WO2008103320A1 - Méthodes de traitement de troubles ophtalmiques utilisant des anthraquinones - Google Patents

Méthodes de traitement de troubles ophtalmiques utilisant des anthraquinones Download PDF

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WO2008103320A1
WO2008103320A1 PCT/US2008/002099 US2008002099W WO2008103320A1 WO 2008103320 A1 WO2008103320 A1 WO 2008103320A1 US 2008002099 W US2008002099 W US 2008002099W WO 2008103320 A1 WO2008103320 A1 WO 2008103320A1
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oxide
amino
dione
bis
azaanthracene
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PCT/US2008/002099
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English (en)
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John G. Curd
Alshad S. Lalani
Jeffrey L. Cleland
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Novacea, Inc.
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Publication of WO2008103320A1 publication Critical patent/WO2008103320A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/732—Pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to compounds having activity for treating ophthalmic disorders. Further, the invention relates to methods of using the compounds, alone or in combination with one or more other active agents or treatments, to treat ophthalmic disorders.
  • Angiogenesis which is often referred to the generation and growth of new blood vessels into a tissue or organ, is key to neovascularization. Under normal physiological conditions, humans and other animals only undergo angiogenesis in very specific, restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonic development, and in the formation of the corpus luteum, endometrium and placenta. However, the angiogenesis process may be altered in a way that makes it pathologic. See U.S. patent 6,890,906 for further detail.
  • 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 new blood vessels.
  • Neovascularization can occur at almost any site in the eye and significantly alter ocular tissue function.
  • Some of the most threatening ocular neovascular diseases involve the retina.
  • many diabetic patients develop a retinopathy or a disorder, which is characterized by the formation of leaky, new blood vessels on the anterior surface of the retina and in the vitreous causing proliferative vitreoretinopathy.
  • Patients with age-related macular degeneration (“AMD”) may develop subretinal neovascularization which leads to their eventual blindness.
  • ALD age-related macular degeneration
  • pathologic neovascularization of the retina is the final common pathway of both proliferative diabetic retinopathy ("PDR") and retinopathy of the prematurity (“ROP”) (Lonchampt, M., et al, Invest. Ophthalmol. Vis. Sci. 42(2):429-32 (2001)) and is thought to play a role in proliferative vitreoretinopathy (Toti, P., et al. J. Submicrosc. Cystol. Pathol. 31(3):363-366 (1999)).
  • PDR proliferative diabetic retinopathy
  • ROP retinopathy of the prematurity
  • PDR and AMD are leading causes of blindness among older people in developed countries, constituting a growing health problem. For example, between six and 10 million Americans are blind from AMD, and hundreds of thousands new cases are diagnosed in the U. S. each year. Crabb, J. W., et al., Proc. Nat. Acad. Sci. 99(23): 14682-87 (2002).
  • Macular degeneration is characterized by the degeneration of macula, the small portion of the central retina responsible for high-acuity vision.
  • the causal events responsible for AMD are not well understood, the presence of numerous and/or confluent, soft drusen in the macula is considered a major risk factor in developing AMD. Indeed, many clinicians refer to individuals with soft drusen in the macula as an early stage of AMD, even in the absence of any vision loss. See Crabb et al.
  • ROP retinal vascular disease associated with oxygen supplementation in the premature infant.
  • ROP occurs in two phases. In the hyperaxia phase (i.e., during oxygen supplementation), cessation of retinal vessel growth is accompanied by suppression of VEGF expression, hi the second phase, lack of retinal vessels causes hypoxia, which induces VEGF expression and stimulates pathological vascularization at the junction of the avascular and vascularized retina. Shih, S.-C, et al, J. CHn. Invest., 112:50-57 (2003).
  • Proliferative vitreoretinopathy is characterized by the formation of contractile cellular membranes on both sides of the retina. While the pathobiology of proliferative vitreoretinopathy is not clear, it appears that retinal pigment epithelium (“RPE”) cells are key to the development of these membranes.
  • RPE retinal pigment epithelium
  • a large body of evidence supports the concept that previously quiescent RPE cells, when displaced into the vitreous cavity and exposed to the appropriate combination of cytokines, will divide and differentiate. Evidence indicates retinal tears as the pathway through which RPE cells move in order to enter the vitreous cavity, and there is an association between the size of a retinal tear and the incidence of proliferative vitreoretinopathy.
  • the RPE cells remain attached to the retinal flap as the retina is displaced into the vitreous cavity or are introduced into the vitreous cavity following cryotherapy of the retina and RPE during retinal detachment repair. See U.S. patent 6,869,935 for further detail.
  • VisudyneTM Photodynamic Therapy An example of a photodynamic therapy, which is recently approved by FDA, is VisudyneTM Photodynamic Therapy. This photodynamic therapy is indicated for the treatment of AMD in patients with predominantly classic subfoveal choroidal neovascularization. VisudyneTM therapy is a two- step procedure that can be performed in a doctor's office. First, VisudyneTM, a light-sensitive drug, is injected intravenously into a patient. VisudyneTM appears to preferentially accumulate in neovasculature, including choroidal neovasculature.
  • the drug is activated by shining a 689 nm laser light delivered to the retina as a single circular spot via a fiber optic and a slit lamp. See Visudyne product insert, distributed by CIBA Vision, A Novartis Company, Duluth, Ga.
  • Angiogenesis is a complex multi-step process that involves the out-sprouting of vascular endothelial cell proliferation, extracellular matrix remodeling, endothelial cell migration and capillary tube formation.
  • VEGF vascular endothelial growth factor
  • VEGF is a 46-kDa homodimeric glycopeptide, which is expressed by, among others, pigment epithelial cells and vascular endothelial cells, is a potent endothelial-cell-specific mitogen. Brainbridge, et al. Clin. Sd. 104:561-75 (2003).
  • VEGF is an attractive target molecule for angiostatic strategies both in the eye and elsewhere.
  • Some anti- VEGF strategies to control ocular neovascularization in experimental models include neutralizing anti-VEGF monoclonal antibodies, soluble VEGF-receptor chimaeric proteins, oligonucleotides and inhibition of VEGF-specific protein kinase. Brainbridge et al., supra.
  • One approach is systemic administration of an anti-VEGF or an angiostatic substance.
  • PEDF pigment epithelium derived factor
  • angiostatic agents appear to offer significant potential advantage.
  • intraocular neovascularization in experimental models decreases by repeated intravitreal injections of neutralizing anti-VEGF monoclonal antibody, recombinant soluble VEGF-receptor chimeric proteins, and antisense oligodeoxynucleotides. Brainbridge et al, 566.
  • the choroidal neovascularization may be selectively targeted via chimeric antibodies. Kijlstra, A., et al., Ocul. Immunol. Inflam. 13:3-11 (2005).
  • a chimeric antibody composed of factor VII conjugated to the Fc domain of an IgGl immunoglobulin, is administered.
  • Factor VII which is the natural ligand for tissue factor, binds to tissue factor, which is selectively expressed on neovascular endothelial cells but not in the normal retinal or choroidal vessels.
  • the endothelial cells After binding of the chimeric antibody, the endothelial cells are cytolyzed via Fc domain-mediated action involving killer cells and activation of the complement system. Treatment of animals with this chimeric antibody prevented the formation of laser induced choroidal neovascularization. Kijlstra, A. et al.
  • Aukunuru et al. teach that intracellular delivery of VEGF antisense oligonucleotides may inhibit VEGF secretion and expression.
  • Aukunuru et al. used a 19-mer antisense phosphorothionate oligonucleotide ("PS-ODN") complementary to bases 6-24 relative to the translational start site of VEGF mRNA.
  • PS-ODN 19-mer antisense phosphorothionate oligonucleotide
  • Intracellular ⁇ delivered 19-mer inhibited VEGF mRNA and protein secretion.
  • siRNA small interfering RNAs
  • target RNA e.g., homologous RNAs in mammalian cells.
  • siRNA directed against VEGF genes reduces the amount of VEGF protein produced under hypoxic conditions. Reich, S. J. et al., MoI. Vision, 9:210-16 (2003).
  • Kijlstra, A. et al. disclose an anti-VEGF therapy that uses anti-VEGF pegylated aptamer EYEOOl (Macugen®), which is a polyethylene glycol (PEG)-conjugated oligonucleotide that binds to the major soluble human VEGF isoform VEGFj 65 .
  • Kijlstra, A. et al. Ocul. Immunol. Inflam. 13:3-11 (2005).
  • Macugen® pegaptanib sodium injection
  • U.S. patent 6,884,879 discloses anti-VEGF antagonistic antibodies which are capable of inhibiting angiogenic activities of VEGF. These anti-VEGF monoclonal antibodies are also candidates for the treatment of various intraocular neovascular disorders.
  • An example of such an anti-VEGF antibody is Genetech's ranibizumab (LucentisTM), which is currently in clinical phase III trial. Ranibizumab is a humanized therapeutic antibody that binds to VEGF and inhibits its activity, thus blocking neovascularization, which is thought to lead to AMD.
  • Bioreductive anticancer prodrugs have also been tested for their retinal toxicity and the toxicity correlated with the extent of retinal hypoxia.
  • Some bioreductive drugs e.g., ((2R)-l-[(2-bromoethyl)amino]-3-(2-nitro-lH- imidazol-l-yl)-2-propanol hydrobromide) cause extensive apoptosis in the outer retina in rodents and monkeys.
  • bioreductive drugs e.g., ((2R)-l-[(2-bromoethyl)amino]-3-(2-nitro-lH- imidazol-l-yl)-2-propanol hydrobromide
  • U.S. Patent No. 5,132,327 describes a group of anthraquinone prodrug compounds having the following structure:
  • R 1 , R 2 , R 3 and R 4 are each separately selected from the group consisting of hydrogen, X, NH-A-NHR and NH-A-N(O)R 1 R" wherein X is hydroxy, halogeno, amino, Ci -4 alkoxy or C 2-8 alkanoyloxy,
  • A is a C 2-4 alkylene group with a chain length between NH and NHR or N(O)R 1 R" of at least 2 carbon atoms and R
  • R' and R" are each separately selected from the group consisting of Ci -4 alkyl groups and C 2-4 hydroxyalkyl and C 2-4 dihydroxyalkyl groups in which the carbon atom attached to the nitrogen atom does not carry a hydroxy group and no carbon atom is substituted by two hydroxy groups, or
  • R' and R" together are a C 2-6 alkylene group which with the nitrogen atom to which R' and R" are attached forms a heterocyclic group having 3 to 7 atoms in the ring,
  • AQ4N has been shown to have potent anti-hyperproliferative activity and to enhance the antitumor effects of radiation and conventional chemotherapeutic agents. Patterson, Drug Metab. Rev. 34:581 (2002).
  • AQ4N is not intrinsically cytotoxic; in hypoxic tumors it is converted to the cytotoxic compound AQ4 (l,4-bis ⁇ [2- (dimethylamino)ethyl]amino ⁇ -5,8-dihydroxyanthracene-9,10-dione).
  • Among the activities associated with AQ4 are intercalation into DNA and inhibition of topoisomerase ⁇ activity.
  • the present invention is related to compositions and methods for treating ophthalmic disorders.
  • One aspect of the invention is drawn to methods for treating, ameliorating or preventing ophthalmic disorders comprising administering to an animal in need thereof a therapeutically effective amounts of compounds having Formula I:
  • X and Y are independently C-R 4 , C-OH or N;
  • Z is C-R 4 or N
  • W is oxygen or is absent
  • R 1 and R 2 are independently hydrogen, halo, alkyl, carboxyl, carboxylester, carboxylamide, thioalkyl, hydroxy, alkoxy, aryloxy, sulfonyl, sulfonic acid, or polyethylene glycol, or R 1 and R 2 together form an aryl or heteroaryl group;
  • R 3 and R 4 independently are hydrogen or fluorine, or R 3 and R 4 together form an aryl group
  • R 5 and R 6 independently are hydrogen, alkyl, or hydroxyalkyl; or R 1 and R 5 together, and/or R 2 and R 6 together, form a carbocyclic or heterocyclic ring;
  • R 7 and R 8 are independently alkyl, hydroxyalkyl, haloalkyl, or together with the neighboring nitrogen form a heterocycle;
  • R 9 and R 10 are independently alkyl, hydroxyalkyl, haloalkyl, or together with the neighboring nitrogen form a heterocycle;
  • a and B independently are (CH 2 ),!, cycloalkyl, heterocyclic, or aryl, or with the two neighboring nitrogens forms a heterocycle; and
  • n is 1, 2, 3, or 4.
  • An additional aspect of the present invention is a method for treating, ameliorating, or preventing an ophthalmic disorder in an animal comprising administering to the animal a therapeutically effective amount of a compound having formula I in combination with one or more active agents or treatments.
  • the ophthalmic disorder is age- related macular degeneration, retinopathy of prematurity, proliferative diabetic retinopathy or proliferative vitreoretinopathy.
  • the one or more anti-VEGF substances can be any anti-VEGF agent which is used, has been used, or is known to be useful for the treatment of ophthalmic disorders.
  • the one or more other active agents are independently selected from the group consisting of VEGF antagonists, anti- VEGF monoclonal antibody, soluble VEGF-receptor chimaeric protein, antisense oligonucleotides, antisense oligodexoynucleotides, siRNAs, anti- VEGF aptamers and pigment epithelium derived factor.
  • the one or more treatments are selected from the group consisting of eye surgery, photocoagulation therapy, cryotherapy, photodynamic therapy and intraocular steroidal injections.
  • the compound having Formula I can be administered prior to, during, and/or beyond administration of the one or more anti-VEGF agents and/or treatments.
  • the method of administering a compound having Formula I in combination with one and/or more anti-VEGF agents and/or treatments is repeated more than once.
  • the combination of a compound having Formula I and one or more anti-VEGF agents and/or treatments of the present invention will have additive potency or an additive therapeutic effect.
  • the invention also encompasses synergistic combinations where the therapeutic efficacy is greater than additive. Preferably, such combinations will reduce or avoid unwanted or adverse effects.
  • the combination therapies encompassed by the invention will provide an improved overall therapy relative to administration of a compound having Formula I or any anti-VEGF agent or treatment alone.
  • doses of existing or experimental anti-VEGF agents or treatments will be reduced or administered less frequently which will increase patient compliance, thereby improving therapy and reducing unwanted or adverse effects.
  • compositions and methods of treating, ameliorating or preventing an ophthalmic disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound having Formula I:
  • X and Y are independently C-R 4 , C-OH or N;
  • Z is C-R 4 or N
  • W is oxygen or is absent
  • R 1 and R 2 are independently hydrogen, halo, alkyl, carboxyl, carboxylester, carboxylamide, thioalkyl, hydroxy, alkoxy, aryloxy, sulfonyl, sulfonic acid, or polyethylene glycol, or R 1 and R 2 together form an aryl or heteroaryl group;
  • R 3 and R 4 independently are hydrogen or fluorine, or R 3 and R 4 together form an aryl group
  • R 5 and R ⁇ independently are hydrogen, alkyl, or hydroxyalkyl; or Ri and R 5 together, and/or R 2 and R 6 together, form a carbocyclic or heterocyclic ring;
  • R 7 and R 8 are independently alkyl, hydroxyalkyl, haloalkyl, or together with the neighboring nitrogen form a heterocycle;
  • R 9 and Rio are independently alkyl, hydroxyalkyl, haloalkyl, or together with the neighboring nitrogen form a heterocycle;
  • a and B independently are (CH 2 ) n , cycloalkyl, heterocyclic, or aryl, or with the two neighboring nitrogens forms a heterocycle; and n is 1, 2, 3, or 4.
  • R 1 is hydrogen, halo or optionally substituted alkyl or alkoxy
  • R 2 , R 3 , and R 4 are hydrogen or halo.
  • the compounds are selected from the compounds shown below and their corresponding non-N-oxide compounds.
  • the invention is drawn to methods employing compounds having Formula HI and their corresponding non-N-oxide compounds: wherein X is (CH 2 ) m and m is 0 to 5.
  • the compounds are selected from the compounds shown below and their corresponding non-N-oxide compounds.
  • Z is (CH2) m and m is 0 to 5.
  • the compounds are selected from the compounds shown below and their corresponding non-N-oxide compounds.
  • Z is (CH 2 ) m and m is 0 to 5.
  • the compounds are selected from the compounds shown below and their corresponding non-N-oxide compounds.
  • a and B are independently cycloalkyl or heterocyclic groups containing 4-12 ring atoms.
  • the compounds are selected from the compounds shown below and their corresponding non-N-oxide compounds.
  • W is CH 2 , O, S, or NRn, wherein R 11 is hydrogen or alkyl.
  • R 11 is hydrogen or alkyl.
  • the compounds are selected from the compounds shown below and their corresponding non-N-oxide compounds.
  • W is CH 2 , O, S, or NRn, wherein Rn is hydrogen or alkyl.
  • Rn is hydrogen or alkyl.
  • R) and R 2 together and/or R 3 and R 4 together form an aryl or heteroaryl group hi particular embodiments the compounds are selected from the compounds shown below and their corresponding non-N-oxide compounds.
  • the invention is drawn to methods employing compounds having Formula X and their corresponding non-N-oxide compounds: wherein at least one of R 7 , R 8 , Rg, and R 10 is haloalkyl.
  • the compounds are selected from the compounds shown below and their corresponding non-N-oxide compounds.
  • the invention is drawn to methods employing compounds having Formula XI and their corresponding non-N-oxide compounds: R 8 ) n ) n R 10 ⁇ i or a pharmaceutically acceptable salt thereof, wherein:
  • R 7 , R 8 , Rg and R ]0 are independently Ci -4 alkyl, C 2-4 hydroxyalkyl, C 2-4 dihydroxyalkyl in which the carbon atom attached to the nitrogen atom does not carry a hydroxy group and no carbon atom is substituted by two hydroxy groups, W is oxygen or is absent; and n is 2 to 4.
  • the compounds are selected from:
  • Useful alkyl groups include straight-chained or branched C MO alkyl groups, especially methyl, ethyl, propyl, isopropyl, t-butyl, sec-butyl, 3-pentyl, adamantyl, norbornyl, and 3-hexyl groups.
  • Useful aryl groups include C 6-I4 aryl, especially phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups.
  • Useful cycloalkyl groups are C 3-8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
  • Useful haloalkyl groups include Ci -1O alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.
  • Useful alkoxy groups include oxygen substituted by one of the Ci-io alkyl groups mentioned above, which may be optionally substituted.
  • Useful alkylthio groups include sulphur substituted by one of the C 1- I 0 alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
  • Useful heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperizinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, mo ⁇ holinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.
  • a therapeutically effective amount of a compound having Formula I, or a pharmaceutically acceptable salt thereof, and at least one other active agent is provided in the form of a pharmaceutical composition having at least one pharmaceutically acceptable carrier.
  • the at least one other active agent is an anti-VEGF agent.
  • Compounds having Formula I may be formulated in a single formulation with the other active agent(s), or formulated independently.
  • anti-VEGF agents include VEGF antagonists, anti-VEGF monoclonal antibodies, soluble VEGF-receptor chimaeric proteins, antisense oligonucleotides, antisense oligodexoynucleotides, siRNAs, anti-VEGF aptamers and pigment epithelium derived factor.
  • methods for treating, ameliorating, or preventing an ophthalmic disorder are provided, wherein a therapeutically effective amount of a compound having Formula I, or a pharmaceutically acceptable salt thereof, is administered to an animal in need thereof.
  • a further aspect of the invention relates to methods for treating, ameliorating, or preventing an ophthalmic disorder comprising administering a therapeutically effective amount of a compound having Formula I, or a pharmaceutically acceptable salt thereof, in combination with at least one other active agent or treatment to a patient in need thereof.
  • combinations of a compound having Formula I with an anti-VEGF agent are administered.
  • Ophthalmic disorders which can be treated with the compositions comprising compounds having Formula I include any hypoxia-aggravated ophthalmic disorders.
  • hypoxia-aggravated ophthalmic disorders include proliferative vitreoretinopathy, age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of the prematurity.
  • Animals which may be treated according to the present invention include all animals which may benefit from administration of compounds having Formula I. Such animals include humans, pets such as dogs and cats, and veterinary animals such as cows, pigs, sheep, goats and the like.
  • ophthalmic disorder includes proliferative vitreoretinopathy, age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of the prematurity.
  • anti-VEGF refers to one or more compounds having inhibitory effect on the activity of VEGF. Such inhibitory effect may be due to down-regulation of the gene that regulates the production of VEGF, inhibition of the mRNA responsible for the biosynthesis of VEGF or direct inhibition of VEGF itself such that while it is produced, its activity is reduced or totally inhibited.
  • anti-VEGF compounds include, but are not limited to, VEGF antagonists, anti-VEGF monoclonal antibody, soluble VEGF-receptor chimaeric protein, antisense oligonucleotides, antisense oligodexoynucleotides, siRNAs, anti-VEGF aptamers and pigment epithelium derived factor.
  • compositions and methods of the present invention may be used in combination with any treatment known to prevent, ameliorate or treat ophthalmic disorders including, but not limited to, photodynamic therapy, surgical treatments, photocoagulation therapies (including laser surgery), cryotherapy and intraocular steroidal injections.
  • Surgical treatments include pneumatic retinopexy, scleral buckling, vitrectomy, macular translocation and retinal cell transplantation.
  • Photocoagulation therapies include pan-retinal photocoagulation and transpupillary thermotherapy.
  • Photodynamic therapy is a laser technique for the treatment of wet
  • AMD uses a laser-sensitive drug called verteporfin (Visudyne) that is administered intravenously.
  • the drug accumulates in the unhealthy blood vessels beneath the macula.
  • the substance destroys the diseased vessels.
  • Pneumatic retinopexy treatment typically involves injection of a gas bubble into the vitreous space inside the eye enabling the gas bubble to push the retinal tear back against the wall of the eye and close the tear.
  • Laser or cryosurgery is used to secure the retina to the eye wall around the retinal tear. The gas bubble will gradually disappear.
  • Scleral buckling involves creating an adhesion between the area that surrounds retinal tear and the RPE. Such adhesion is obtained either by burning or by freezing the external wall of the eye in the correct location. A silicone rubber implant is then placed on the external wall of the eye over the location of the retinal tear. A drainage hole is then made in the outer wall of the eye, releasing the fluid located between the detached retina and RPE. Once the fluid is removed, the sutures that hold the silicone rubber implant in place are tightened and a permanent indentation of the globe results.
  • Vitrectomy surgery is typically performed to clear blood and debris from the eye, to remove scar tissue, or to alleviate traction on the retina. Blood, inflammatory cells, debris, and scar tissue obscure light as it passes through the eye to the retina, resulting in blurred vision. The vitreous is also removed if it is pulling or tugging the retina from its normal position.
  • Macular translocation involves detaching the retina and relocating the macula away from the blood vessel growth. The abnormal blood vessels are then destroyed using, for example, photodynamic therapy.
  • Retinal cell transplantation involves either RPE cell transplants or photoreceptor cell transplants. Since RPE cells are implicated in many ophthalmic disorders, RPE cell transplants are thought to prevent, halt or slow the progress of the disorders. Photoreceptor cell transplants are intended to restore vision by transplanting healthy, functioning photoreceptor cells.
  • Pan-retinal photocoagulation therapy typically involves the use of an intense beam of light, including laser, in the eye to coagulate targeted tissues in the retina and is used to treat retinal detachments, retinal holes, aneurysms, hemorrhages, and malignant and benign neoplasms.
  • Targeted laser applications can treat specific areas in the central vision that are leaking.
  • Transpupillary thermotherapy ( 11 TTT") is a technique in which heat is delivered to the choroid and retinal pigment epithelium through the pupil using a modified diode laser.
  • This laser technique contrasts with the laser used in standard photocoagulation therapy in that TTT uses a low power laser for prolonged periods of time and is designed to gently heat the choroidal lesion, thus limiting damage to the overlying retinal pigment epithelium.
  • TTT uses laser energy to coagulate vessels in the wet form of AMD and is typically intended to alter the disease process and preserve vision.
  • Cryotherapy typically involves freezing areas of retinal tears to seal the retina to the back wall of the eye. Cryotherapy is typically used to prevent progression to a retinal detachment.
  • Intraocular steroidal injections are used to close a leaking blood vessel without destroying the overlying retina.
  • compositions and methods of the present invention include antioxidant and zinc therapy where antioxidant vitamins such as beta-carotene (vitamin A) and vitamins C and E and zinc are used to prevent the development of AMD.
  • antioxidant vitamins such as beta-carotene (vitamin A) and vitamins C and E and zinc are used to prevent the development of AMD.
  • the compositions and methods of the present invention may also combined in combination with gene therapy.
  • non-N-oxide refers to an amine compound that is not oxidized at the nitrogen atom.
  • AQ4 is the non-N-oxide form of AQ4N.
  • compositions are to be understood as defining compositions of which the individual components or ingredients are themselves pharmaceutically acceptable, e.g., where oral administration is foreseen, acceptable for oral use; where topical administration is foreseen, topically acceptable; and where intravenous administration is foreseen, intravenously acceptable.
  • a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to result in amelioration of one or more symptoms of a disorder, or prevent advancement of a disorder, or cause regression of the disorder.
  • a therapeutically effective amount preferably refers to the amount of a therapeutic agent that decreases the rate of neovascularization, decreases rate of retina detachment, or increases time to retina detachment by at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
  • prevention refers to a decrease in the occurrence of pathological neovascularization in an animal.
  • the prevention may be complete, e.g., the total absence of pathological neovasculature in a subject.
  • the prevention may also be partial, such that the occurrence of pathological neovasculature in a subject is less than that which would have occurred without the present invention.
  • compositions having Formula I can be provided as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate and oxalate; and inorganic and organic base addition salts with bases such as sodium hydroxy, Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and N-methyl-glucamine.
  • TMS Tris(hydroxymethyl)aminomethane
  • the salts typically have similar physiological properties compared to the free base, certain acid addition salts may demonstrate preferred physicochemical properties, e.g., enhanced solubility, improved stability.
  • One particular pharmaceutically acceptable salt is the maleate, such as the dimaleate.
  • Certain of the compounds of the present invention may exist as stereoisomers including optical isomers.
  • the invention includes all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
  • compounds having Formula I are administered in combination with one or more other active agents (e.g., anti-VEGF agents) or treatments.
  • active agents e.g., anti-VEGF agents
  • a patient may be treated for an ophthalmic disorder by the administration of a therapeutically effective amount of a compound having Formula I in combination with anti-VEGF agent/treatment.
  • In combination refers to the use of more than one treatment.
  • the use of the term “in combination” does not restrict the order in which treatments are administered to a subject being treated for an ophthalmic disorder.
  • a first treatment can be administered prior to, concurrently with, after, or within any cycling regimen involving the administration of a second treatment to a subject with an ophthalmic disorder.
  • the first treatment can be administered 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before a treatment; or the first treatment can be administered 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after a second treatment.
  • Such treatments include, for example, the administration of compounds having Formula I in combination with one or more anti-VEGF agents and/or treatments.
  • the pharmaceutical compositions of the present invention may further comprise one or more additives.
  • Additives that are well known in the art include, e.g., detackifiers, anti-foaming agents, buffering agents, antioxidants (e.g., ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, malic acid, fumaric acid, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, and tocopherols, e.g., ⁇ -tocopherol (vitamin E)), preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacif ⁇ ers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • the amounts of such additives can be readily determined by one skilled in the art, according to the particular
  • the additive may also comprise a thickening agent.
  • suitable thickening agents may be of those known and employed in the art, including, e.g., pharmaceutically acceptable polymeric materials and inorganic thickening agents.
  • Exemplary thickening agents for use in the present pharmaceutical compositions include polyacrylate and polyacrylate co-polymer resins, for example poly-acrylic acid and poly-acrylic acid/methacrylic acid resins; celluloses and cellulose derivatives including: alkyl celluloses, e.g., methyl-, ethyl- and propyl-celluloses; hydroxyalkyl-celluloses, e.g., hydroxypropyl- celluloses and hydroxypropylalkyl-celluloses such as hydroxypropyl-methyl- celluloses; acylated celluloses, e.g., cellulose-acetates, cellulose- acetatephthallates, cellulose-acetatesuccinates and hydroxypropylmethyl- cellulose phthallates; and
  • Such thickening agents as described above may be included, e.g., to provide a sustained release effect. However, where oral administration is intended, the use of thickening agents may not be required. Use of thickening agents is, on the other hand, indicated, e.g., where topical application is foreseen.
  • compounds having Formula I are formulated as described in WO 03/076387.
  • the compounds are formulated such that upon dissolution in aqueous solution the pH of the solution is in the range of 5 to 9.
  • the dosage of the compound having Formula I will vary according to the activity and/or toxicity of the particular compound, the condition being treated, and the physical form of the pharmaceutical composition being employed for administration, it may be stated by way of guidance that a dosage selected in the range from 0.1 to 20 mg/kg of body weight per day will often be suitable, although higher dosages, such as 0.1 to 50 mg/kg of body weight per day may be useful. Those of ordinary skill in the art are familiar with methods for determining the appropriate dosage.
  • Methods for assessing the toxicity, activity and/or selectivity of the compounds having Formula I may be carried out as described in Lee et ai, supra, and PCT Published International Application WO 92/15300, supra, and may be useful for approximating and/or determining dose ranges for compounds having Formula I.
  • the dosage of the compounds having Formula I will be lower, e.g., when used in combination with at least a second ophthalmic disorder treatment, and may vary according to the activity and/or toxicity of the particular compound, the condition being treated, and the physical form of the pharmaceutical composition being employed for administration.
  • the compound having Formula I will preferably be present in an amount of between 0.01 and 2000 mg per unit dose. More preferably, the amount of compound having Formula I per unit dose will be about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, or 2000 mg or any amount therein.
  • the total quantity of ingredients present in the capsule is preferably about 10-1000 ⁇ L. More preferably, the total quantity of ingredients present in the capsule is about 100-300 ⁇ L. In another embodiment, the total quantity of ingredients present in the capsule is preferably about 10-1500 mg, preferably about 100- 1000 mg.
  • the relative proportion of ingredients in the compositions of the invention will, of course, vary considerably depending on the particular type of composition concerned.
  • the relative proportions will also vary depending on the particular function of ingredients in the composition.
  • the relative proportions will also vary depending on the particular ingredients employed and the desired physical characteristics of the product composition, e.g., in the case of a composition for topical use, whether this is to be a free flowing liquid or a paste. Determination of workable proportions in any particular instance will generally be within the capability of a person of ordinary skill in the art. All indicated proportions and relative weight ranges described below are accordingly to be understood as being indicative individually inventive teachings only and not as not limiting the invention in its broadest aspect.
  • compositions of the invention will of course vary, e.g., depending on the intended route of administration and to what extent other components are present. In general, however, the compound having Formula I will suitably be present in an amount of from about 0.005% to 20% by weight based upon the total weight of the composition. In certain embodiments, the compound having Formula I is present in an amount of from about 0.01% to 15% by weight based upon the total weight of the composition.
  • the present invention also provides a process for the production of a pharmaceutical composition as hereinbefore defined, which process comprises bringing the individual components thereof into intimate admixture and, when required, compounding the obtained composition in unit dosage form, for example filling said composition into tablets, gelatin, e.g., soft or hard gelatin, capsules, or non-gelatin capsules.
  • Fluorohydroquinone (9) (Feiring et al, J. Org. Chem. 40:2543 (1975)) treated with difluorophthalic anhydride (11) as per Lee and Denny will give trifluoroanthraquinone (12).
  • Selective fluorination of (14) on the reactive hydroquinone ring using fluorinating reagent 6 will give 6,7-difluoro-AQ4N (15).
  • a third alternative route to (15) begins with commercially available 2,3-diflurohydroquinone (10) (SYNTHON Chemicals GmbH & Co. KG) and will follow a route analogous to that of (9) to (14).
  • N,N-dimethyl-N'-alkylated ethylenediamines may be used in place of (17), for example, the commercially available secondary amine, 2- ⁇ [2-(diethylamino)ethyl]amino ⁇ ethanol.
  • (19a) will be the AQ4N derivative that will be synthesized using the chemistry shown in Scheme 3. It will be apparent to those skilled in the art that non-N-oxidized analogs of compounds (19a) and (20)-(24) can be prepared using Scheme 3.
  • Scheme 4 provides a synthetic route to a family of 2-fluorinated AQ4N derivatives.
  • 2,3,5-trifluorophthalic anhydride (EP 514863 A2) reacted separately with hydroquinones (10) or (25) as per Lee and Denny, will afford fluorinated anthraquinones (27) and (28), respectively.
  • Reaction of either with diamine (3) will proceed selectively with displacement of the highly reactive fluorine atoms at positions 1 and 4 and will give AQ4 analogs (29) and (30), respectively.
  • Oxidation with MCPBA will give 2,6,7-trifiuoro- AQ4N (31) and 2-fluoro-AQ4N (32), respectively.
  • Fluoride (32) may undergo nucleophilic aromatic substitution (Smith et ah, Advanced Organic Chemistry, Fifth Ed., Wiley, New York, 2001, pp. 850-893) by displacement of the fluorine atom at position 3 under somewhat more vigorous conditions with a variety of nucleophiles, as will be apparent to those skilled in the art.
  • nucleophilic aromatic substitution Smith et ah, Advanced Organic Chemistry, Fifth Ed., Wiley, New York, 2001, pp. 850-893
  • propargyl alcohol Levin et al, Synthetic Commun. 52:1401 (2002)
  • (32) under basic conditions to give propargyl ether (32a).
  • Scheme 6 illustrates general routes to AQ4N analogs in which the two terminal N,N-dimethylamine TV-oxide moieties of AQ4N are replaced by rings, for example, azetidine- and pyrrolidine N-oxides.
  • N-Alkylazetidine N-oxides are stable compounds.
  • anthraquinone (16) will be replaced by other anthraquinones, for example, (2), (12), (27), (28), (34), and (35) leading to a series of AQ4 ⁇ analogs, for example, (59)-(64). It will be apparent to those skilled in the art that non-N-oxidized analogs of compounds (59)-(64) can be prepared using Scheme 6.
  • R CH 3 , CH 2 CH 3 , CH 2 CH 2 OH etc.
  • 3,6-difluorophthalic anhydride (11) will serve as a precursor for a family of 4-substituted 3,6-difluorophthalic anhydrides as shown in Scheme 7.
  • 3,6-dichlorophthalic anhydride will also be used in place of (11) if the fluorine atoms in the phthalic anhydride derivatives become too reactive toward nucleophilic displacement. While the anhydride forms are shown in Scheme 7, parallel chemistry will be performed in many cases on the corresponding phthalic acid should the anhydride become hydrolyzed. Reconversion of the diacid into the anhydride will be effected by heating the diacid.
  • chlorosulfonation of (11) with chlorosulfonic acid will lead to sulfonyl chloride (66).
  • This compound will be reacted with a variety of alcohols or amines to give the corresponding sulfonyl derivative, for example, (65).
  • Nitration of (11) will give (67), which upon reduction and acylation will give a series of amides exemplified by (68).
  • Commercially available 2,5- dichlorotrimellitic anhydride (69) will serve as a precursor for several 4- carbonyl-3,6-dichlorophthalic anhydrides, for example, esters (71) and amides (72) via the acid chloride (70).
  • Scheme 8 shows the generalized synthesis of a series of AQ4 and
  • the trans 1,2-diamines exist in either of two enantiomeric forms, either of which may be used in the synthesis.
  • Representative 1,2-diamino cyclic compounds include (95)-(99). It will be apparent to those skilled in the art that non-N-oxidized analogs of (94) can be prepared using Scheme 10.
  • AQ4N itself will be obtained by fusing a piperazine ring to the C1-C2 bond in AQ4N as shown in Scheme 11.
  • (16) will be treated with 1 equiv of triamine (102) to give anthraquinone (103).
  • Reaction of (103) with one equivalent of diamine (3) will give anthraquinone (104).
  • Catalytic debenzylation with H 2 /Pd will give pentaamine (105).
  • AQ4N itself will be obtained by fusing a piperidine ring to the C1-C2 bond as exemplified by AQ4N analog (117) (Scheme 12). Alternatively, a piperidine ring will be fused to both the C1-C2 bond and the C3-C4 bond in AQ4N as exemplified by AQ4N analog (119).
  • AQ4 analog (116) and AQ4N analog (117) are prepared as follows. l,2,3,4-Tetrahydroquinoline-8-carboxylic acid (Norman et al, J. Med. Chem.
  • Octahydro-4,7-phenanthroline 120 (Smith et al., J. Am. Chem. Soc. 74:1096 (1952)) will be fos-N-alkylated with l-bromo-2-(N,vV-dimethylamino)ethane to give tetraamine (121). Monobromination of the activated aromatic ring will give bromide (122), which will be lithiated and then carboxylated will give carboxylic acid (123). This compound will be converted into N,N- diethylamide (124) and will be ortho lithiated and then carboxylated to give carboxylic acid (125). Hydrolysis to the diacid followed by heating will give the substituted phthalic anhydride (126).
  • AQ4N itself will be obtained by the following routes.
  • Difluoride (16) will be reacted with 1 equiv. of the appropriately N-substituted 2-aminothiophenol (127) under basic conditions (JP 63081164 A2) to give (128) (Scheme 13).
  • Reaction of (128) with a second equiv. of (127) will give AQ4 analog (129).
  • MCPBA oxidation then will give the AQ4N analog (130).
  • (128) will be treated with diamine (3) then one will obtain mixed AQ4N analog (131) after MCPBA oxidation. It will be apparent to those skilled in the art that non-N-oxidized analogs of (131) can be prepared using Scheme 13.
  • a further variation leading to AQ4N analogs with additional rings is as follows. Replacement of phthalic anhydride (11), for example, with a phthalic anhydride containing an additional fused ring, for example, (132)-(135), will lead to analogs of the above AQ4 and AQ4N molecules containing a fused aryl or heteroaryl ring attached to C2-C3 as shown in Scheme 14.
  • l,4-Difluoro-6-azanthracene-9,10-dione is prepared as generally presented above in Scheme 16, and is reacted with a (N,N-disubstituted- amino)alkylamine in an appropriate solvent, such as pyridine or dry DMF, in a temperature range of O 0 C to reflux temperature (optionally under nitrogen atmosphere) for up to about 48 h to produce the l,4-bis- ⁇ [(disubstituted- amino)alkyl] amino ⁇ -6-azaanthracene-9,10-dione product. The mixture is then poured into brine and stirred at room temperature for 30 min.
  • an appropriate solvent such as pyridine or dry DMF
  • the desired product is eluted from the column and extracted successively with CH 2 Cl 2 /Me0H (10:1) and CH 2 Cl 2 /Me0H/Et 2 N (90:10:1). The combined extracts are filtered and evaporated to give the desired 1,4-bis- ⁇ [(disubstituted-amino)alkyl] amino ⁇ -6-azaanthracene-9, 10-dione.
  • the tertiary amine end product in Scheme I can be selectively oxidized using known oxidizing agents.
  • oxidizing agents that are known in the art for preparing the iV-oxides from tertiary amine groups include, without limitation, potassium monopersulfate, monoperoxyphthalate acid, magnesium monoperoxyphthalate (MMPP), hydrogen peroxide, peracetic, trifluoroperacetic, perbenzoic, 3-chloroperbenzoic acid (CPBA), and 2- benzenesulfonyl-3-pheyloxaziridine (Davis reagent).
  • the oxidation reaction can be carried out in a solvent such as chloroform, methylene chloride, 1,2- dichloroethane, or acetic acid, optionally in the presence of an alkali or alkaline-earth metal carbonate or bicarbonate.
  • the reaction can be run from about 1 to 48 hours at a temperature of O 0 C to reflux temperature, and checked periodically for the presence of the desired bis-N-oxide.
  • reaction times may need to be adjusted accordingly to obtain appropriate quantities of the desired bis-N-oxide product. See also Lee et al, " ⁇ itracrine ⁇ -oxides: effects of variations in the nature of the side chain N-oxide on hypoxia-selective cytotoxicity" Anticancer Drug Des. 14(6):487-497 (1999).
  • 6-azaanthracene-9,10-dione is stirred in CH 2 Cl 2 /Me0H (5:1) and is treated dropwise over about 30 min to about 2 h with a solution of 2-benzenesulfonyl- 3-phenyloxaziridine (Davis reagent). After addition, the mixture is stirred at 2O 0 C in the dark for a further 90 min. It is then concentrated under reduced pressure at about 15-4O 0 C and then diluted successively with EtOAc and petroleum ether. The mixture is stirred at 20 0 C for 15 min, then kept at -1O 0 C for 2 h.
  • the precipitate is collected by filtration, washed with EtO Ac/petroleum ether (1 :1; 4 times), and suctioned dry. It is then dissolved in MeOH and the solution is treated with anhydrous HCl gas until it remains acidic (pH ca. 2). After storing at -1O 0 C overnight, the precipitate is collected by filtration and washed successively with MeOH/EtOAc (1 :1; 5 times) and EtOAc (2 times), and dried under vacuum to give dihydrochloride product.
  • ARPE 19 adult retinal pigment epithelium cells
  • AQ4N is cytotoxic to ARPE 19 cells at 10 mM under normoxia as well as 1% hypoxia.
  • 10 mM AQ4N under hypoxia did not result in greater loss in cell viability compared to normoxia.
  • AQ4 is cytotoxic to ARPE 19 cells at 0.1 mM under normoxic conditions.
  • AQ4 is approximately 100 times more cytotoxic to ARPE 19 cells when compared to AQ4N.
  • exposure to AQ4 results in a 17% loss of cell viability for ARPE 19 cells under 1% O 2 hypoxia.
  • RF/6A cells were tested in vitro under normoxic and 1% O 2 hypoxic conditions. RF/6A cells were exposed to the compounds at concentrations ranging from 1 nM to 10 mM for 24 hours and were stained 24-72 hours post-drug exposure. AQ4N is not cytotoxic to RF/6A cells at up to a concentration of 10 mM under normoxia as well as 1% hypoxia. However, AQ4 is cytotoxic to RF/6A 19 cells at 0.1 mM under normoxic conditions as well as 1% O 2 hypoxic conditions. EXAMPLE 3
  • the antiproliferative activity of AQ4 and AQ4N on ARPE 19 cells were tested in vitro under normoxic and 1% O 2 hypoxic conditions at concentrations ranging from 1 nM to 10 mM.
  • the antiproliferative effect was measured using the 5-bromo-2'-deoxyuridine ("BrDU") incorporation technique.
  • ARPE cells were exposed to the compounds in the presence of BrDU for 24 hours.
  • BrDU is incorporated into the replicating cellular DNA. After cell fixation and washing, the incorporated BrDU is determined in a specific ELISA using an antibody specific to BrDU coupled to peroxidase.
  • AQ4N does not have significant antiproliferative activity in ARPE 19 cells at concentrations tested of up to 1O mM under normoxia as well as 1% O 2 hypoxia. However, AQ4 is antiproliferative at 20 ⁇ M concentrations in ARPE cells under normoxic as well as 1% O 2 hypoxic conditions.
  • the antiproliferative activity of AQ4 and AQ4N on RF/6A cells were tested in vitro under normoxic and 1% O 2 hypoxic conditions at concentrations ranging from 1 nM to 10 mM.
  • the anti-proliferative effect was measured using the 5-bromo-2'-deoxyuridine ("BrDU") incorporation technique.
  • RF/6A cells were exposed to the compounds in the presence of BrDU for 24 hours. BrDU is incorporated into the replicating cellular DNA. After cell fixation and washing, the incorporated BrDU is determined in a specific ELISA using an antibody specific to BrDU coupled to peroxidase.
  • AQ4N does not have significant anti-proliferative activity in RF/6A cells at concentrations tested of up to 10 mM under normoxia as well as 1% O 2 hypoxia. However, AQ4 is antiproliferative at 20 ⁇ M concentrations in RF/6A under normoxic as well as 1% O 2 hypoxic conditions.
  • AQ4 and AQ4N were tested in vitro under normoxic and 1% O 2 hypoxic conditions at concentrations ranging from 1 nM to 10 mM. ARPE cells were exposed to the compounds for 24 hours and the amount of VEGF secreted was determined. AQ4N did not significantly affect VEGF secretion from ARPE 19 cells at 10 mM under normoxia as well as 1% hypoxia. Under 1% O 2 hypoxia, elevated VEGF secretion is observed compared to normoxic conditions. Moreover, AQ4 causes a significant decrease in VEGF secretion from ARPE 19 cells at 20 ⁇ M under normoxic conditions as well as 1% O 2 hypoxic conditions.

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Abstract

La présente invention concerne des composés anthraquinones possédant une activité permettant de traiter les troubles ophtalmiques. Cette invention concerne également des méthodes d'utilisation de ces composés, seuls ou combinés à un ou plusieurs autres agents actifs ou traitements, pour traiter les troubles ophtalmiques.
PCT/US2008/002099 2007-02-16 2008-02-19 Méthodes de traitement de troubles ophtalmiques utilisant des anthraquinones WO2008103320A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents

Citations (8)

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Publication number Priority date Publication date Assignee Title
US5132327A (en) * 1989-10-13 1992-07-21 National Research Development Corporation Anti-cancer compounds
WO1992015300A1 (fr) * 1991-03-08 1992-09-17 The University Of Vermont 6,9 BIS(AMINO-SUBSTITUE)BENZO[g]ISOQUINOLINE-5,10-DIONES
US6649596B1 (en) * 1995-12-08 2003-11-18 Hybridon, Inc. Modified VEGF Oligonucleotides for Inhibition of tumor growth
US20040167091A1 (en) * 2001-11-09 2004-08-26 Guyer David R. Methods for treating ocular neovascular diseases
US20050096257A1 (en) * 2003-08-27 2005-05-05 David Shima Combination therapy for the treatment of ocular neovascular disorders
US20060014776A1 (en) * 2004-07-16 2006-01-19 Instituto Biomar S.A. Antitumoral compounds
US7074835B2 (en) * 2002-03-15 2006-07-11 Btg International Limited Formulations of anthraquinone derivatives
US20070117784A1 (en) * 2005-03-04 2007-05-24 Novacea, Inc. Treatment of hyperproliferative diseases with anthraquinones

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5132327A (en) * 1989-10-13 1992-07-21 National Research Development Corporation Anti-cancer compounds
WO1992015300A1 (fr) * 1991-03-08 1992-09-17 The University Of Vermont 6,9 BIS(AMINO-SUBSTITUE)BENZO[g]ISOQUINOLINE-5,10-DIONES
US6649596B1 (en) * 1995-12-08 2003-11-18 Hybridon, Inc. Modified VEGF Oligonucleotides for Inhibition of tumor growth
US20040167091A1 (en) * 2001-11-09 2004-08-26 Guyer David R. Methods for treating ocular neovascular diseases
US7074835B2 (en) * 2002-03-15 2006-07-11 Btg International Limited Formulations of anthraquinone derivatives
US20050096257A1 (en) * 2003-08-27 2005-05-05 David Shima Combination therapy for the treatment of ocular neovascular disorders
US20060014776A1 (en) * 2004-07-16 2006-01-19 Instituto Biomar S.A. Antitumoral compounds
US20070117784A1 (en) * 2005-03-04 2007-05-24 Novacea, Inc. Treatment of hyperproliferative diseases with anthraquinones

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents

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