WO2008070169A2 - Use of carboxyamidotriazole (cai) orotate in macular degeneration - Google Patents

Use of carboxyamidotriazole (cai) orotate in macular degeneration Download PDF

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WO2008070169A2
WO2008070169A2 PCT/US2007/025041 US2007025041W WO2008070169A2 WO 2008070169 A2 WO2008070169 A2 WO 2008070169A2 US 2007025041 W US2007025041 W US 2007025041W WO 2008070169 A2 WO2008070169 A2 WO 2008070169A2
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angiogenesis
carboxyamidotriazole
orotate
amino
macular degeneration
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PCT/US2007/025041
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WO2008070169A3 (en
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Rashida A. Karmali
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Tactical Therapeutics Inc
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Priority to CA2682596A priority Critical patent/CA2682596C/en
Priority to JP2009540307A priority patent/JP5344764B2/en
Priority to KR1020097011574A priority patent/KR101414922B1/en
Priority to ES07853268.6T priority patent/ES2488093T3/en
Priority to AU2007328027A priority patent/AU2007328027B2/en
Priority to EP07853268.6A priority patent/EP2089021B1/en
Publication of WO2008070169A2 publication Critical patent/WO2008070169A2/en
Publication of WO2008070169A3 publication Critical patent/WO2008070169A3/en
Priority to IL199158A priority patent/IL199158A/en

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Definitions

  • the present invention is directed to the treatment of age-related macular degeneration by the administration of an inhibitor of angiogenesis, Carboxyamidotriazole or 5 amino 1,2,3- triazole orotate (CAI Orotate).
  • CAI Orotate an inhibitor of angiogenesis
  • CAI Orotate 5 amino 1,2,3- triazole orotate
  • the invention relates to pharmaceutical compositions and methods for treating angiogenesis-dependent diseases.
  • Age-related macular degeneration the leading cause of blindness among persons over fifty in the United States and in other countries.
  • Two forms of age-relayed macular degeneration are known: 1) neovascular, also known as exudative age-related macular degeneration, and 2) nonneovascular, known as nonexudativeage-related macular degeneration.
  • the neovascular macular degeneration involves angiogenesis.
  • 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 situations such as 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.
  • 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.
  • advanced 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 bums, 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.
  • Carboxyamidotriazole or 5 amino 1 ,2,3-triazole orotate (CAI Orotate) is currently under development for clinical use as an antitumor agent based on its antiangiogenic, antiproliferative and antimetastatic effects Kohn et al Cancer Res 52: 3208-3212, (1992); Bauer et al J. Pharm Exp Ther 292: 31-37 (2000) and Purow et al, Cancer Investigation 22: 577-587, (2004).
  • an orotate salt of CAI compared with CAI was found to have improved antitumor effect in the Dunning rat model for prostate cancer.
  • the mechanism of action for the enhancement in antitumor activity of CAI orotate was not described but was suggested to involve an alteration in cyclic nucleotide activity in the liver.
  • the present invention relates to the angiogenesis inhibitor, Carboxyamidotriazole or 5 amino 1,2,3 -triazole orotate (CAI Orotate) and method for its use.
  • therapy with the inhibitor exhibits strong anti-macular degeneration activity.
  • the present invention provides methods and compositions for treating diseases and processes mediated by undesired and uncontrolled angiogenesis by administering to a human or animal with the undesired angiogenesis a composition comprising Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate), in a dosage sufficient to inhibit angiogenesis.
  • CAI Orotate Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate
  • the present invention is particularly useful for treating or for repressing macular degeneration.
  • Fig. 1 illustrates the results of the proliferation assay for endothelial cells (HUVEC) .
  • the present invention relates to Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate) and its the ability to inhibit endothelial proliferation when added to proliferating endothelial cells in vitro.
  • CAI Orotate of the invention is useful for treating angiogenesis-related diseases, particularly macular degeneration, and angiogenesis-dependent diseases.
  • Angiogenesis-related diseases may be diagnosed and treated using the endothelial cell proliferation inhibiting compounds of the present invention.
  • Angiogenesis-related diseases include, but are not limited to, ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis; angiogenesis-dependent cancer, including, for example, solid tumors, blood born tumors such as leukemias, and tumor metastases; benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; rheumatoid arthritis; psoriasis; Osier- Webber Syndrome; myocardial angiogenesis; plaque neovascularization; telangiectasia; hemophiliac joints; angiofibroma; and wound granulation.
  • the endothelial cell proliferation inhibiting proteins of the present invention are useful in the treatment of disease of excessive or abnormal stimulation of endothelial cells.
  • diseases include, but are not limited to, intestinal adhesions, atherosclerosis, scleroderma, and hypertrophic scars, i.e., keloids. They are also useful in the treatment of diseases that have angiogenesis as a pathologic consequence such as cat scratch disease (Rochele minalia quintosa) and ulcers (Helobacter pylori).
  • the Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate) salt was prepared using the procedure described in U.S.Pat. No 5,861,406. The molecular weight of CAI orotate is 581.
  • Example 2 Inhibition of Angiogenesis with Carboxyamidotriazole Orotate Human umbilical vein endothelial cells (HUVEC) were treated with three different concentrations of Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate) for 3 days. The cell number of each culture under different treatment conditions was counted. The assays were done in triplicate and the data are expressed as mean +/- standard deviation. Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate) inhibited angiogenesis in a dose related manner ( Figure 1)

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Abstract

Method and composition of Carboxyamidotriazole orotate for treating age-related macular degeneration and other angiogenesis-dependent diseases.

Description

USE OF CARBOXIAMIDOTRIAZOLE (CAI) OROTATE IN MACULAR
DEGENERATION
1. FIELD OF INVENTION
The present invention is directed to the treatment of age-related macular degeneration by the administration of an inhibitor of angiogenesis, Carboxyamidotriazole or 5 amino 1,2,3- triazole orotate (CAI Orotate). The invention relates to pharmaceutical compositions and methods for treating angiogenesis-dependent diseases.
2. BACKGROUND TO THE INVENTION
Age-related macular degeneration the leading cause of blindness among persons over fifty in the United States and in other countries. Two forms of age-relayed macular degeneration are known: 1) neovascular, also known as exudative age-related macular degeneration, and 2) nonneovascular, known as nonexudativeage-related macular degeneration. The neovascular macular degeneration involves angiogenesis. As used herein, the term "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 situations such as 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.
One example of a disease mediated by angiogenesis is 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 advanced 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. Other diseases associated with 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 bums, 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 (neovasculariation of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy.
Another disease in which angiogenesis is believed to be involved is rheumatoid arthritis. 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.
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. 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.
Thus, new methods and compositions are needed that are capable of inhibiting angiogenesis and treating angiogenesis-dependent diseases.
Carboxyamidotriazole or 5 amino 1 ,2,3-triazole orotate (CAI Orotate) is currently under development for clinical use as an antitumor agent based on its antiangiogenic, antiproliferative and antimetastatic effects Kohn et al Cancer Res 52: 3208-3212, (1992); Bauer et al J. Pharm Exp Ther 292: 31-37 (2000) and Purow et al, Cancer Investigation 22: 577-587, (2004). U.S. Patent No.5,861,406 issued on January 19, 1999 and U.S. Pat No 5,912,346 issued on July 15, 1999, describe treatment and prevention of neoplasms with salts of aminoimizazole carboxamide and CAI triazole . Specifically, an orotate salt of CAI compared with CAI, was found to have improved antitumor effect in the Dunning rat model for prostate cancer. The mechanism of action for the enhancement in antitumor activity of CAI orotate was not described but was suggested to involve an alteration in cyclic nucleotide activity in the liver.
3. SUMMARY OF THE INVENTION
The present invention relates to the angiogenesis inhibitor, Carboxyamidotriazole or 5 amino 1,2,3 -triazole orotate (CAI Orotate) and method for its use. In particular, therapy with the inhibitor exhibits strong anti-macular degeneration activity.
The present invention provides methods and compositions for treating diseases and processes mediated by undesired and uncontrolled angiogenesis by administering to a human or animal with the undesired angiogenesis a composition comprising Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate), in a dosage sufficient to inhibit angiogenesis. The present invention is particularly useful for treating or for repressing macular degeneration.
4. BRIEF DESCRIPTION OF FIGURES
Fig. 1 illustrates the results of the proliferation assay for endothelial cells (HUVEC) .
5. DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate) and its the ability to inhibit endothelial proliferation when added to proliferating endothelial cells in vitro. CAI Orotate of the invention is useful for treating angiogenesis-related diseases, particularly macular degeneration, and angiogenesis-dependent diseases.
Angiogenesis-related diseases may be diagnosed and treated using the endothelial cell proliferation inhibiting compounds of the present invention. Angiogenesis-related diseases include, but are not limited to, ocular angiogenic diseases, for example, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis; angiogenesis-dependent cancer, including, for example, solid tumors, blood born tumors such as leukemias, and tumor metastases; benign tumors, for example hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; rheumatoid arthritis; psoriasis; Osier- Webber Syndrome; myocardial angiogenesis; plaque neovascularization; telangiectasia; hemophiliac joints; angiofibroma; and wound granulation. The endothelial cell proliferation inhibiting proteins of the present invention are useful in the treatment of disease of excessive or abnormal stimulation of endothelial cells. These diseases include, but are not limited to, intestinal adhesions, atherosclerosis, scleroderma, and hypertrophic scars, i.e., keloids. They are also useful in the treatment of diseases that have angiogenesis as a pathologic consequence such as cat scratch disease (Rochele minalia quintosa) and ulcers (Helobacter pylori).
6. EXAMPLES Example 1.
The Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate) salt was prepared using the procedure described in U.S.Pat. No 5,861,406. The molecular weight of CAI orotate is 581. Example 2 Inhibition of Angiogenesis with Carboxyamidotriazole Orotate Human umbilical vein endothelial cells (HUVEC) were treated with three different concentrations of Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate) for 3 days. The cell number of each culture under different treatment conditions was counted. The assays were done in triplicate and the data are expressed as mean +/- standard deviation. Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate (CAI Orotate) inhibited angiogenesis in a dose related manner (Figure 1)
The present invention is not to be limited in scope by the embodiment disclosed in the example which is intended as an illustration of one aspect of the invention and any methods which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, any equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the claims.

Claims

What is claimed is:
1. A method of treating macular degeneration in an individual comprising administering to an individual a macular degeneration inhibiting amount of Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate
2. A method of inhibiting angiogenesis with an effective amount of
Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate , wherein the angiogenesis causes an angiogenesis dependent disease.
3. The method of claim 2, wherein the angiogenesis dependent disease is ocular angiogenic diseases, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, rubeosis, solid tumors, blood born tumors, leukemias, tumor metastases, benign tumors, acoustic neuromas, neurofibromas, trachomas, pyogenic granulomas, rheumatoid arthritis, psoriasis, Osier- Webber Syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, or wound granulation.
4. The method of claim 1 wherein the Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate is orally administered in an effective and safe dosage form and amount.
5. The method of claim 2 The method of claim 1 wherein the Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate is orally administered in an effective and safe dosage form and amount wherein the Carboxyamidotriazole or 5 amino 1,2,3-triazole orotate is orally administered in an effective and safe dosage form and amount
PCT/US2007/025041 2006-12-06 2007-12-05 Use of carboxyamidotriazole (cai) orotate in macular degeneration WO2008070169A2 (en)

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CA2682596A CA2682596C (en) 2006-12-06 2007-12-05 Use of carboxyamidotriazole (cai) orotate in macular degeneration
JP2009540307A JP5344764B2 (en) 2006-12-06 2007-12-05 Use of orotic acid carboxamidotriazole (CAI) in macular degeneration
KR1020097011574A KR101414922B1 (en) 2006-12-06 2007-12-05 Use of carboxyamidotriazole (cai) orotate in macular degeneration
ES07853268.6T ES2488093T3 (en) 2006-12-06 2007-12-05 Use of carboxyamidotriazole orotate (CIA) in macular degeneration
AU2007328027A AU2007328027B2 (en) 2006-12-06 2007-12-05 Use of Carboxyamidotriazole (CAI) orotate in macular degeneration
EP07853268.6A EP2089021B1 (en) 2006-12-06 2007-12-05 Use of carboxyamidotriazole (cai) orotate in macular degeneration
IL199158A IL199158A (en) 2006-12-06 2009-06-04 Compositions containing triazole compounds for inhibiting angiogenesis and treating related diseases

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US11/634,422 US7750018B2 (en) 2006-12-06 2006-12-06 Use of carboxiamidotriazole (CAI) orotate in macular degeneration

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IL199158A (en) 2014-07-31
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KR101414922B1 (en) 2014-07-04
JP2010512318A (en) 2010-04-22
CA2682596A1 (en) 2008-06-12
EP2089021B1 (en) 2014-06-04
WO2008070169A3 (en) 2008-11-06
US7750018B2 (en) 2010-07-06
US20100298363A1 (en) 2010-11-25
CN104382905A (en) 2015-03-04
CN103251601A (en) 2013-08-21
EP2089021A4 (en) 2009-12-30
AU2007328027A2 (en) 2010-07-08
CN101578099A (en) 2009-11-11
EP2089021A2 (en) 2009-08-19

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