ZA200503468B - Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment and management of macular degeneration - Google Patents
Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment and management of macular degeneration Download PDFInfo
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- ZA200503468B ZA200503468B ZA200503468A ZA200503468A ZA200503468B ZA 200503468 B ZA200503468 B ZA 200503468B ZA 200503468 A ZA200503468 A ZA 200503468A ZA 200503468 A ZA200503468 A ZA 200503468A ZA 200503468 B ZA200503468 B ZA 200503468B
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- carbon atoms
- alkyl
- phenyl
- hydrogen
- stereoisomer
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Description
- r ,
METHODS OF USING AND COMPOSITIONS
COMPRISING SELECTIVE CYTOKINE INHIBITORY DRUGS FOR
TREATMENT AND MANAGEMENT OF MACULAR DEGENERATION
This application claims the benefit of U.S. provisional application no. 60/422,900 filed on October 31, 2002, the entirety of which is incorporated herein by reference. 1. FIELD OF THE INVENTION
This invention relates to methods of treating, preventing and managing macular degeneration (MD) and related syndromes, which comprise the administration of selective cytokine inhibitory drugs alone or in combination with known therapeutics. The invention also relates to pharmaceutical compositions and dosing regimens. In particular, the invention encompasses the use of selective cytokine inhibitory drugs in conjunction with surgical intervention, and/or other standard therapies for macular degeneration. 2. | BACKGROUND OF THE INVENTION 21 PATHOBIOLOGY OF MACULAR DEGENERATION
Macular degeneration (MD) is an eye disease that destroys central vision by damaging the macula. The macula is part of the retina, a thin layer of nerve cells that lines most of the inside of the eyeball. The nerve cells in the retina detect light and send to the brain signals about what the eye sees. The macula is near the center of the retina at the back of the eyeball and provides the clear, sharp central vision that an animal uses for focusing on what is in front of it. The rest of the retina provides side (peripheral) vision.
There are two forms of MD: atrophic (“dry”) and exudative (“wet”). Riordan-Eva,
P., Eye, in Current Medical Diagnosis and Treatment, 41 ed. 210-211 (2002). Ninety percent of patients have the dry form, while only ten percent have the wet form. However, patients with the wet form can lose up to ninety percent of their vision. DuBosar, R., J. of
Ophthalmic Nursing and Technology, 18: 60-64 (1998).
Macular degeneration results in the presence of choroidal neovascularisation (CNVM) and/or geographic atrophy of retinal pigment epithelium (RPE) in an eye with drusen. Bird, A.C., Surv. Ophthamol. 39:367-74 (1995). Drusen are rounded whitish- yellowish spots in the fundus, located external to the neuroretina. Additional symptoms of
MD clude RPE detachment (PED) and submacular disciform scar tissue, Al gvere, P.V.,,
Acta Ophthalmologica Scandinavica 80:136-143 (2002).
; ;
Choroidal neovascularisation is a problem that is related to a wide variety of retinal diseases, but is most commonly associated with MD. CNVM is characterized by abnormal blood vessels stemming from the choroid (the blood vessel-rich tissue layer just beneath the retina) growing up through the retinal layers. These new vessels are very fragile and break , easily, causing blood and fluid to pool within the layers of the retina. As the vessels leak, they disturb the delicate retinal tissue, causing the vision to deteriorate. The severity of the symptoms depends on the size of the CNVM and its proximity to the macula. Patients’ symptoms may be very mild, such as a blurry or distorted area of vision, or more severe, such as a central blind spot.
Patients having drusen and possibly pigmentary abnormalities, but no CNVM or geographic atrophy, are generally diagnosed as having age-related maculopathy (ARM). Jd.
The histopathological halimark of ARM and MD is a continuous layer of fine granular material deposited in the inner part of Bruch’s membrane at the base of the RPE cells.
Sarks, J.P., et al., Eye 2(Pt. 5):552-77 (1988). These basal deposits are though to be accumulated as waste products from the continuing RPE phagocytosis or photoreceptor outer segment material. The basal deposits lead to a thickening and decreased permeability of Bruch’s membrane. It has been hypothesized that decreased water permeability impairs an exchange of nutrients, traps water and enhances the development of soft drusen and PED and eventually leads to atrophy of RPE cells. Jd. However, the current overall understanding of ARM and MD pathogenesis is incomplete. Cour, M., et al., Drugs Aging 19:101-133 (2002).
Because MD is most prevalent in the elderly, the fastest growing segment of the population, MD is destined to become a major problem economically and socially. Macular “degeneration is the most common cause of visual loss in developed countries in individuals over the age of 60. Macular degeneration has obliterated the central vision of 1.7 million
Americans and another 11 million are at risk. DuBosar, R., J. of Ophthalmic Nursing and
Technology, 18: 60-64 (1998). Currently, there is no known cure. Rhoodhooft, J., Bull.
Soc. belge Ophtalmol. 276:83-92 (2000). Thus, there is an urgent need for effective treatments for MD. 22 TREATMENTS OF AGE-RELATED
MACULAR DEGENERATION
Until recently, laser photocoagulation was the only treatment routinely used for MD, and it provides only modest results. Laser photocoagulation is a type of laser surgery that uses an intense beam of light to burn small areas of the retina and the abnormal blood vessels beneath the macula. The burns form scar tissue and seal the blood vessels, Keeping them from leaking under the macula. Laser photocoagulation is effective only for patients having wet MD. Furthermore, laser photocoagulation is a viable option for only about 13% of those patients. Joffe, L. et al., International Ophthalmology Clinics 36(2): 95-116 (1996). Laser photocoagulation does not cure wet MD, rather it sometimes slow down or prevent further loss of central vision. Without treatment, however, vision loss from wet
MD may progress until 2 person has no remaining central vision.
The most serious drawback to laser surgery is that the laser damages some of the nerve cells in the macula that react to light, causing some vision loss. Sometimes, the vision loss resulting from surgery is as severe or worse than the vision loss resulting from no treatment. In some patients, however, laser surgery initially worsens vision, but prevents more severe loss of vision over time.
Verteporfin has recently been used to treat wet MD. Cour, M., ef al., Drugs Aging 19:101-133 (2002). Verteporfin is a blood-vessel-blocking photoreactive dye that is administered via injection. The dye moves to the blood vessels that are responsible for the loss of sight and is then activated by shining a non-burning beam of light into the eye in the presence of oxygen. Verteporfin is transported in the plasma primarily by lipoproteins.
Activated verteporfin generates highly reactive, short-lived singlet oxygen and reactive oxygen radicals, resulting in local damage to neovascular endothelium. This causes vessel occlusion. Damaged endothelium is known to release procoagulant and vasoactive factors through the lipo-oxygenase (leukotriene) and cyclo-oxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction. Verteporfin appears to somewhat preferentially accumulate in neovasculature, including choroidal neocovasculature. However, animal models indicate that verteporfin also accumulates in the retina. Therefore, verteporfin administration might collaterally damage retinal structures, including the retinal pigmented epithelium and outer nuclear layer of the retina.
Another strategy curently being investigated for the treatment of MD is pharmacological antiangiogenic therapy. Cour, M., et al., Drugs Aging 19:101-133 (2002).
However, a first clinical trial with an antiangiogenic agent, interferon-c, showed that it was effective at treating MD and resulted in a high rate of adverse effects. Arch. Ophthalmol. 115:865-72 (1997).
Intravitreal jection of triamcinolone reportedly inhibits the growth of laser-induced
CNVM in monkeys, but fails to prevent severe visual loss over a one-year period in patients with MD in a randomized trial. Gillies, M.C., ef al, Invest. Ophthalmol. Vis. Sci. 42:8522 (2001). A number of other antiangiogenic drugs are in various stages of development for use in patients with MD, including angiostatic steroids (e.g., anecortave acetate, Alcon) and vascular epidermal growth factor (VEGF) antibodies or fragments thereof. Guyer, D.R., er .
Sal, Invest. Ophthalmol. Vis. Sci. 42:5522 (2001). One such VEGF antibody is rhuFab.
Additional new drugs for the treatment of MD include EYE101 (Eyetech Pharmaceuticals), :
LY333531 (Eli Lilly), Miravant and RETISERT implant (Bausch & Lomb), which exudes a steroid into the eye for up to three years.
Although new and promising strategies for the treatment of MD and related macular degenerative diseases are being investigated, there is still no effective treatment available.
Accordingly, there remains a need in the art for an effective treatment for MD. 2.3 SELECTIVE CYTOKINE INHIBITORY DRUGS
Compounds referred to as SelCIDs™ (Celgene Corporation) or Selective Cytokine
Inhibitory Drugs have been synthesized and tested. These compounds potently inhibit :
TNF-a production, and exhibit modest inhibitory effects on LPS induced IL.18 and IL12.
L.G. Corral, et al., Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999).
Further characterization of the selective cytokine inhibitory drugs shows that they are potent PDE4 inhibitors. PDE4 is one of the major phosphodiesterase isoenzymes found in human myeloid and lymphoid lineage cells. The enzyme plays a crucial part in regulating cellular activity by degrading the ubiquitous second messenger cAMP and maintaining it at low intracellular levels. Jd. Inhibition of PDE4 activity results in increased cAMP levels leading to the modulation of LPS induced cytokines including inhibition of TNF-¢ production in monocytes as well as in lymphocytes. 3. SUMMARY OF THE INVENTION
This invention encompasses methods of treating and preventing macular degeneration, which comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The invention also encompasses methods of managing MD (e.g., lengthening the time of remission) which comprise administering to a patient in need of such management a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
Another embodiment of the invention encompasses the use ot a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in combination with another therapeutic useful to treat or prevent MD such as, but not limited to, a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an antiangiogenesis compound, or a combination thereof.
Yet another embodiment of the invention encompasses methods for treating, preventing or managing MD, comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in combination with a conventional therapy used to treat or prevent MD such as, but not limited to, surgical intervention (e.g., laser photocoagulation therapy and photodynamic therapy).
The invention further encompasses pharmaceutical compositions, single unit dosage forms, and kits suitable for use in treating, preventing and/or managing MD, which comprise a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. 4. DETAILED DESCRIPTION OF THE INVENTION
A first embodiment of the invention encompasses methods of treating and preventing MD, which comprise administering to a patient (e.g., a mammal such asa human) in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The invention further relates to the treatment or prevention of specific types of MD and related syndromes including, but not limited to, atrophic (dry) MD, exudative (wet) MD, age-related maculopathy (ARM), choroidal neovascularisation (CNVM), retinal pigment epithelium detachment (PED), and atrophy of retinal pigment epithelium (RPE).
As used herein, the term macular degeneration (MD) encompasses all forms of macular degenerative diseases regardless of a patient's age, although some macular degenerative diseases are more common in certain age groups. These include, but are not limited to, Best's disease or vitelliform (most common in patients under about 7 years of age); Stargardt’s disease, juvenile macular dystrophy or fundus flavimaculatus (most
N a. - common in patients between about 5 and about 20 years of age); Belir’§ disease, Sorsby’s disease, Doyne’s disease or honeycomb dystrophy (most common in patients between about 30 and about 50 years of age); and age-related macular degeneration (most common in patients of about 60 years of age or older). .
Causes of MD include, but are not limited to, genetic, physical trauma, diseases such as diabetes, and infection, such as bacterial infection (e.g., leprosy and ENL in : particular),
Another embodiment of the invention encompasses methods of managing MD which comprise administering to a patient in need of such management a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
Another embodiment of the invention encompasses a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier.
Also encompassed by the invention are single unit dosage forms comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier.
Another embodiment of the invention encompasses a kit comprising: a pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention further encompasses kits comprising single unit dosage forms. Kits encompassed by this invention can further comprise additional active agents. A specific kit comprises an Amsler grid useful for detecting or diagnosing MD.
Without being limited by theory, it is believed that certain selective cytokine inhibitory drugs and other medications that may be used to treat symptoms of MD can act in complementary or synergistic ways in the treatment or management of MD. Therefore, one embodiment of the invention encompasses a method of treating, preventing and/or managing MD, which comprises administering to a patient in need thereof 2 therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug : thereof, and a therapeutically or prophylactically effective amount of a second active agent.
Examples of second active agents include, but are not limited to, conventional ) therapeutics used to treat or prevent MD such as steroids, light sensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neutrotrophic factors,
/ } r regulators of neovascularization, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds and antiangiogenesis compounds, and other therapeutics found, for example, in the Physician's Desk Reference 2003. Specific examples of second active agents include, but are not limited to, verteporfin, purlytin, an angiostatic steroid, rhuFab, interferon-2¢, an integrin, an antioxidant, and pentoxifylline.
The invention also encompasses pharmaceutical compositions, single unit dosage forms, and kits which comprise a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent. For example, a kit may contain a compound of the invention and a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoesirogen, an anti-inflammatory compound or an antiangiogenesis compound, or a combination thereof, or other drug capable of relieving or alleviating a symptom of MD.
It is believed that particular selective cytokine inhibitory drugs can reduce or eliminate adverse effects associated with the administration of therapeutic agents used to treat MD, thereby allowing the administration of larger amounts of the agents to patients and/or increasing patient compliance. Consequently, another embodiment of the invention encompasses a method of reversing, reducing or avoiding an adverse effect associated with the administration of a second active agent in a patient suffering from MD, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
As discussed elsewhere herein, symptoms of MD can be treated with surgical intervention, such as, but not limited to, light or laser therapy, radiation therapy, retinal pigment epithelium transplantation, and foveal translocation. Without being limited by theory, it is believed that the combined use of such conventional therapies and a selective cytokine inhibitory drug can be highly effective. Therefore, this invention encompasses a method of treating, preventing and/or managing MD, which comprises administering to a patient a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before, during, or after surgical intervention, or other conventional, non-drug based therapies. . -
41 SELECTIVE CYTOKINE INHIBITOR FDRUGS'
Compounds used in the invention include racemic, stereomerically pure and stereomerically enriched selective cytokine inhibitory drugs, stereomerically and enantiomerically pure compounds that have selective cytokine inhibitory activities, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof. Preferred compounds used in the invention are known Selective Cytokine
Inhibitory Drugs (SelCIDs™) of Celgene Corporation, NJ.
As used herein and unless otherwise indicated, the terms “selective cytokine inhibitory drugs” and “SelCIDs™ encompass small molecule drugs, e.g, small organic molecules which are not peptides, proteins, nucleic acids, oligosaccharides or other macromolecules. Preferred compounds inhibit TNF-a production. Compounds may also have a modest inhibitory effect on LPS induced IL18 and IL12. More preferably, the compounds of the invention are potent PDE4 inhibitors.
Specific examples of selective cytokine inhibitory drugs include, but are not limited to, the cyclic imides disclosed in U.S. patent nos. 5,605,914 and 5,463,063; the cycloalkyl amides and cycloalkyl nitriles of U.S. patent nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281; the aryl amides (for example, an embodiment being N-benzoyl-3- amino-3-(3’,4’-dimethoxyphenyl)-propanamide) of U.S. patent nos. 5 ,801,195, 5,736,570, 6,046,221 and 6,284,780; the imide/amide ethers and alcohols (for example, 3-phthalimido- 3-(3’,4’-dimethoxyphenyl)propan-1-ol) disclosed in U.S. patent no. 5,703,098; the succinimides and maleimides (for example methyl 3-(3°,4’,5°6’-petrahydrophthalimdo)-3- (3”,4”-dimethoxyphenyl)propionate) disclosed in U.S. patent no. 5,658,940; imido and amido substituted alkanohydroxamic acids disclosed in U.S. patent no. 6,214,857 and WO 99/06041; substituted phenethylsulfones disclosed in U.S. patent nos. 6,011,050 and 6,020,358; substituted imides (for example, 2-phthalimido-3-(3 > 4’-dimethoxyphenyl) propane) disclosed in U.S. patent no. 6,429,221; substituted 1,3,4-oxadiazoles (for example, 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(1,3,4-oxadiazole-2-ylethyl]-5- methylisoindoline-1,3-dione) disclosed in U.S. patent no. 6,326,388; cyano and carboxy derivatives of substituted styrenes (for example, 3,3-bis-(3,4-dimethoxyphenyl) acrylonitrile) disclosed in U.S. patent nos. 5,929,117, 6,130,226, 6,262,101 and 6,479,554; isoindoline-1-one and isoindoline-1,3-dione substituted in the 2-position with an o=(3,4- ’ disubstituted phenyl)alkyl group and in the 4- and/or 5-position with a nitrogen-containing group disclosed in WO 01/34606; and imido and amido substituted acylhydroxamic acids (for example, (3-(1,3-dioxoisoindoline-2-y1)-3-(3-ethoxy-4-methoxyphenyl)
. propanoylamino) propanoate disclosed in WO 01/4570%. The shifts of sah é fhe patents and patent applications identified herein are incorporated herein by reference.
Additional selective cytokine inhibitory drugs belong to a family of synthesized chemical compounds of which typical embodiments include 3-(1,3-dioxobenzo-[f]isoindol- 3 2-y1)-3-(3-cyclopentyloxy-4-methoxyphenyl)propionamide and 3-(1,3-dioxo-4-azaisoindol- 2-y1)-3-(3 ,4-dimethoxyphenyl)-propionamide.
Other specific selective cytokine inhibitory drugs belong to a class of non- polypeptide cyclic amides disclosed in U.S. patent nos. 5,698,579 and 5,877,200, both of " which are incorporated herein. Representative cyclic amides include compounds of the formula: 0
Rs” “ N— CH— (C,H. ne R12 \, y, I nan
HH wherein n has a value of 1, 2, or 3;
R’is o-phenylene, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, cartbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkcyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo;
R’ is (1) phenyl or phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of I to 10 carbon atoms, and halo, (it) benzyl unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbothoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (iii) naphthyl, and (1v) benzyloxy;
Ris -OH, alkoxy of 1 to 12 carbon atoms, or
RE
No
RS is hydrogen or alkyl of 1 to 10 carbon atoms; and
R’ is hydrogen, alkyl of 1 to 10 carbon ators, -COR', or -SO;R™®, wherein R'is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl. ’ Corrected sheet: 16 May 2006
(
Specific compounds of this class include, buf drenét lickited id: 3-phenyl-2-(1-oxoisoindolin-2-yl)propionic acid; 3-phenyl-2-(1-oxoisoindolin-2-yl)propionamide; 3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid; 3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide; 3-(4-methoxyphenyl)-3-(1-oxisoindolin-yl)propionic acid; 3-(4-methoxyphenyl)-3-(1-oxisoindolin-yl)propionamide; 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionic acid; 3~(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydroisoindol-2-yl)propionamide; 3-(3,4-dimethoxyphenyl)-3-(1-oxisoindolin-2-yl)propionamide; 3-(3,4-diethoxyphenyl)-3-(1-oxoisoindolin-yl)propionic acid; methyl 3-(1-oxoisoindolin-2-y1)-3-(3 ethoxy-4-methoxyphenyl)propionate; 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid; 3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionic acid; 3-(1-oxoisoindolin-2-y1)-3-(3-butoxy-4-methoxyphenyl)propionic acid; : 3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propionamide; 3~(1-oxoisoindolin-2-y1)-3-(3-butoxy-4-methoxyphenyl)propionamide; methyl 3-(1-oxoisoindolin-2-y1)-3-(3-butoxy-4-methoxyphenyl)propicnate; and methyl 3-(1-oxoisoindolin-2-y1)-3-(3-prop oxy-4-methoxyphenyl)propionate.
Other specific selective cytokine inhibitory drugs include the imido and amido substituted alkanohydroxamic acids disclosed in WO 99/06041, which is incorporated herein by reference. Examples of such compound include, but are not limited to:
Oo
R1 u R3
T “N— ox. Q rz” R® (CaHzn)—C—N—0— RS
RY wherein each of R! and R?, when taken independently of each other, is hydrogen, lower alkyl, or R! and R?, when taken together with the depicted carbon atoms to which each is bound, is o-phenylene, o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting 3 of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl ofl to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo;
R® is phenyl substituted with from one to four Substitutrits sefebtéd frofi the’ grotip consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy ] of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C4-Cy-cycloalkylidenemethyl, C;3-Cjo-alkylidenemethyl, indanyloxy, and halo;
R* is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl;
R¥ is hydrogen or alkyl of 1 to 6 carbon atoms;
R’ is -CH,-, -CH;-CO-,-SO-,-S-, or -NHCO-; n has a value of 0, 1, or 2; and "the acid addition salts of said compounds which contain a nitrogen atom capable of being protonated.
Additional specific selective cytokine inhibitory drugs used in the invention include, but are not limited to: 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1 -oxoisoindolinyl)propionamide; : 3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)propionamide;
N-benzyloxy-3 -(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide;
N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3 -(3-nitrophthalimido)propionamide;
N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(1 -oxoisoindolinyl)propionamide; 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide;
N-hydroxy-3-(3,4-dimethoxyphenyl)-3-phthalimidopropionamide; 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3-nitrophthalimido)propionamide;
N-hydroxy-3-(3 A-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide; 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3 ~(4-methyl-phthalimido)propionamide; 3-(3-cyclop entyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide; 3-(3-ethoxy-4-methoxypheny!)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H- benzo[flisoindol-2-yDpropionamide;
N-hydroxy-3- {3-(2-propoxy)-4-methoxyphenyl} -3-phthalimidopropionamide; 3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-diflucrophthalimido)-N- hydroxypropionamide; 3-(4-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide; 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide;
N-hydroxy-3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide; 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl) propionamide; and
CT wo eomeust f PCT/US2003/034535
N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-343-hittophiitdlin¥do)propishiathide.
Additional selective cytokine inhibitory drugs used in the invention include the substituted phenethylsulfones substituted on the phenyl group with a oxoisoindine group.
Examples of such compounds include, but are not limited to, those disclosed in U.S. patent mo. 6,020,358, which is incorporated herein, which include the following:
RS
R1 0 - R6
Rr?
N—CH* es NCH, SO,~R7
R4 wherein the carbon atom designated * constitutes a center of chirality;
Y is C=0, CHa, 803, or CH,C=0; each of R', R% R?, and R*, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or -NR®R®; or any two of R!, R%, R?, and R* on adjacent carbon atoms, together with the depicted phenylene ring are naphthylidene; each of R® and R®, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms;
Ris hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NRYR; each of R® and R® taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R® and R’ is hydrogen and the other is -COR'® or - SO,R "in which R'is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl, or R® and R® taken together are tetramethylene, pentamethylene, hexamethylene, or -CH,CH,X'CH,CH,- in which X! is -O-, -S- or -NH-; and each of R¥ and RY taken independently of the other is hydrogen, alkyl of 1to 8 carbon atoms, phenyl, or benzyl, or one of R® and RY is hydrogen and the other is -COR'”’ or =SO;R'" in which R'" is hydrogen, alkyl 1 to 8 carbon atoms, or phenyl, or R* and R” taken together are tetramethylene, pentamethylene, hexamethylene, or -
CH,CH,X’CH,CH;- in which X? is -O-, -S-, or -NH-.
It will be appreciated that while for convenience the above compounds are identified as phenethylsulfones, they include sulfonamides when R’ is NR¥R". :
Specific groups of such compounds are those in which Y is C=0 or CH,.
A further specific group of such compounds are those in which each of R}, R%, R?, and R* independently of the others, is hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy, or -NR®R’ in which each of R® and R® taken independently of the other is hydrogen or methyl or one of R® and R? is hydrogen and the other is -COCH;. 12 Corrected sheet: 16 May 2006
. -
Particular compounds are those in which on¢ of R*, RRS aR 1$=NH> atid the remaining of R!, R?, R?, and R* are hydrogen.
Particular compounds are those in which one of R!, R%, R?, and R*is -NHCOCH; and the remaining of RY, R% R® and R* are hydrogen.
Particular compounds are those in which one of R!, R% R? and R*is -N(CH3), and the remaining of RY R?, rR? and R* are hydrogen.
A further preferred group of such compounds are those in which one of R, R%, RS, and R* is methyl and the remaining of R!, R%, R®, and R* are hydrogen.
Particular compounds are those in which one of R, R% R’, and R*is fluoro and the remaining of R!, R?, R®, and R* are hydrogen.
Particular compounds are those in which each of R® and R%, independently of the other, is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentoxy, or cyclohexoxy.
Particular compounds are those in which R® is methoxy and R® is monocycloalkoxy, polycycloalkoxy, and benzocycloalkoxy.
Particular compounds are those in which R® is methoxy and R® is ethoxy.
Particular compounds are those in which R” is hydroxy, methyl, ethyl, phenyl, benzyl, or NR¥R” in which each of R® and R taken independently of the other is hydrogen or methyl.
Particular compounds are those in which R'is methyl, ethyl, phenyl, benzyl or
NR¥RY in which each of R®" and R®" taken independently of the other is hydrogen or methyl.
Particular compounds are those in which R” is methyl.
Particular compounds are those in which R” is NR¥R®" in which each of R® and R* taken independently of the other is hydrogen or methyl.
Other specific selective cytokine inhibitory drugs include fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds found in United States Provisional Application No. 60/436,975 to G. Muller ef al., filed December 30, 2002, which is incorporated herein in its entirety by reference. Representative fluoroalkoxy-substituted 1,3-dihydro-isoindelyl compounds include compounds of the formula:
O—R,
X4 @) jog
Xs R,
N -
X4 ' wherein:
Y is -C(O)-, CHa, -CH,C(0)-, -C(O)CH,-, or SO;
Z is —H, -C(O)R?, -(Cy.1-alkyl)-S0,-(C14-2lkyl), -Cis-alkyl, -CH20H, CH>(0)(C,.5- alkyl) or -CN;
R, and R; are each independently -CHE», -Ci.s-alkyl, -Cs.15-cycloalkyl, or -(Ci-10- alkyl)(Cs.15-cycloalkyl), and at least one of R; and Ry is CHF»;
R? is -NR*R’, -alkyl, -OH, ~O-alkyl, phenyl, benzyl, substituted phenyl, or substituted benzyl;
R* and R® are each independently —H, -C; s-alkyl, -OH, -OC(O)R’;
RS is —C.s-alkyl, -amino(C s-alkyl), -phenyl, -benzyl, or -aryl;
X,, X», X3, and X; are each independent -H, halogen, -nitro, -NH;, -CF;, -C;.¢-alkyl, (Cous-alkyD)~(Cs g-cycloalkyl), (Cos-alkyl)-NR'R®, {Cou-aliy))-NEH)C(0)-R®), (Cos- alkyl)-NEC(OINR RY), (Co.4-alkeyl)-NEH)C(O)ORR?), (Cou-alky)-OR’, (Co-s-alkyl)- imidazolyl, (Cos-alkyl)-pyrrolyl, (Cos-alkyl)-oxadiazolyl, or (Cou-alkyl)-triazolyl, or two of
X;, Xa, X3, and X4 may be joined together to form a cycloalkyl or heterocycloalkyl ring, (e.g, Xi and X3, X; and Xs, X;3 and X4, X; and X33, Xz and Xy, or X; and X4 may form a 3, 4,5, 6, or 7 membered ring which may be aromatic, thereby forming a bicyclic system with the isoindolyl ring); and
R” and R® are each independently H, Cy.o-alkyl, Cs.s-cycloalkyl, (C4-alkyl)-(Ca.s- cycloalkyl), (Ci.s-alkyl)-N@R'R®), (C1-alkyl)-OR®, phenyl, benzyl, or aryl; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
Preferred compounds of the invention include, but are not limited to: 3-(4-Acetylamino-1,3-dioxo-1,3 -dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy- i 4-difluoromethoxy-phenyl)-propionic acid; 3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-iseindol-2-yl)-3-(3-cyclopropylmethoxy- . 4-diflucromethoxy-phenyl)-N,N-dimethyl-propionamide; :
: ( 3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindel-2 -yl)43H(3 eyetoprop Vinetnoxy-4 difluoromethoxy-phenyl)-propionamide; 3.(3-Cyclopropylmethoxy-4-diflucromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro- isoindol-2-yl)-propionic acid; 3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(1,3-dioxo-1,3-dihydro- isoindol-2-yl)-N-hydroxy-propionamide; 3-(3 -Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro- 1-oxo-1,3- dihydro-isoindol-2-yl)-propionic acid methyl ester; 3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3 -(7-nitro-1-ox0-1,3- dihydro-isoindol-2-yl)-propionic acid; 3-(3-Cyclopropylmethoxy-4-diftuoromethoxy-phenyl -3-(7-nitro-1-0%0-1,3-dihydr isoindol-2-v1)- )-N,N-dimethyl-propionamide; 3-(7-Amino-1-o0xo-1,3-dihydro-isoindol-2-y1)-3-(3-cyclopropylmethoxy-4- difluoromethoxy-phenyl)-N,N-dimethyl-propionamide; 3-(4-Difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-0x0-1,3 -dihydro-isoindol-2- y1)-propionic acid methyl ester; 3-(7-Amino-1-o0x0-1,3-dihydro-isoindol-2-y1)-3-(4-diflucromethoxy-3 -ethoxy- phenyl)-propionic acid methyl ester; 3.[7-(Cyclopropanecarbonyl-amino}-1-0xo-1,3-dilydro-isoindol-2-y1]-3-(4- difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester; 3-(7-Acetylamino-1-oxo-1 ,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3- ethoxy-phenyl)-propionic acid methyl ester; 3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-y1)-3-(4-difluoromethoxy-3- ethoxy-phenyl)-propionic acid; 3.[7-(Cyclopropanecarbonyl-amino)-1-oxo-1 ,3-dihydro-isoindol-2-y1]-3-(4- difluoromethoxy-3-ethoxy-phenyl)-propionic acid;
Cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy- phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide;
Cyclopropanecarboxylic acid {2-[1-(4-diflucromethoxy-3-ethoxy-phenyl)-2- dimethylcarbamoyl-ethyl]-3-0x0-2,3-dihydro-1H-isoindol-4-y1}-;
Cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2- hydroxycarbamoyl-ethyl]-3-0xo-2,3-dihydro-1H-isoindol-4-yl}-amide; 3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3~(4-diflucromethoxy-3- ethoxy-phenyl)-propionamide;
3-(7-Acetylamino-1-0x0-1,3-dihydro-isoinddl-2=yl)-3-(4-ditliicfomethoxy-3- ethoxy-phenyl)-N,N-dimethyl-propionamide; 3-(7-Acetylamino-1-o0x0-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3- ethoxy-phenyl)-N-hydroxy-propionamide; } 3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3- ethoxy-phenyl)-propionic acid; : . 3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-y1)-3-(4-difluoromethoxy-3- ethoxy-phenyl)-propionamide; 3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3- ethoxy-phenyl)-N,N-dimethyl-propionamide; 3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3- ethoxy-phenyl)-N-hydroxy-propionamide;
Cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2- methanesulfonyl-ethyl}-3-0x0-2,3-dihydro-1H-i1soindol-4-yl} -amide;
N-{2-[1-(4-Difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo- 2,3-dihydro-1H-isoindol-4-yl}-acetamide; and
Cyclopropanecarboxylic acid {2-{2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy- phenyl)-ethyl]-7-chloro-3-0x0-2,3-dihydro-1H-isoindol-4-yl} -amide.
Other selective cytokine inhibitory drugs include 7-amido-substituted isoindolyl compounds found in United States Provisional Application No. 60/454,155 to G. Muller ez al., filed March 12, 2003, which is incorporated herein in its entirety by reference.
Representative 7-amido-substituted isoindolyl compounds include compounds of the formula: i O—R, ne NH ') 0
R,
N
Y z
X
25 . wherein:
Y is -C(0O)-, -CHa,, -CH>C(O)-or SOz; .
Xis H; .
Z is (Coz-alkyD)-C(O)R?, C,4-alkyl, (Co.s-alkyl)-OH, (C; 4-alkyl)-O(C, 4-alkyl),
- { . (Ci 4-alkyl)-SO2(Cr.4-alkyD), (Co-alicyl)-SO(Chr.4-allF (C5. BUG NEL i-ntieyly
N(Ci.3-alkyl)s, (Co-s-alkyl)-N(EH)(OH), CH;NSOA(C14-alkyl);
R, and R, are independently C,.g-alkyl, cycloalkyl, or(Cy4-alkyl)cycloalkyl,
Ris, NR? R®, OH, or O~(Cs-alkyl);
R*is H;
R® is -OH, or -OC(O)R’;
RS is Cy5-alkyl, amino-(Cy.s-alkyl), (Cy.s-alkyl)-(Cs.¢-cycloalkyl), Cy.scycloalkyl, phenyl, benzyl, or aryl; : or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof; or the formula: 0] 0—Ry \ // R,
N
Y 7
X wherein:
Y is -C(0)-, -CHj, ~-CH,C(0O)-, or SOx;
X is halogen, -CN, -NR;R3, -NO, or -CF3,
Wis
IC al
YOY OF
: 6 ng ,
Tr Te Rg
N (Coa) N J .
Re hd “or RE Cod)
Rg
Z is (Co-salkyl)-SO,(Cy4-alkyl), -(Coualkyl)-CN, ~(Co4alkyl)-C(O)R?, Ci.4-alkyl, (Co4-alkyl)OH, (Cos-alky))O(Ci4-alkyl), (Cou-alky)SO(Cius-alkyl), (Cou-alkyl)NHz, (Co-s- alky)N(Cy-s-alkyl)s, (Co.4-alkyl) N(HYOH), or (Co4-alikyl)NSO,(C1-4-alkyl);
W is -Css-cycloalkyl, -(Cy.g-alkyl)-(Cs.s.cycloalkyl), -(Co-s-alkyl)-(C3.cycloalkyl)-
NR7Rg, (Cos-alkyl)-NR7Rs, (Co4-alkyl)-CHRo~(Co4-alkyl)-NR7Rg;
-
R, and R; are independently Cy.g-alkyl, cycldalkyliof (&% Edis DeycloalicyL;
R3 is Cys-alkyl, NR* R®, OH, or O-(Cy_s-alkyl);
R* and R’ are independently H, Ci.s-alkyl, (Cos-alkyl)-(Cs-cycloalkyl), OH, or ~OC(O)RS;
RS is Cy.g-allyl, (Co.s-alkyl)-(Cs-cycloalkyl), amino-(Cy.g-alkyl), phenyl, benzyl, or aryl;
R; and Rg are each independently B, C;.g-alkyl, (Co.salkyl)-(Cas-cycloalkyl), phenyl, benzyl, aryl, or can be taken together with the atom connecting them to form a 3 to 7 membered heterocycloalkyl or heteroaryl ring;
Ry is C14-alkyl, (Cou-alkyl)aryl, (Cos-alkyl)-(Css-cycloalkyl), (Cou-alkyl)- heterocylcle; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
Still other selective cytokine inhibitory drugs include N-alkyl-hydroxamic acid- isoindolyl compounds found in United States Provisional Application No. 60/454,149 to G.
Muller ef al., filed March 12, 2003, which is incorporated herein in its entirety by reference.
Representative N-alkyl-hydroxamic acid-isoindolyl compounds include compounds of the formula:
O0—R; :
Xs 0 Q
X3 R, x5 Y Zs
X4 A —
Z,—0 o} wherein:
Y is -C(0)-, -CH,, -CH,C(O)- or SO»;
R,; and R; are independently C,.s-alkyl, CF.H, CF3, CH,CHE, cycloalkyl, or (Cys- alkycycloalkyl;
Z, is H, Cy.¢-alkyl, -NH, -NRaR4 or ORs;
Z, is H or C(O)Rs; '
X 1, Xa, X5 and X4 are each independent H, halogen, NOz, OR3, CF3, Crs-alkyl, (Co. s-alkyD)-(Cs.¢-cycloalkyl), (Co.a-alkyl)-N-(RsRs), (Co-4-alkyl)-NHC(0)-(Rs), (Cos-alkyl)- )
NHC(O)CH®Rs)(Rs), (Co-s-alkyl)-NHC(O)N(RsRs), (Co4-alkyl)-NHC(O)O(Rs), (Co-4-
alkyl)-O-Rs, (Cos-alkyl)-imidazolyl, (Cos-alkyl)-pytroliil, (Co s=alk 1)-6X adiazolyi, (Coa alkyl}-triazolyl or (Co.s-alkyl)-heterocycle;
R3,R4, and Rs are each independently H, C;-alkyl, 0-Ci.¢-alkyl, phenyl, benzyl, or aryl;
Re and Ry are independently H or C, s-alkyl;
Rg and Ry are each independently H, C.o-alkyl, Cis-cycloalkyl, (Cy.s-alkyl)-(Cs¢- cycloalkyl), (Co.¢-alkyl)-N(R4Rs), (C1¢-alkyl)-ORs, phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrolidinyl, morpholino, or Cs.g-heterocycloalkyl; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or © 10 prodmg thereof.
Specific selective cytokine inhibitory drugs include, but are not limited to: 2-[1(-3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]isoindolin-1-one; 2-{1-(3-ethoxy-4-methoxyphenyl)-2-(N,N-dimethyl-aminosulfonyl)ethyl]isoindolin- 1-one; 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl)isoindoline-1,3-dione; 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sulfonylethyl]-5-nitro-isoindoline-1,3- dione; 2-{1-(3-ethoxy-4-methoxyphenyl)-2-methyl-sul fonylethyl]-4-nitroiscindoline- 1 ,3- dione; 2-{1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline-1 3 dione; 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-methylisoindoline-1,3- dione: 2-[1-(3-~ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-acetamidoisoindoline- 1,3-dione; 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- dimethylaminoisondoline-1,3-dione; 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-3- dimethylaminoisoindoline-1,3-dione; ( 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl}benzo[e]isoindotine-1,3- dione; 2-1-3 -ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyi soindoline- 1,3-dione; 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl-amine;
2-1 _(3-cyclopentyloxy-4-methoxyphenyl)-2 mth ISulforyisityllissindolme-1 3- dione; and 2-[1-(3 -cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- dimethylaminoisoindoline-1,3-dione.
Additional selective cytokine inhibitory drugs include the enantiomerically pure compounds disclosed in U.S. patent application no. 10/392,195 filed on March 19, 2003; international patent application no. PCT/US03/0873, filed on March 20, 2003; U.S. provisional patent application nos. 60/438,450 and 60/438,448 to G. Muller ez al., both of which were filed on January 7, 2003; and U.S. provisional patent application no. 60/452,460 to G. Muller ef al. filed on March 5, 2003, all of which are incorporated herein by reference. Preferred compounds include an enantiomer of 2-[1-(3-ethoxy-4- methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione and an enantiomer of 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)- propionamide.
Preferred selective cytokine inhibitory drugs used in the invention are 3-(3,4- dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide and cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl- ethyl]-3-o0x0-2,3-dihydro-1 H-isoindol-4-yl}-amide, which are available from Celgene
Corp., Warren, NJ. 3-(3,4-Dimethoxy-phenyl)-3-(1-oxo-1 ,3-dihydro-isoindol-2-yl)- propionamide has the following chemical structure: 0”
SN
2 Q
Cr
Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-methanesulfonyl-ethyl]-3- 0x0-2,3-dihydro-1 H-isoindol-4-yl}-amide has the following chemical structure: o oO O_~ oo 0
O —
Compounds of the invention can either be commercially purchased or prepared according to the methods described in the patents or patent publications disclosed herein.
Further, optically pure compositions can be asymmetrically synthesized or resolved using known resolving agents or chiral columns as well as other standard synthetic organic chemistry techniques.
As used herein and unless otherwise indicated, the term “pharmaceutically acceptable salt” encompasses non-toxic acid and base addition salts of the compound to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases known in the art, which include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, and the like.
Compounds that are acidic in nature are capable of forming salts with various pharmaceutically acceptable bases. The bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations such as, but not limited to, alkali metal or alkaline earth metal salts and the calcium, magnesium, sodium or potassium salts in particular. Suitable organic bases include, but are not limited to,
N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine.
As used herein and unless otherwise indicated, the term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of selective cytokine inhibitory drugs that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of a selective cytokine inhibitory drug that comprise -NO, -NO,, -ONO, or -ONO; moieties.
Prodrugs can typically be prepared using well-known methods, such as those described in 1 : 30 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985).
As used herein and unless otherwise indicated, the terms “biohydrolyzable amide,” “biohydrolyzable ester,” “biohydrolyzable carbamate,” “biohydrolyzable carbonate,” “biohydrolyzable ureide,” and “biohydrolyzable phosphate” mean an amide, ester,
r . carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active . compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl, ‘ aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, e-amino acid amides, alkoxyacyl amides, and alkcylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
Various selective cytokine inhibitory drugs contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of selective cytokine inhibitory drugs may be used in methods and compositions of the invention. The purified (R) or (S) enantiomers of the specific compounds disclosed herein may be used substantially free of its other enantiomer.
As used herein and unless otherwise indicated, the term "stereomerically pure” means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
A typical stereomerically pure compound comprises greater than about 80% by wei ght of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers ) of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. :
As used herein and unless otherwise indicated, the term "stereomerically enriched" means a composition that comprises greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, more preferably greater than about 80% by weight of one stereoisomer of a compound.
As used herein and unless otherwise indicated, the term “enantiomerically pure” means a stereomerically pure composition of a compound having one chiral center.
Similarly, the term "enantiomerically enriched” means a stereomerically enriched composition of a compound having one chiral center.
It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. 4.2 SECOND ACTIVE AGENTS
A second active agent can be used in the methods and compositions of the invention together with a selective cytokine inhibitory drug. In a preferred embodiment, the second active agent is capable of inhibiting or relieving macular damaging conditions, providing antiangiogenesis or anti-inflammatory effects, or ensuring patient comfort.
Examples of second active agents include, but are not limited to, steroids, light sensitizers, integrins, antioxidants, interferons, Xanthine derivatives, growth hormones, neutrotrophic factors, regulators of neovascularization, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds, antiangiogenesis compounds, other therapeutics known to inhibit or relieve a symptom of MD, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, prodrugs and pharmacologically active metabolites thereof. In certain embodiments, the second active agent is verteporfin, purlytin, an angiostatic steroid, thuFab, interferon-2a, or pentoxifylline.
Examples of light sensitizers include, but are not limited to, verteporfin, tin etiopurpurin and motexafin lutetium. Verteporfin can be used to treat wet MD. Cour, M., et al., Drugs Aging 19:101-133 (2002). Verteporfin is a blood-vessel-blocking photoreactive dye that may be administered via injection.
Examples of xanthine derivatives include, but are not limited to, pentoxyfylline.
Examples of anti-VEGF antibodies include, but are not limited to, rhuFab.
Examples of steroids include, but are not limited to, 9-fluoro-11,21-dihydroxy -16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione.
Examples of prostaglandin F,a derivatives include, but are not limited to, latanoprost (see U.S. Patent No. 6,225,348, which is incorporated by reference herein in its entirety). }
Examples of antibiotics include, but are not limited to, tetracycline and its derivatives, rifamycin and its derivatives, macrolides, and metronidazole (see U.S. Patent
Nos. 6,218,369 and 6,015,803, the entireties of which are incorporated by reference herein).
Examples of phytoestrogens include, but are not limited to, genistein, genistin, 6’-O-Mal genistin, 6°-O-Ac genistin, daidzein, daidzin, 6’-0-Mal daidzin, 6’-O-Ac daidzin, glycitein, glycitin, 6’-O-Mal glycitin, biochanin A, formononetin, and a mixture thereof (see U.S. Patent No. 6,001,368, which is incorporated by reference herein in its entirety).
Examples of anti-inflammatory agents include, but are not limited to, triamcinolone acetomide and dexamethasone (see U.S. Patent No. 5,770,589, which is incorporated by reference herein in its entirety).
Examples of antiangiogenesis compounds include, but are not limited to, thalidomide and immunomodulatory compounds (IMiDs™ Celgene Corp., N.I.).
Examples of interferons include, but are not limited to, interferon-2cv.
In another embodiment, the second active agent is glutathione (see U.S. Patent No. 5,632,984, which is incorporate by reference herein in its entirety).
Examples of growth hormones include, but are not limited to, basic fibroblast growth factor (bFGF) and transforming growth factor b (TGF-b).
Examples of neurotrophic factors include, but are not limited to, brain-derived neurotrophic factor (BDNF).
Examples of regulators of neovascularization include, but are not limited to, plasminogen activator factor type 2 (PAI-2).
Additional drugs which may be used for the treatment of MD include, but are not limited to, EYE10! (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant and
RETISERT implant (Bausch & Lomb). 43 METHODS FOR TREATMENT AND PREVENTION
This invention encompasses methods of preventing, treating and/or managing various types of MD.
Claims (22)
1. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the manufacture of a medicament for use in a method of treating, preventing or managing macular degeneration, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of the drug, salt, solvate or stereoisomer.
2. The use of claim 1, wherein the method further comprises administering to the patient a therapeutically or prophylactically effective amount of a second active agent.
3. The use of claim 2, wherein the second active agent is a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an antiangiogenesis compound. b>
4. The use of claim 2, wherein the second active agent is thalidomide, verteporfin, purlytin, an angiostatic steroid, rhuFab, interferon-2¢t or pentoxifylline; cra pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
5. The use of claim 4, wherein the antiangiogenesis compound is thalidomide.
6. The use of claim 1, wherein the macular degeneration is wet macular degeneration, dry macular degeneration, age-related macular degeneration, age-related maculopathy, choroidal neovascularisation, retinal pigment epithelium detachment, atrophy of retinal pigment epithelium, Best’s disease, vitelliform, Stargardt’s disease, juvenile macular dystrophy, fundus flavimaculatus, Behr’s disease, Sorsby’s disease, Doyne’s disease, honeycomb dystrophy, or macular damaging condition.
7. The use of claim 1, wherein the selective cytokine inhibitory drug is stereomerically pure. Amended cheats 1R Mav 2006
E WO 2004/041181 PCT/US2003/034535
8. Use of 3-(3,4-dimethoxy-phenyl)-3-(1-oxo0-1 ,3-dihydro-isoindol-2-yl)- propionamide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the manufacture of a medicament for use in a method of treating, preventing or managing macular degeneration, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of the compound, salt, solvate or stereoisomer.
9. The use of claim 8, wherein the 3-(3,4-dimethoxy-phenyl)-3-(1-o0xo0-1,3 -dihydro-isoindol-2-yl)-propionamide is enantiomerically pure.
10. Use of cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)- 2-methanesulfonyl-ethyl]-3-0x0-2,3-dihydro-1 H-isoindol-4-yl-amide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the manufacture of a medicament for use in a method of treating, preventing or managing macular degeneration, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of the compound, salt, solvate or stereoisomer.
11. The use of claim 10, wherein the cyclopropanccarboxylic acid {2-[1-(3- ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-0x0-2,3-dihydro-1 H-isoindol -4-yl}-amide is enantiomerically pure.
12. The use of claim 1, wherein the selective cytokine inhibitory drug is of formula (I): I 0 i. NCH (CHa) — C— R12 NS L re NH D wherein n has a value of 1, 2, or 3; Ris o-phenylene, unsubstituted or substituted with. 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo; Corrected sheet: 16 May 2000 Amended sheet: 18 May 2000
R’ is (i) phenyl or phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo, (ii) benzyl 40A Corrected sheet: 16 May 2006 Amended sheet: 18 May 2006 unsubstituted or substituted with 1 to 3 substituents selected from the group consisting ot nitro, cyano, trifluoromethyl, carbothoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of I to 10 carbon “atoms, and halo, (11i) naphthyl, and (iv) benzyloxy; R" is -OH, alkoxy of 1 to 12 carbon atoms, or RS ~—N “RY R% is hydrogen or alkyl of 1 to 10 carbon atoms; and R’ is hydrogen, alkyl of 1 to 10 carbon atoms, -COR!'?, or -SO,R'?, wherein R'is hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.
13. The use of claim 12, wherein the sclective cytokine inhibitory drug is enantiomerically pure.
14. The usc of claim 1, wherein the selective cytokine inhibitory drug is of formula (II) 0 RT i R3 T N—CH 2 pz R> (CH zp)—C— N— O—R* RY Ls (I wherein each of R' and R?, when taken independently of each other, is hydrogen, lower alkyl, or R' and R?, when taken together with the depicted carbon atoms to which each 1s bound, is o-phenylene, o-naphthylene, or cyclohexene-1,2-diyl, unsubstituted or substituted with 1 to 4 substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1fo 10 carbon atoms, and halo; R’ is phenyl substituted with from one to four substituents sclected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbometaoxy, carbopropoxy, acetyl. carbameyvl, acetoxy, carboxy. hvdroxy, amino, alkv! of 1 to 10 carbon atoms, alkoxy of I to 10 carben atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cyelealkoxy of 3 to 6 4 Amended sheet: 18 May 2000 carbon atoms, Cy-Cs-cycloalkylidenemethyl, Cs-C¢-alkylidenemethyl, indanyloxy, and halo; Ris hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl, RY is hydrogen or alkyl of 1 to 6 carbon atoms; R’ is -CHa-, -CHz-CO-,-S0-,-S-, or -NHCO-; and n has a value of 0, 1, or 2.
1S. The use of claim 14, wherein the selective cytokine inhibitory drug is enantiomerically pura.
16. The use of claim 1, wherein the selective cytokine inhibitory drug is of formula (11D): . ps ooo « R A be I N—CH R3 TTY CHy— SO,—R7 (Im) wherein the carbon atom designated * constitutes a center of chirality; Y is C=0, CHa, SO», or CH,C=0; 13 each of R', RZ, R’, and R”, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or -NR*R?; or anv two of RY, R*, R®, and R* on adjacent carbon atoms, together with the depicted phenylene ring are naphthvlidene; each of R* and B®, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms; R'is hydroxy, alkyl of 1 to § carbon atoms, phenyl, benzyl, or NR*R; each of R® and R” taken independently of the other is hydrogen, alky! of to § carbon atoms, phenyl, or benzyl, or one of R® and R® is hydrogen and the other is -COR'? ar - SOR" in which R'? js hydrogen, alkyl of 1 to § carbon atoms, or phenyl, or R® and R’ taken together are tetramethvlene, pentamethylene, hexamethylene, Or -CHCH XP CH CH= in whieh XC is 20 _S- or -NH-; and - Corrected sheet: 16 May 2000 Amended sheet: 18 May 2000 vo WO 2004/041181 PCT/US2003/034535 each of R¥ and R® taken independently of the other is hydrogen, alkyl ot 1 to § carbon atoms, phenyl, or benzyl, or one of R¥ and R®’ is hydrogen and the other is -COR'”’ or - SO,R'" in which R'? is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl, or R¥ and R” taken together are tetramethylene, pentamethylene, hexamethylene, or -CH;CH,X’CH,CH,- in which X? is -O-, -S-, or -NH-.
17. The use of claim 16, wherein the selective cytokine inhibitory drug is enantiomerically pure.
18. Use of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in the manufacture of a medicament for use in a method of treating, preventing or managing macular degeneration, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of the drug, salt, solvate or : stereoisomer, before, during or after surgical intervention directed at reducing or avoiding a symptom of macular degeneration in the patient.
19. The use of claim 17, wherein the surgical intervention is light therapy, laser therapy, radiation therapy, retinal pigment epithelium transplantation, or foveal translocation.
20. A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second active agent capable of reducing or avoiding a symptom of macular degeneration.
21. The pharmaceutical composition of claim 20, wherein the second active agent is a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine } derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an antiangiogenesis compound.
22. The pharmaceutical composition of claim 20, wherein the second active agent is thalidomide, verteporfin, purlytin, an angiostatic steroid, rhuFab, interferon-2¢ or pentoxifylline, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 43 Corrected sheet: 16 May 2006 Amended sheet: 18 May 2006
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JP (1) | JP2006509743A (en) |
KR (1) | KR20050062649A (en) |
CN (1) | CN1731997A (en) |
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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 |
MX347928B (en) * | 2011-01-10 | 2017-05-19 | Celgene Corp | Phenethylsulfone isoindoline derivatives as inhibitors of pde 4 and/or cytokines. |
KR101908330B1 (en) | 2017-02-17 | 2018-10-16 | 인제대학교 산학협력단 | Novel anti-vascular endothelial growth factor antibody and composition for preventing or treating age-related macular degeneration comprising thereof |
CN113226020A (en) * | 2018-11-14 | 2021-08-06 | 珠海岐微生物科技有限公司 | Animal models, screening methods and treatment methods for intraocular diseases or disorders |
EP3886852B1 (en) * | 2018-12-03 | 2024-01-31 | Smilebiotek Zhuhai Limited | Octyl gallate and esters thereof of for use in the treatment and prevention of age-related macular degeneration caused by bacillus megaterium |
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US577589A (en) * | 1897-02-23 | Valve for explosive-engines | ||
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US5605914A (en) * | 1993-07-02 | 1997-02-25 | Celgene Corporation | Imides |
US5770589A (en) * | 1993-07-27 | 1998-06-23 | The University Of Sydney | Treatment of macular degeneration |
DE69813876T2 (en) * | 1997-07-31 | 2004-01-29 | Celgene Corp | SUSSITITATED ALKANY HYDROXAMIC ACID AND METHOD FOR REDUCING TNF ALPHASIC MIRROR |
WO1999058096A2 (en) * | 1998-05-11 | 1999-11-18 | Entremed, Inc. | Analogs of 2-phthalimidinoglutaric acid and their use as inhibitors of angiogenesis |
US6020358A (en) * | 1998-10-30 | 2000-02-01 | Celgene Corporation | Substituted phenethylsulfones and method of reducing TNFα levels |
JP2000159761A (en) * | 1998-11-30 | 2000-06-13 | Yoshio Takeuchi | Fluorothalidomide |
US6667316B1 (en) * | 1999-11-12 | 2003-12-23 | Celgene Corporation | Pharmaceutically active isoindoline derivatives |
ATE370952T1 (en) * | 2002-04-19 | 2007-09-15 | Smithkline Beecham Corp | NEW CONNECTIONS |
NZ536908A (en) * | 2002-05-17 | 2008-09-26 | Celgene Corp | Treating or preventing cancer comprising administering an effective amount of cytokine inhibitory drug plus a second active ingredient |
EP1551385A4 (en) * | 2002-10-15 | 2008-10-22 | Celgene Corp | Selective cytokine inhibitory drugs for treating myelodysplastic syndrome |
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CA2504263A1 (en) | 2004-05-21 |
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JP2006509743A (en) | 2006-03-23 |
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