott Research Laboratory Nasally administrable compositions containing physiologically active peptides
US5908824A (en) * 1995-11-01 1999-06-01 Dott Research Laboratory Nasally administrable compositions containing physiologically active peptides
EP2305663A1 (en) * 1996-07-24 2011-04-06 Celgene Corporation Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and 1-oxoisoindolines and method of reducing TNF alpha levels
CZ304569B6 (cs) * 1996-07-24 2014-07-09 Celgene Corporation 1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindolin pro použití pro snížení nežádoucí hladiny TNFα u savce
WO1998003502A1 (en) * 1996-07-24 1998-01-29 Celgene Corporation Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels
EP1285916A1 (en) * 1996-07-24 2003-02-26 Celgene Corporation Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and -1-oxoisoindolines and method of reducing TNF alpha levels
US7041680B2 (en) 1996-07-24 2006-05-09 Celgene Corporation (R) and (S) isomers of substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and 1-oxoisoindolines and methods of using the same
EP2859895A1 (en) * 1996-07-24 2015-04-15 Celgene Corporation Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and 1-oxoisoindolines and method of reducing TNF alpha levels
EP2177517A1 (en) * 1996-07-24 2010-04-21 Celgene Corporation Amino substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimide for reducing TNF alpha levels
US7119106B2 (en) 1996-07-24 2006-10-10 Celgene Corporation Pharmaceutical compositions of 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline
EP2298300A1 (en) * 1996-11-05 2011-03-23 The Children's Medical Center Corporation Compositions for inhibition of anglogenesis comprising thalidomide and aspirin
EP1920773A1 (en) * 1996-11-05 2008-05-14 The Children's Medical Center Corporation Compositions for inhibition of anglogenesis
AU2005202596B2 (en) * 1996-11-05 2009-10-22 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
EP2143444A1 (en) * 1996-11-05 2010-01-13 The Children's Medical Center Corporation Compositions for inhibition of anglogenesis
EP1586322A3 (en) * 1996-11-05 2005-10-26 The Children's Medical Center Corporation Compositions for inhibition of anglogenesis
AU2010200186B2 (en) * 1996-11-05 2011-11-17 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
WO1998019649A3 (en) * 1996-11-05 1998-06-25 Childrens Medical Center Methods and compositions for inhibition of angiogenesis
AU780296B2 (en) * 1996-11-05 2005-03-17 Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US7435745B2 (en) 1996-11-05 2008-10-14 Celgene Corporation Methods and compositions for inhibition of angiogenesis
WO1998019649A2 (en) * 1996-11-05 1998-05-14 The Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US8039488B2 (en) 1996-11-05 2011-10-18 Children's Medical Center Corporation Methods and compositions for inhibition of angiogenesis
US5981508A (en) * 1997-01-29 1999-11-09 Vanderbilt University Facilitation of repair of neural injury with CM101/GBS toxin
US6569838B1 (en) 1997-01-29 2003-05-27 Vanderbilt University Facilitation of keloid healing with CM101/GBS toxin
US6476002B1 (en) 1997-01-29 2002-11-05 Vanderbilt University Treatment of chronic inflammatory diseases with CM101/GBS toxin
US6476001B1 (en) 1997-01-29 2002-11-05 Vanderbilt University Facilitation of repair of neural injury with CM101/GBS toxin
US6028060A (en) * 1997-01-29 2000-02-22 Vanderbilt University Treatment of chronic inflammatory diseases with CM101/GBS toxin
US5858991A (en) * 1997-01-29 1999-01-12 Vanderbilt University Facilitation of wound healing with CM101/GBS toxin
US7459466B2 (en) 1997-05-30 2008-12-02 Celgene Corporation Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and -1-oxoisoindolines and method of reducing TNFα levels
EP1486496A1 (en) * 1997-05-30 2004-12-15 Celgene Corporation Substituted 2-(2,6-Dioxopiperidin-3-YP)-Phthalimides and 1-Oxoisoindolines and method fo reducing TNF alpha levels
EP1956017A1 (en) * 1997-05-30 2008-08-13 Celgene Corporation Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and method of reducing TNF alpha levels
AU741982B2 (en) * 1997-05-30 2001-12-13 Celgene Corporation Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and 1-oxoisoindolines and method of reducing TNFalpha levels
WO1998054170A1 (en) * 1997-05-30 1998-12-03 Celgene Corporation SUBSTITUTED 2-(2,6-DIOXOPIPERIDIN-3-YL)-PHTHALIMIDES AND 1-OXOISOINDOLINES AND METHOD OF REDUCING TNFα LEVELS
US6518298B2 (en) 1997-10-16 2003-02-11 Entremed, Inc. Methods and compositions for inhibition of angiogenesis with EM-138
US6228879B1 (en) 1997-10-16 2001-05-08 The Children's Medical Center Methods and compositions for inhibition of angiogenesis
EP1308444A1 (en) * 1997-11-18 2003-05-07 Celgene Corporation Substituted 2-(2,6-Dioxo-3-Fluoropiperidine-3-YL)-Isoindolines and their use to reduce TNF-alpha Levels
EP1710242A1 (en) * 1997-11-18 2006-10-11 Celgene Corporation Substituted 2-(2,6-Dioxo-3-Fluoropiperidine-3-YL)-Isoindolines and their use to reduce TNF-alpha levels
US5955476A (en) * 1997-11-18 1999-09-21 Celgene Corporation Substituted 2-(2,6-dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing inflammatory cytokine levels
CZ299808B6 (cs) * 1997-11-18 2008-12-03 Celgene Corporation Substituované 2-(2,6-dioxo-3-fluoropiperidin-3-yl)izoindoliny a jejich použití za úcelem snížení hladin TNFalfa
US6670337B1 (en) 1998-01-29 2003-12-30 Yeda Reaearch And Development Co., Ltd. Facilitation of wound healing with CM101/GBS toxin
WO1999046258A1 (en) * 1998-03-13 1999-09-16 Celgene Corporation SUBSTITUTED 2-(2,6-DIOXO-3-FLUOROPIPERIDIN-3-YL)-ISOINDOLINES AND THEIR USE TO REDUCE TNFα LEVELS
AU749356B2 (en) * 1998-05-11 2002-06-27 Children's Medical Center Corporation Analogs of 2-phthalimidinoglutaric acid and their use as inhibitors of angiogenesis
WO1999058096A2 (en) 1998-05-11 1999-11-18 Entremed, Inc. Analogs of 2-phthalimidinoglutaric acid and their use as inhibitors of angiogenesis
WO1999058096A3 (en) * 1998-05-11 2000-05-18 Entremed Inc Analogs of 2-phthalimidinoglutaric acid and their use as inhibitors of angiogenesis
US6673828B1 (en) 1998-05-11 2004-01-06 Children's Medical Center Corporation Analogs of 2-Phthalimidinoglutaric acid
US7112602B2 (en) 1998-05-11 2006-09-26 The Children's Medical Center Corporation Methods of treating undesired angiogenesis with 2-methyl-EM-138
US8609614B2 (en) 1998-07-22 2013-12-17 Vanderbilt University GBS toxin receptor compositions and methods of use
WO2000041547A2 (en) * 1999-01-13 2000-07-20 The Rockefeller University Methods of promoting or enhancing interleukin-12 production through administration of thalidomide
WO2000041547A3 (en) * 1999-01-13 2000-11-30 Univ Rockefeller Methods of promoting or enhancing interleukin-12 production through administration of thalidomide
US6380239B1 (en) 1999-03-18 2002-04-30 Celgene Corporation Substituted 1-oxo- and 1,3-dioxoisoindoline and method of reducing inflammatory cytokine levels
EP1040838A1 (de) * 1999-03-31 2000-10-04 Grünenthal GmbH Stabile wässrige Lösung von EM 12
US6306879B1 (en) 1999-03-31 2001-10-23 Gruenenthal Gmbh Stable aqueous solution of 3-(1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2-6-dione
US8288415B2 (en) 1999-05-07 2012-10-16 Celgene Corporation Pharmaceutical compositions of 3-(4-amino-1-oxoisoindolin-2yl)-piperidine-2,6-dione
US7709502B2 (en) 1999-05-07 2010-05-04 Celgene Corporation Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and 1-oxoisoindolines
US7629360B2 (en) 1999-05-07 2009-12-08 Celgene Corporation Methods for the treatment of cachexia and graft v. host disease
US8158653B2 (en) 1999-05-07 2012-04-17 Celgene Corporation Pharmaceutical compositions of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-amino isoindoline
US7479499B2 (en) 2000-05-15 2009-01-20 Celgene Corporation Methods of using thalidomide in combination with irinotecan
US7435726B2 (en) 2000-05-15 2008-10-14 Celgene Corporation Compositions and methods for the treatment of cancer
US6914067B2 (en) 2000-05-15 2005-07-05 Celgene Corporation Compositions and methods for the treatment of colorectal cancer
US7834033B2 (en) 2000-11-14 2010-11-16 Celgene Corporation Methods for treating cancer using 3-[1,3dioxo-4-benzamidoisoindolin-2-yl]-2,6-dioxo-5-hydroxypiperidine
EP1226824A1 (en) * 2001-01-24 2002-07-31 TTY Biopharm Company Limited Use of thalidomide for the treatment of hepatocellular carcinoma
EP1389203B1 (en) * 2001-02-27 2009-12-02 The Governement of the United States of America, represented by The Secretary Department of Health and Human services Analogs of thalidomide as angiogenesis inhibitors
US8716315B2 (en) 2001-02-27 2014-05-06 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors
US7320991B2 (en) 2001-02-27 2008-01-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Analogs of thalidomide as potential angiogenesis inhibitors
US8735428B2 (en) 2002-05-17 2014-05-27 Celgene Corporation Methods for treating multiple myeloma with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
US7968569B2 (en) 2002-05-17 2011-06-28 Celgene Corporation Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
US8207200B2 (en) 2002-05-17 2012-06-26 Celgene Corporation Methods for treating multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroindol-2-yl)-piperidine-2,6-dione follow by autologous stem cell transplantation
US8198306B2 (en) 2002-05-17 2012-06-12 Celgene Corporation Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with a proteasome inhibitor
US8410136B2 (en) 2002-05-17 2013-04-02 Celgene Corporation Methods for treatment of hepatocellular carcinoma using 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione
US8492406B2 (en) 2002-05-17 2013-07-23 Celgene Corporation Methods for treatment of follicular lymphoma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione
US10206914B2 (en) 2002-05-17 2019-02-19 Celgene Corporation Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation
US8188118B2 (en) 2002-05-17 2012-05-29 Celgene Corporation Method for treating multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with antibodies
US8648095B2 (en) 2002-05-17 2014-02-11 Celgene Corporation Methods for treating multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with proteasome inhibitor
US8673939B2 (en) 2002-05-17 2014-03-18 Celgene Corporation Methods for treating multiple myeloma with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
US9393238B2 (en) 2002-05-17 2016-07-19 Celgene Corporation Methods for treating non-hodgkin's lymphoma with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in combination with a second active agent
US8722705B2 (en) 2002-05-17 2014-05-13 Celgene Corporation Methods for treating diffuse large B-cell lymphoma with 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with second active agents
US8722647B2 (en) 2002-05-17 2014-05-13 Celgene Corporation Methods for treating amyloidosis using 4-(amino)-2-(2,6-Dioxo(3-piperidyl))- isoindoline-1,3-dione
US9498472B2 (en) 2002-05-17 2016-11-22 Celgene Corporation Methods using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of certain leukemias
US8198262B2 (en) 2002-05-17 2012-06-12 Celgene Corporation Methods for treating multiple myeloma using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
US9283215B2 (en) 2002-05-17 2016-03-15 Celgene Corporation Methods for treating multiple myeloma using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione in combination with antibodies
US9155730B2 (en) 2002-05-17 2015-10-13 Calgene Corporation Methods for treating non-hodgkin's lymphoma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with a second active agent
US9050324B2 (en) 2002-05-17 2015-06-09 Celgene Corporation Methods for treating amyloidosis with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione
US9056103B2 (en) 2002-05-17 2015-06-16 Celgene Corporation Methods using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of certain leukemias
USRE48890E1 (en) 2002-05-17 2022-01-11 Celgene Corporation Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation
US9101621B2 (en) 2002-05-17 2015-08-11 Celgene Corporation Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation
US9101622B2 (en) 2002-05-17 2015-08-11 Celgene Corporation Methods for treating newly diagnosed multiple myeloma 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in combination with dexamethasone
US11116782B2 (en) 2002-10-15 2021-09-14 Celgene Corporation Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine
WO2005016326A3 (en) * 2003-07-11 2005-06-16 Us Gov Health & Human Serv Analogs of thalidomide as potential angiogenesis inhibitors
WO2005016326A2 (en) * 2003-07-11 2005-02-24 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Analogs of thalidomide as potential angiogenesis inhibitors
US8853253B2 (en) 2003-09-17 2014-10-07 P2D, Inc. Thalidomide analogs
US7973057B2 (en) 2003-09-17 2011-07-05 The United States Of America As Represented By The Department Of Health And Human Services Thalidomide analogs
US8546430B2 (en) 2003-09-17 2013-10-01 P2D, Inc. Thalidomide analogs
US10220028B2 (en) 2011-12-02 2019-03-05 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
US9623020B2 (en) 2011-12-02 2017-04-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
US9084783B2 (en) 2011-12-02 2015-07-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thio compounds
US10278953B2 (en) 2013-06-24 2019-05-07 Menlo Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
US9974769B2 (en) 2013-06-24 2018-05-22 Menlo Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
US9198898B2 (en) 2013-06-24 2015-12-01 Tigercat Pharma, Inc. Use of NK-1 receptor antagonists in pruritus
US9968588B2 (en) 2013-06-24 2018-05-15 Menlo Therapeutics Inc. Use of NK-1 receptor antagonists in pruritus
US10617671B2 (en) 2013-06-24 2020-04-14 Menlo Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
US11026920B2 (en) 2013-06-24 2021-06-08 Vyne Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
US9737508B2 (en) 2013-06-24 2017-08-22 Menlo Therapeutics Inc. Use of NK-1 receptor antagonists in pruritus
US10702499B2 (en) 2013-06-24 2020-07-07 Menlo Therapeutics Inc. Use of NK-1 receptor antagonists in pruritus
US9474741B2 (en) 2013-06-24 2016-10-25 Menlo Therapeutics Inc. Use of NK-1 receptor antagonists in pruritus
US9381188B2 (en) 2013-06-24 2016-07-05 Tigercat Pharma, Inc. Use of NK-1 receptor antagonists in pruritus
US9486439B2 (en) 2013-06-24 2016-11-08 Menlo Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
US10278952B2 (en) 2013-06-24 2019-05-07 Menlo Therapeutics Inc. Use of NK-1 receptor antagonists in pruritus
US9737507B2 (en) 2013-06-24 2017-08-22 Menlo Therapeutics Inc. Use of NK-1 receptor antagonist serlopitant in pruritus
US10034872B2 (en) 2014-08-22 2018-07-31 Celgene Corporation Methods of treating multiple myeloma with immunomodulatory compounds in combination with antibodies
US10017492B2 (en) 2014-10-30 2018-07-10 Kangpu Biopharmaceuticals, Ltd. Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
US10001483B2 (en) 2015-06-26 2018-06-19 Celgene Corporation Methods for the treatment of Kaposi's sarcoma or KSHV-induced lymphoma using immunomodulatory compounds, and uses of biomarkers
US10730835B2 (en) 2015-09-30 2020-08-04 The United States Of America, As Represented By The Secretary, Health And Human Services Thalidomide analogs and methods of use
US10836721B2 (en) 2015-09-30 2020-11-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thalidomide analogs and methods of use
AU2016330967B2 (en) * 2015-09-30 2021-03-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Thalidomide analogs and methods of use
WO2017059062A1 (en) * 2015-09-30 2017-04-06 Theunited States Of America, As Represented By The Secretary, Department Of Health And Human Service Thalidomide analogs and methods of use
US11440880B2 (en) 2015-09-30 2022-09-13 The Usa, As Represented By The Secretary, Department Of Health And Human Services Thalidomide analogs and methods of use
US11001575B1 (en) 2015-10-21 2021-05-11 Otsuka Pharmaceutical Co., Ltd. Benzolactam compounds as protein kinase inhibitors
US10457669B2 (en) 2015-10-21 2019-10-29 Otsuka Pharmaceutical Co., Ltd. Benzolactam compounds as protein kinase inhibitors
US11939321B2 (en) 2015-10-21 2024-03-26 Otsuka Pharmaceutical Co., Ltd. Benzolactam compounds as protein kinase inhibitors
US11142518B2 (en) 2017-04-20 2021-10-12 Otsuka Pharmaceutical Co., Ltd. 6-pyrimidin-isoindole derivative as ERK1/2 inhibitor

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