CN1731997A - Methods of treating and managing macular degeneration using compositions comprising selective cytokine inhibitory drugs - Google Patents

Abstract

Methods of treating, preventing and/or managing macular degeneration are disclosed. Specific embodiments encompass the administration of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent and/or surgery. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Description

Methods of treating and managing macular degeneration using compositions comprising selective cytokine inhibitory drugs

technical field

This application claims priority to U.S. Provisional Application No. 60/422,900, filed October 31, 2002, which is incorporated herein by reference in its entirety.

1. Field of invention

The present invention relates to methods of treatment, prevention and management of macular degeneration (MD) and related syndromes, comprising selective cytokine inhibitory drugs administered alone or in combination with known therapeutic agents. The invention also relates to pharmaceutical compositions and dosing regimens. The invention specifically includes the use of selective cytokine inhibitory drugs in combination with surgical intervention and/or other standard therapies for the treatment of macular degeneration.

2. Background of the invention

2.1 Pathology 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, the thin layer of nerve cells that lines most of the inside of the eye. Nerve cells in the retina detect light and send signals to the brain about what the eye is seeing. The macula is near the center of the retina at the back of the eye and provides the clear, sharp central vision that animals use to focus on objects in front of it. The rest of the retina provides side (peripheral) vision.

There are two types of MD: atrophic ("dry") and exudative ("wet"), Riordan-Eva, P., Eye, Current Medical Diagnosis and Treatment, 41 ed. 210-211 (2002). 90% of patients suffer from dry type, while only 10% of patients suffer from humid type. However, humid patients can lose up to 90% of their vision. DuBosar, R., J. of Ophthalmic Nursing and Technology, 18:60-64 (1998).

Macular degeneration results in the presence of choroidal neovascularization (CNVM) and/or geographic atrophy of the retinal pigment epithelium (RPE) in eyes with drusen. Bird, A.C., Surv. Ophthamol. 39:367-74 (1995). Drusen are round white to pale yellow spots in the base, outside the neural retina. Other symptoms of MD include RPE detachment (PED) and submacular discoid scar tissue. Algvere, P.V., Acta Ophthalmologica Scandinayica 80: 136-143 (2002).

Choroidal neovascularization is a problem that is involved in many retinal diseases, but is most commonly associated with MD. CNVM is characterized by abnormal vascular stems growing from the choroid (the blood vessel-rich tissue layer just below the retina) into the retinal layer. These new blood vessels are very fragile and break easily, allowing blood and secretions to pool into the layers of the retina. When blood vessels leak, they disturb the delicate retinal tissue, making vision worse. The severity of this symptom depends on the size of the CNVM and its proximity to the macula. Symptoms can be mild, such as blurred vision or distortion of the visual field, or more severe, such as a central blind spot.

Patients with drusen and possibly pigmentary abnormalities but without CNVM or geographic atrophy are generally diagnosed with age-related macular degeneration (ARM). The source is the same as above. The histopathological hallmark of ARM and MD is a continuous layer of fine granular material deposited inside Bruch's membrane on the RPE cell base. Sarks, J.P., et al., Eye 2 (Pt. 5): 552-77 (1988). These accumulated basal deposits are believed to result from ongoing RPE phagocytosis or waste products of proglottic material outside the photoreceptors. This basal deposit thickens and makes Bruch's membrane less permeable. It has been hypothesized that reduced permeability to water impairs nutrient exchange, traps water and enhances the formation of soft drusen and PED and ultimately leads to atrophy of RPE cells. The source is the same as above. However, a comprehensive understanding of the pathogenesis of ARM and MD is currently insufficient. Cour, M., et al., Drugs Aging 19: 101-133 (2002).

Because MD is most prevalent in the middle-aged and older age groups (the fastest growing group), MD is destined to become a major economic and social problem. Macular degeneration is the most common cause of vision loss in individuals over the age of 60 in developed countries. Macular degeneration has caused the loss of central vision in 1.7 million Americans and an additional 11 million are at risk. DuBosar, R., J. of Ophthalmic Nursing and Technology, 18:60-64 (1998). Currently, there is no known cure for it. Rhoodhooft, J., Bull. Soc. belge Ophtalmo 1276:83-92 (2000). Therefore, effective treatments for MD are urgently needed.

2.2 Treatment of age-related macular degeneration

Until recently, laser photocoagulation has been the only conventional treatment for MD, and it has provided mediocre results. Laser photocoagulation is a type of laser surgery that uses an intense beam of light to burn a small area of the retina and abnormal blood vessels beneath the macula. This burning creates scar tissue and seals off the blood vessels so that they cannot leak under the macula. Laser photocoagulation is only effective in patients with wet MD. Furthermore, laser photocoagulation is an available option in only about 13% of these patients. Joffe, L. et al., International Ophthalmology Clinics 36(2):99-116 (1996). Laser photocoagulation does not cure wet MD, it only sometimes slows or prevents further loss of central vision. However, without treatment, vision loss from wet MD will continue until a person has lost central vision completely.

The most serious disadvantage of laser surgery is that the laser damages some of the nerve cells in the macula that respond to light, causing some vision loss. Vision loss from this procedure is sometimes more severe or worse than vision loss from no treatment. However, for some patients, laser surgery initially makes vision worse, but over time prevents more severe vision loss.

Verteporfin has recently been used to treat wet MD. Cour, M., et al., Drugs Aging 19: 101-133 (2002). Verteporfin is a blood vessel-blocking photoreactive dye administered by injection. The dye travels to the blood vessels responsible for vision loss and is then activated by a non-burning beam of light shone on the eye in the presence of oxygen. Verteporfin is transported in plasma mainly by lipoproteins. Activated verteporfin produces highly reactive, short-lived singlet oxygen and reactive oxygen free radicals, producing localized damage to the neovascular endothelium. It causes the blood vessels to close. Damaged endothelium is known to release procoagulant and angiogenic factors through lipo-oxygenase (leukotrienes) and cyclo-oxygenase (eicosanes such as thromboxane) pathways, resulting in platelet aggregation, Fibrin clot formation and vasoconstriction. It was shown that verteporfin to some extent preferentially accumulates in the neovasculature including the choroidal cardiovascular system. However, animal models have shown that verteporfin also accumulates in the retina. Therefore, the use of verteporfin may damage both retinal structures, including the retinal pigment epithelium and the outer nuclear layer of the retina.

Another strategy currently under investigation for the treatment of MD is pharmacological anti-angiogenic therapy. Cour, M., et al., Drugs Aging 19: 101-133 (2002). But the first clinical trials with an anti-angiogenic agent, interferon-α, showed that it was ineffective and had a high incidence of adverse effects in the treatment of MD. Arch. Op Athalmol. 115:865-72 (1997).

Intravitreal injection of triamcinolone was reported to inhibit the growth of laser-induced CNYM in monkeys, but it failed to prevent severe vision loss within one year in a randomized trial of patients with MD. Gillies, M.C., et al., Invest. Ophthalmol. Vis. Sci. 42:S522 (2001). Many other anti-angiogenic agents for patients with MD are in various stages of development, including angiostatin steroids (eg, anecorta acetate, Alcon) and antibodies to vascular epidermal growth factor (VEGF) or fragments thereof . Guyer, D.R., et al., Invest. Ophthalmol. Vis. Sci. 42:S522 (2001). One such VEGF antibody is rhuFab. Additional new drugs to treat MD include EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant, and the RETISERT implant (Bausch & Lomb), which sheds steroids into the eye for up to three years.

Although new and promising therapeutic strategies for MD and related macular degeneration diseases are being investigated, effective treatments are still not available. Therefore, there remains a need in the art for an effective method of treating MD.

2.3 Selective cytokine inhibitory drugs

Compounds known as SeICIDs ^™ (Celgene Corporation) or Selective Cytokine Inhibitory Drugs have been synthesized and tested. These compounds potently inhibit TNF-α production and exhibit moderate inhibitory effects on LPS-induced IL1β and IL12. LG Corral, et al., Ann. Rheum. Dis. 58: (Suppl I) 1107-1113 (1999).

Additional tailoring of selective cytokine inhibitory drugs suggests that they are potent PDE4 inhibitors. PDE4 is an important phosphodiesterase isozyme found in cells of human myeloid and lymphoid lineages. This enzyme plays a key role in cellular activities by degrading the ubiquitous second messenger cAMP and maintaining it at low intracellular levels. The source is the same as above. Inhibition of PDE4 activity resulted in increased cAMP levels, which modulated LPS-induced cytokines, including suppression of TNF-α production in monocytes as well as lymphocytes.

3. Outline of the invention

The present invention includes methods of treating and/or preventing MD, said method comprising 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 Constructs, clathrates or prodrugs. The present invention also includes a method of controlling MD (e.g. prolonging remission), said method comprising 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 thereof compounds, stereoisomers, clathrates or prodrugs.

Another embodiment of the present invention comprises a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in combination with another drug for the treatment or prevention of MD. Therapeutic agents such as but not limited to steroids, photosensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neutrotrophic factors, modulators of neovascularization, anti-VEGF antibodies , prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or angiogenesis-inhibiting compounds or combinations thereof.

Another embodiment of the present invention includes a method of treating, preventing or managing MD comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug or its agent in combination with a conventional therapy for treating or preventing MD. Pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs, such as conventional therapies such as but not limited to surgical interventions (eg laser photocoagulation therapy and photodynamic therapy).

The present invention also includes a pharmaceutical composition comprising a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug suitable for the treatment, prevention and/or management of MD , single unit dosage forms and kits.

4. Detailed Description of the Invention

A first embodiment of the present invention includes methods of treating and preventing MD, said method comprising administering a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug or a pharmaceutically acceptable amount thereof to a patient (e.g., a mammal such as a human) in need thereof. Use salts, solvates, hydrates, stereoisomers, clathrates or prodrugs. The present invention also 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 macular degeneration (ARM), Choroidal neovascularization (CNVM), retinal pigment epithelial detachment (PED), and retinal pigment epithelial (RPE) atrophy.

Although some macular degenerative diseases are more common in certain age groups, the term macular degeneration (MD) as used herein includes all forms of macular degenerative disease regardless of the patient's age. These include, but are not limited to, Best's disease or vitelloform macular degeneration (most common in patients under the age of seven); ages); Bell's disease, Sorsby's disease, Doyne's disease, or cellular dystrophy (most common in patients between about 30 and about 50 years of age); and age-related macula Degeneration (most common in patients about 60 years of age or older).

Causes of MD include, but are not limited to, genetics, physical trauma, diseases such as diabetes, and infections such as bacterial infections (such as leprosy and especially ENL).

Another embodiment of the invention includes a method of managing MD comprising 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.

Another embodiment of the present invention includes a pharmaceutical composition comprising a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof and optionally carrier.

The invention also includes single unit dosage forms comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and optionally a carrier.

Another embodiment of the invention includes a kit comprising: a drug comprising a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof combination. The invention also includes kits comprising single unit dosage forms. Particular kits contain an Amsler grid that can be used to detect or diagnose MD.

While not wishing to be bound by theory, it is believed that some selective cytokine inhibitory drugs may act in a complementary or synergistic manner with other drugs available to treat symptoms of MD to treat or manage MD. Accordingly, one embodiment of the present invention includes a method of treating, preventing and/or managing MD, said method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug or a pharmaceutically acceptable salt thereof, A solvate, hydrate, stereoisomer, clathrate or prodrug and a therapeutically or prophylactically effective amount of a second active agent.

Examples of second active agents include, but are not limited to, commonly used therapeutic agents for the treatment or prevention of MD, such as steroids, photosensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neurotrophic Factors, neovascularization modulators, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds and angiogenesis inhibitory compounds, and other therapeutic agents described in, for example, Physician's Desk Reference 2003. Specific examples of second active agents include, but are not limited to, verteporfin, purlytin, angiogenic steroids, rhuFab, interferon-2α, integrins, antioxidants, and pentoxifylline.

The present invention also includes pharmaceutical compositions, single unit dosage forms and kits comprising 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 comprise a compound of the invention in combination with steroids, photosensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neurotrophic factors, modulators of neovascularization, anti-VEGF antibodies, Prostaglandins, antibiotics, phytoestrogens, anti-inflammatory or angiogenesis-inhibiting compounds or combinations thereof, or other drugs capable of slowing or alleviating MD.

It is believed that specific selective cytokine-inhibiting drugs reduce or eliminate adverse effects associated with the administration of therapeutic agents for the treatment of MD, thereby allowing greater amounts of therapeutic agents to be administered to patients and/or improving patient compliance. Accordingly, another embodiment of the invention includes a method of reversing, alleviating or avoiding adverse effects associated with administration of a second active agent in MD patients comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selected Cytokine inhibitory drugs or their pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs.

As described elsewhere herein, the symptoms of MD can be treated with surgical interventions such as, but not limited to, light or laser therapy, radiation therapy, retinal pigment epithelial transplantation, and central translocation. While not wishing to be bound by theory, it is believed that conventional therapy combined with selective cytokine inhibitory drugs can be highly effective. Accordingly, the present invention includes methods of treating, preventing and/or managing MD comprising administering to a patient a selective cytokine inhibitory drug or a pharmaceutically acceptable Salts, solvates, hydrates, stereoisomers, clathrates or prodrugs.

4.1 Selective cytokine inhibitory drugs

Compounds useful in the present invention include racemic, stereoisomerically pure and stereoisomer-enriched selective cytokine inhibitory drugs, stereoisomers and enantiomerically pure compounds having selective cytokine inhibitory activity , and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates and prodrugs thereof. Preferred compounds for use in the present invention are the known Selective Inhibitor Drugs (SelCIDs ^(TM )) from Celgene Corporation, NJ.

Unless otherwise stated, the terms "selective cytokine inhibitory drug" and "SelCIDs ^™ " include small molecule drugs, such as small organic molecules that are not peptides, proteins, nucleic acids, oligosaccharides or other macromolecules. Preferred compounds inhibit TNF-alpha production. Compounds may also have modest inhibitory effects on LL1β 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. Patents 5,605,914 and 5,463,063, the cycloalkylamides and cycloalkanes disclosed in U.S. cyanonitriles, aryl amides disclosed in U.S. Patents 5,801,195, 5,736,570, 6,046,221 and 6,284,780 (for example, one embodiment is N-benzoyl-3-amino-3-(3',4'-dimethoxyphenyl )-propionamide); imides/amide ethers and alcohols (e.g., 3-phthalimido-3-(3′,4′-dimethoxyphenyl)propane) disclosed in U.S. Patent 5,703,098 -1-ol); succinimide and maleimide compounds disclosed in U.S. Patent 5,658,940 (e.g. 3-(3',4',5'6'-pentahydrophthalimide) - 3-(3", 4"-dimethoxyphenyl)propionic acid methyl ester); imido- and amido-substituted alkanehydroxamic acids disclosed in U.S. Patent 6,214,857 and WO99/06041; in U.S. Patent Substituted phenethylsulfone compounds disclosed in 6,011,050 and 6,020,358; substituted imides disclosed in U.S. Patent 6,429,221 (such as 2-phthalimido-3-(3',4'-dimethoxy phenyl)propane); substituted 1,3,4-oxadiazoles disclosed in U.S. Patent 6,326,388 (eg, 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)- 2-(1,3,4-oxadiazol-2-yl)ethyl]-5-methylisoindoline-1,3-dione); in U.S. Patents 5,929,117, 6,130,226, 6,262,101, and 6,479,554 Disclosed cyano and carboxyl derivatives of substituted styrene (e.g. 3,3-bis-(3,4-dimethoxyphenyl)acrylonitrile); Isoindolin-1-ones and isoindolin-1s substituted with (3,4-disubstituted phenyl)alkyl groups and substituted at the 4- and/or 5-position by nitrogen-containing groups, 3-diketone compounds; imido and amido-substituted acyl hydroxamic acids (eg (3-(1,3-dioxoisoindolin-2-yl)-3 -(3-Ethoxy-4-methoxyphenyl)propionylamino)propionate. Each patent and patent application mentioned herein is incorporated herein by reference in its entirety.

Additional selective cytokine inhibitory drugs are synthetic compounds, typical embodiments of which include 3-(1,3-dioxobenzo-[f]isoindol-2-yl)-3-(3-cyclopentanyl Oxy-4-methoxyphenyl) propanamide and 3-(1,3-dioxo-4-azaisindol-2-yl)-3-(3,4-dimethoxy phenyl)-propionamide.

Other specific selective cytokine inhibitory drugs belong to the non-polypeptide cyclic amides disclosed in U.S. Patents 5,698,579 and 5,877,200, both of which are incorporated herein by reference. Representative cyclic amides include compounds of the formula:

where n is 1, 2 or 3;

R is o ^- phenylene, which is unsubstituted or substituted by 1-4 substituents independently selected from the group consisting of nitro, cyano, trifluoromethyl, ethoxycarbonyl, methyl Oxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl having 1-10 carbon atoms, having 1- Alkyl and halogen of 10 carbon atoms;

R ⁷ is (i) phenyl or phenyl substituted by one or more groups independently selected from the following groups: nitro, cyano, trifluoromethyl, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl , acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl having 1-10 carbon atoms, alkoxy having 1-10 carbon atoms and halogen, (ii) unsubstituted or replaced by Benzyl substituted with 1-3 groups selected from the group consisting of nitro, cyano, trifluoromethyl, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl , hydroxyl, amino, alkyl having 1-10 carbon atoms, alkoxy having 1-10 carbon atoms and halogen, (iii) naphthyl, and (iv) benzyloxy;

R ¹² is -OH, an alkoxy group with 1-12 carbon atoms or

^R is hydrogen or an alkyl group having 1-10 carbon atoms; and

R ⁹ is hydrogen, an alkyl group having 1-10 carbon atoms, -COR ¹⁰ or -SO ₂ R ¹⁰ , wherein R ¹⁰ is hydrogen, an alkyl group having 1-10 carbon atoms, or a phenyl group.

Specific compounds of this class include, but are not limited to:

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-oxoisoindolin-yl)propionic acid;

3-(4-methoxyphenyl)-3-(1-oxoisoindolin-yl)propionamide;

3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionic acid;

3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydroisoindol-2-yl)propionamide;

3-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolin-2-yl)propionamide;

3-(3,4-diethoxyphenyl)-3-(1-oxoisoindolin-yl)propanoic acid;

Methyl 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoate;

3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid;

3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propanoic acid;

3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propionic acid;

3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propanamide;

3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propanamide;

Methyl 3-(1-oxoisoindolin-2-yl)-3-(3-butoxy-4-methoxyphenyl)propanoate; and

methyl 3-(1-oxoisoindolin-2-yl)-3-(3-propoxy-4-methoxyphenyl)propanoate.

Other specific selective cytokine inhibitory drugs include the imido and amido substituted alkanehydroxamic acids disclosed in WO 99/06041, which is incorporated herein by reference. Examples of such compounds include, but are not limited to:

Wherein, when independent of each other, ^R1 and ^R2 are hydrogen, lower alkyl respectively, or when together with the carbon atom to which they are bonded, ^R1 and ^R2 together are ortho-phenylene, ortho-naphthylene Or cyclohexene-1,2-diyl, which is unsubstituted or substituted by 1-4 substituents independently selected from the following: nitro, cyano, trifluoromethyl, ethoxycarbonyl, methoxycarbonyl , propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl having 1-10 carbon atoms, having 1-10 Alkoxy and halogen of carbon atoms;

^R is phenyl, which is unsubstituted or substituted by 1-4 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, acetyl group, carbamoyl group, acetoxy group, carboxyl group, hydroxyl group, amino group, alkyl group having 1-10 carbon atoms, alkoxy group having 1-10 carbon atoms, alkylthio group having 1-10 carbon atoms , benzyloxy, cycloalkoxy having 3-6 carbon atoms, C ₄ -C ₆ -cycloalkylenemethyl, C ₃ -C ₁₀ alkylenemethyl, indanyloxy and halogen;

R ⁴ is hydrogen, alkyl having 1-6 carbon atoms, phenyl or benzyl;

R ^4' is hydrogen or an alkyl group with 1-6 carbon atoms;

R ⁵ is -CH ₂ -, -CH ₂ -CO-, -SO ₂ -, -S- or -NHCO-;

n is 0, 1 or 2;

and acid addition salts of said compounds containing a nitrogen atom capable of being protonated.

Additional specific and selective cytokine inhibitory drugs that can be used in the present 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-(3,4-dimethoxyphenyl)-3-(1-oxoisoindolinyl)propionamide;

3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(4-methyl-phthalimido)propionamide;

3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide;

3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindole -2-yl) propionamide;

N-Hydroxy-3-{3-(2-propoxy)-4-methoxyphenyl)-3-phthalimidopropionamide;

3-(3-ethoxy-4-methoxyphenyl)-3-(3,6-difluorophthalimido)-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)propanamide; and

N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)propanamide.

Additional selective cytokine inhibitory drugs that may be used in the present invention include phenethyl sulfones substituted with oxindole groups on the phenyl groups.

Examples of such compounds include, but are not limited to, those disclosed in U.S. Patent 6,020,358, which is incorporated herein by reference, and include the following compounds:

wherein the carbon atom marked with * constitutes a chiral center;

Y is C=O, _CH2 , _SO2 or _CH2C =O;

Each of R ¹ , R ² , R ³ and R ⁴ is independently hydrogen, halogen, alkyl having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms, nitro, cyano, Hydroxy or -NR ⁸ R ⁹ ; or any two of R ¹ , R ² , R ³ and R ⁴ on adjacent carbon atoms are naphthylene together with the indicated benzene ring; each of R ⁵ and R ⁶ independently of each other is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano or cycloalkoxy having up to 18 carbon atoms;

R ⁷ is hydroxyl, alkyl having 1-8 carbon atoms, phenyl, benzyl or NR ^8' R ^9' ;

Each of R ^{and R} is independently of each other hydrogen, alkyl having 1-8 carbon atoms, phenyl or benzyl, or one of ^R and ^R is hydrogen and the other is ^-COR or -SO ₂ R ¹⁰ , or R ⁸ and R ⁹ together are tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ¹ CH ₂ CH ₂ -, wherein X ¹ is -O-, -S- or -NH-; and

Each of R ^8' and R ^9' is independently of each other hydrogen, alkyl having 1-8 carbon atoms, phenyl or benzyl, or one of R ^8' and R ^9' is hydrogen and the other is -COR ^10' or -SO ₂ R ^10' , or R ^8' and R ^9' together are tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ² CH ₂ CH ₂ -, Wherein X ² is -O-, -S- or -NH-.

It should be understood that while the above compounds are referred to as benzene and sulfones for convenience, when R ⁷ is NR ^8' R ^9' they include sulfonamide compounds.

A particular group of such compounds are those wherein Y is C=O or _CH2 .

A specific group of such compounds are those defined as follows: wherein R ¹ , R ² , R ³ and R ⁴ are independently of each other hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxyl or -NR ⁸ R ⁹ , wherein each of R ⁸ and R ⁹ is independently hydrogen or methyl, or one of R ⁸ and R ⁹ is hydrogen and the other is -COCH ₃ .

Particular compounds are those defined as follows: one of R ¹ , R ² , R ³ and R ⁴ is -NH ₂ and the remaining R ¹ , R ² , R ³ and R ⁴ are hydrogen.

Particular compounds are those defined as follows: one of R ¹ , R ² , R ³ and R ⁴ is -NHCOCH ₃ and the remaining R ¹ , R ² , R ³ and R ⁴ are hydrogen.

Particular compounds are those defined as follows: one of R ¹ , R ² , R ³ and R ⁴ is -N(CH ₃ ) ₂ and the remaining R ¹ , R ² , R ³ and R ⁴ are hydrogen.

Particular compounds are those defined as follows: one of R ¹ , R ² , R ³ and R ⁴ is methyl and the remaining R ¹ , R ² , R ³ and R ⁴ are hydrogen.

Particular compounds are those defined as follows: one of R ¹ , R ² , R ³ and R ⁴ is fluorine and the remaining R ¹ , R ² , R ³ and R ⁴ are hydrogen.

Particular compounds are those defined as follows: wherein each ^R5 and ^R6 independently of each other is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentyloxy or Cyclohexyloxy.

Particular compounds are those defined as follows: wherein R ⁵ is methoxy, and R ⁶ is monocycloalkoxy, polycycloalkoxy and benzocycloalkoxy.

Particular compounds are those defined as follows: wherein R ⁵ is methoxy and R ⁶ is ethoxy.

Particular compounds are those defined as follows: wherein R ⁷ is hydroxyl, methyl, ethyl, phenyl, benzyl, or -NR ^8' R ^9' , wherein each R ^8' and R ^9' are independently hydrogen or methyl.

Particular compounds are those defined as follows: wherein R ⁷ is methyl, ethyl, phenyl, benzyl, or -NR ^8' R ^9' , wherein each R ^8' and R ^9' are independently of each other hydrogen or methyl base.

Particular compounds are those wherein ^R7 is methyl.

Particular compounds are those defined as follows: wherein R ⁷ is -NR ^8' R ^9' , wherein each R ^8' and R ^9' is independently of the other hydrogen or methyl.

Other specific selective cytokine inhibitory drugs include the fluoroalkoxy-substituted 1,3-dihydroiso Indolyl Compounds, this application is incorporated herein by reference in its entirety. Representative fluoroalkoxy-substituted 1,3-dihydroisoindolyl compounds include those of the formula:

in:

Y is -C(O)-, _-CH2 , _-CH2C (O)-, -C(O) _CH2- or _SO2 ;

z is -H, -C(O)R ³ , -(C _0-1 -alkyl)-SO ₂ -(C1-4-alkyl), -C _1-8 -alkyl, -CH ₂ OH, CH ₂ (O)(C _1-8 -alkyl) or —CN;

R ₁ and R ₂ are independently -CHF ₂ , -C _1-8 -alkyl, -C _3-18 -cycloalkyl or -(C _1-10 -alkyl)(C _3-18 -cycloalkane base), and at least one of R ₁ and R ₂ is CHF ₂ ;

R ³ is -NR ⁴ R ⁵ , -alkyl, -OH, -O-alkyl, phenyl, benzyl, substituted phenyl, or substituted benzyl;

R ⁴ and R ⁵ are independently -H, -C _1-8 -alkyl, -OH, -OC(O)R ⁶ ;

R ⁶ is -C _1-8 -alkyl, -amino(C _1-8 -alkyl), -phenyl, -benzyl or -aryl;

X ₁ , X ₂ , X ₃ and X ₄ are independently -H, -halogen, -nitro, -NH ₂ , -CF ₃ , -C _1-6 -alkyl, -(C _0-4 -alk base)-(C _3-6 -cycloalkyl), (C _0-4 -alkyl)-NR ⁷ R ⁸ , (C _0-4 -alkyl)-N(H)C(O)-(R ⁸ ), (C _0-4 -alkyl)-N(H)C(O)N(R ⁷ R ⁸ ), (C _0-4 -alkyl)-N(H)C(O)O(R ⁷ R ⁸ ), (C _0-4 -alkyl)-OR ⁸ , (C _0-4 -alkyl)-imidazolyl, (C _0-4 -alkyl)-pyrrolyl, (C _0-4- Alkyl)-oxadiazolyl, (C _0-4 -alkyl)-triazolyl, or two X ₁ , X ₂ , X ₃ and X ₄ can be linked together to form cycloalkyl or heterocycloalkyl Rings (for example X ₁ and X ₂ , X ₂ and X ₃ , X ₃ and X ₄ , X ₁ and X ₃ , X ₂ and X ₄ or X ₁ and X _{4 may form 3, 4, 5} which may be aromatic , 6 or 7 membered ring, thereby forming a bicyclic ring system with an isoindolyl ring); and

R ⁷ and R ⁸ are independently of each other H, C _1-9 -alkyl, C _3-6 cycloalkyl, (C _1-6 -alkyl)-(C _3-6 -cycloalkyl), (C _1-6 -Alkyl)-N(R ⁷ R ⁸ ), (C _1-6 -Alkyl)-OR ⁸ , phenyl, benzyl or aryl; or pharmaceutically acceptable salts, solvates, and hydrates thereof , stereoisomers, clathrates or prodrugs.

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-4-difluoromethane Oxy-phenyl)-propionic acid;

3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethane Oxy-phenyl)-N,N-dimethyl-propionamide;

3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethane Oxy-phenyl)-propionamide;

3-(3-cyclopropylmethoxy-4-difluoromethoxy-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-isoindole-2- base) - methyl propionate;

3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindole-2- base)-propionic acid;

3-(3-Cyclopropylmethoxy-4-difluoromethoxy-phenyl-3-(7-nitro-1-oxo-1,3-dihydroisoindol-2-yl) -)-N,N-Dimethyl-propionamide;

3-(7-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl )-N,N-dimethyl-propionamide;

3-(4-Difluoromethoxy-3-ethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)- Methyl propionate;

3-(7-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propane Acid methyl ester;

3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy -phenyl)-methyl propionate;

3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl) - methyl propionate;

3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl) - propionic acid;

3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-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-difluoromethoxy-3-ethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3- Dihydro-1 H-isoindol-4-yl}-;

Cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro -1H-isoindol-4-yl}-amide;

3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl) - Propionamide;

3-(7-Acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl) -N,N-Dimethyl-propionamide;

3-(7-Acetylamino-1-oxo-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-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-methylsulfonyl-ethyl]-3-oxo-2,3-dihydro- 1H-isoindol-4-yl}-amide;

N-{2-[1-(4-Difluoromethoxy-3-ethoxy-phenyl)-2-methylsulfonyl-ethyl]-1,3-dioxo-2,3-di Hydrogen-1H-isoindol-4-yl}-acetamide; and

Cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3 -Dihydro-1H-isoindol-4-yl}-amide.

Other selective cytokine inhibitory drugs include the 7-acylamino-substituted isoindolyl compounds in U.S. Provisional Application No. 60/454,155, filed March 12, 2003, by G. The application is incorporated herein by reference in its entirety. Representative 7-amido-substituted isoindolyl compounds include those of the formula:

in:

Y is -C(O)-, _-CH2 , _-CH2C (O)- or _SO2 ;

X is H;

Z is (C _0-4- alkyl)-C(O)R ³ , (C _1-4 -alkyl), (C _0-4 -alkyl)-OH, (C _1-4 -alkyl)-O (C _1-4 -alkyl), (C _1-4 alkyl)-SO ₂ (C _1-4 alkyl), (C _0-4 alkyl)-SO(C _1-4 alkyl), ( C _0-4 -alkyl)-NH ₂ , (C _0-4- alkyl)N(C _1-8 -alkyl) ₂ , (C _0-4 -alkyl)-N(H)(OH), CH ₂ NSO ₂ (C _1-4 alkyl);

R ₁ and R ₂ are independently C _1-8 -alkyl, cycloalkyl or (C _1-4 -alkyl)cycloalkyl;

R ³ is NR ⁴ R ⁵ , OH or O-(C _1-8 -alkyl);

^R4 is H;

R ⁵ is -OH or -OC(O)R ⁶ ;

R ⁶ is C _1-8 -alkyl, amino-(C _1-8 -alkyl), (C _1-8 -alkyl)-(C _3-6 -cycloalkyl), C _3-6 cycloalkane base, phenyl, benzyl or aryl;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof,

or a compound of the formula:

in:

Y is -C(O)-, _-CH2 , _-CH2C (O)- or _SO2 ;

X is halogen, -CN, -NR ₇ R ₈ , -NO ₂ or -CF ₃ ,

W is

Z is (C _0-4 alkyl)-SO ₂ (C _1-4 alkyl), -(C _0-4 alkyl)-CN, -(C _0-4 alkyl)-C(O)R ³ , C _1-4 alkyl, (C _0-4 alkyl) OH, (C _0-4 alkyl) O (C _1-4 alkyl), (C _0-4 alkyl) SO (C _1-4 -alkyl), (C _0-4 -alkyl)NH ₂ , (C _0-4 -alkyl)N(C _1-8 -alkyl) ₂ , (C _0-4 -alkyl)N(H )(OH) or (C _0-4 alkyl)NSO ₂ (C _1-4 alkyl);

W is -C _3-6 -cycloalkyl, -(C _1-8 -alkyl)-(C _3-6 -cycloalkyl), -(C _0-8 -alkyl)-(C _3-6 Cycloalkyl)-NR ₇ R ₈ , (C _0-8 alkyl)-NR ₇ R ₈ , (C _0-4 alkyl)-CHR ₉ -(C _0-4 alkyl)-NR ₇ R ₈ ;

R ₁ and R ₂ are independently C _1-8 -alkyl, cycloalkyl or (C _1-4 -alkyl)cycloalkyl;

R ³ is C _1-8 -alkyl, NR ⁴ R ⁵ , OH or O—(C _1-8 -alkyl);

R ⁴ and R ⁵ are independently H, C _1-8 -alkyl, (C _0-8 -alkyl)-(C _3-6 -cycloalkyl), OH or -OC(O)R ⁶ ;

R ⁶ is C _1-8 -alkyl, (C _0-8 -alkyl)-(C _3-6 -cycloalkyl), amino-(C _1-8 -alkyl), phenyl, benzyl or Aryl;

R ₇ and R ₈ are independently H, C _1-8 -alkyl, (C _0-8 alkyl)-(C _3-6 -cycloalkyl), phenyl, benzyl, aryl, or can be together with the atoms connecting them form a 3-7 membered heterocycloalkyl or heteroaryl ring;

R ₉ is C _1-4 -alkyl, (C _0-4 alkyl) aryl, (C _0-4 alkyl)-(C _3-6 cycloalkyl), (C _0-4 alkyl)- Heterocycle;

Or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof.

Other selective cytokine inhibitory drugs include the N-alkyl-hydroxamic acid-isoindolyl compounds described in U.S. Provisional Application No. 60/454,149, filed March 12, 2003, by G. Muller et al. This application is incorporated herein by reference in its entirety.

Representative N-alkyl-hydroxamic acid-isoindolyl compounds include those of the formula:

in:

Y is -C(O)-, _-CH2 , _-CH2C (O)- or _SO2 ;

R ₁ and R ₂ are independently C _1-8 -alkyl, CF ₂ H, CF ₃ , CH ₂ CHF ₂ , cycloalkyl or (C _1-8 -alkyl)cycloalkyl;

Z ₁ is H, C _1-6 -alkyl, -NH ₂ -NR ₃ R ₄ or OR ₅ ;

Z ₂ is H or C(O)R ₅ ;

X ₁ , X ₂ , X ₃ and X ₄ are independently H, halogen, NO ₂ , OR ₃ , CF ₃ , C _1-6 -alkyl, (C _0-4 -alkyl)-(C _{3- 6} -cycloalkyl), (C _0-4 alkyl)-N-(R ₈ R ₉ ), (C _0-4 alkyl)-NHC(O)-(R ₈ ), (C _0-4 alkyl Base)-NHC(O)CH(R ₈ )(R ₉ ), (C _0-4 -Alkyl)-NHC(O)N(R ₈ R ₉ ), (C _0-4- Alkyl)-NHC( O)O(R ₈ ), (C _0-4 -alkyl)-OR ₈ , (C _0-4- alkyl)-imidazolyl, (C _0-4- alkyl)-pyrrolyl, (C _0-4 Alkyl)-oxadiazolyl, (C _0-4 -alkyl)-triazolyl or (C _0-4- alkyl)-heterocycle;

R ₃ , R ₄ and R ₅ are independently H, C _1-6 -alkyl, OC _1-6 -alkyl, phenyl, benzyl or aryl;

R ₆ and R ₇ are independently H or C _1-6 -alkyl;

R ₈ and R ₉ are independently H, C _1-9 -alkyl, C _3-6 -cycloalkyl, (C _1-6 -alkyl)-(C _3-6 -cycloalkyl), ( C _0-6 -alkyl)-N(R ₄ R ₅ ), (C _1-6 -alkyl)-OR ₅ , phenyl, benzyl, aryl, piperidinyl, piperazinyl, pyrrolidinyl , morpholino or C _3-7 heterocycloalkyl;

Or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug 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-sulfonylethyl]-4-nitroisoindoline-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-acetylaminoisoindoline-1,3-dione;

2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-dione;

2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-dimethylaminoisoindoline-1,3-dione;

2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]benzo[e]isoindoline-1,3-dione;

2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyisoindoline-1,3-dione;

1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl-amine;

2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione; and

2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoisoindoline-1,3-one .

Additional selective cytokine inhibitory drugs include enantiomerically pure compounds disclosed in: U.S. Patent Application 10/392,195, filed March 19, 2003; International Patent Application PCT/ US 03/0873; U.S. Provisional Patent Application Nos. 60/438,450 and 60/438,448, filed January 7, 2003, by G. Muller et al; U.S. Provisional Patent Application No. 60/452,460, all of which are incorporated herein by reference. Preferred compounds include 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3- Enantiomers of diketones and 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide Enantiomer.

A preferred selective cytokine inhibitory drug for use in the present invention is 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-hydro-isoindole-2- base)-propionamide and cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3 -Dihydro-1H-isoindol-4-yl}-amide 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:

Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-methylsulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindo Indol-4-yl}-amides have the following chemical structure:

Compounds of the present invention are either commercially available or prepared by methods described in the patents and patent publications mentioned herein. Furthermore, optically pure compositions can be synthesized asymmetrically, or can be 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" includes acid and base addition salts of the compounds 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, including, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, heptanoic acid, etc.

Acidic compounds are capable of forming salts with various pharmaceutically acceptable bases. Bases useful in the preparation of pharmaceutically acceptable base addition salts of acidic compounds are those which form non-toxic base addition salts, which are salts containing pharmaceutically acceptable cations such as, but not limited to, alkali metals or alkaline earth metals. Salts, especially calcium, magnesium, sodium or potassium salts. Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine acid and procaine.

As used herein and unless otherwise indicated, the term "prodrug" refers to a derivative of a compound that can undergo hydrolysis, oxidation, or other reaction under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, containing biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and Derivatives of Biohydrolyzable Phosphate Analogs for Selective Cytokine Inhibitory Drugs. Other examples of prodrugs include derivatives of selective cytokine inhibitory drugs comprising -NO, _-NO2 , -ONO or _-ONO2 moieties. Prodrugs can generally be prepared by well-known methods, for example in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolffed., 5th ed. 1995) and Design of Prodrugs (31. Bundgaarded. , Elselvier, New York 1985) described in the method.

As used herein and unless otherwise specified, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable "Biohydrolyzable ureide" and "biohydrolyzable phosphate" refer to an amide, ester, carbamate, carbonate, ureide, or phosphate ester of a compound that: 1) does not interfere with the biological activity of the compound, But in vivo may confer favorable properties on the compound, such as uptake, duration of action or onset of action; or 2) have no biological activity, but are converted to a biologically active compound in vivo. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactone-based esters (such as 2-benzo[c]furanonyl and thiophthalides), lower alkoxyacyloxyalkyl esters (such as formazan oxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and acylaminoalkyl esters (such as acetamidomethyl base esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyetheramines.

Various selective cytokine inhibitory drugs contain one or more chiral centers and can exist as a racemic mixture of enantiomers or as a mixture of diastereomers. The present invention includes the use of the compounds in stereoisomerically pure form as well as the use of mixtures of these forms. For example, mixtures comprising equal or unequal amounts of enantiomers of a selective cytokine inhibitory drug may be used in the methods and compositions of the invention. The purified (R) or (S) enantiomer of a particular compound disclosed herein may be used substantially free of the other enantiomer.

As used herein and unless otherwise indicated, the term "stereoisomerically pure" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of said compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereomerically pure compound having two chiral centers will be substantially free of the other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, more preferably greater than about 90% by weight. % by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight % by weight of the other stereoisomer 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 stereoisomer of the compound.

As used herein and unless otherwise stated, the term "stereoisomer-enriched" means comprising greater than about 60% by weight of a compound of one stereoisomer, preferably greater than about 70% by weight, more preferably greater than about A composition of 80% by weight of one stereoisomer of a compound.

As used herein and unless otherwise stated, the term "enantiomerically enriched" refers to a stereomerically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a stereoisomerically enriched composition of a compound having one chiral center.

It should be noted that if there is a discrepancy between the described structure and the given name of the structure, the described structure should be relied upon. Furthermore, if the stereochemistry of a structure or a portion of a structure is not indicated by, for example, a bold line or a dashed line, it is understood that the structure or a portion of a structure includes all stereoisomers thereof.

4.2 Second active agent

A second active agent can be used in the methods and compositions of the invention together with a selective cytokine inhibitory drug. In preferred embodiments, the second active agent is capable of inhibiting or attenuating a macular damage condition, providing an anti-angiogenic or anti-inflammatory effect, or ensuring patient comfort.

Examples of second active agents include, but are not limited to, steroids, photosensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neurotrophic factors, modulators of neovascularization, anti-VEGF antibodies , prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds, angiogenesis inhibitory compounds, other therapeutic agents known to inhibit or alleviate the symptoms of MD, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers thereof complexes, prodrugs and active metabolites. In some embodiments, the second active agent is verteporfin, purlytin, an angiogenic steroid, rhuFab, interferon-2α, or pentoxifylline.

Examples of photosensitizers include, but are not limited to, verteporfin, tin etiopurpurin, and lutetium motesafin. Verteporfin can be used to treat wetness. Cour, M., et al., Drugs Aging 19: 101-133 (2002). Verteporfin is an angioblocking photoreactive dye that can be administered by injection.

Examples of xanthine derivatives include, but are not limited to, pentoxifylline.

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-methylidenebis(oxy)pregna-1,4-diene-3,20-di ketone.

Examples of prostaglandin F _2a derivatives include, but are not limited to, latanoprost (see US 6,225,348, which is incorporated herein by reference in its entirety).

Examples of antibiotics include, but are not limited to, tetracycline and its derivatives, rifamycin and its derivatives, macrolides, and metronidazole (see US6,218,369 and US6,015,803, which are incorporated herein by reference in their entirety) .

Examples of phytoestrogens include, but are not limited to, genistein, genistin, 6'-O-Mal genistin, 6'-O-Ac genistin, daidzein, daidzein, 6'-O-Mal Daidzein, 6'-O-Ac daidzein, glycitin, glycitin, 6'-O-Mal glycitin, biochanin A, formononetin and mixtures thereof (see US 6,001,368, which is incorporated herein in its entirety for reference).

Examples of anti-inflammatory agents include, but are not limited to, triamcinolone acetomide and dexamethasone (see US 5,770,589, which is incorporated herein by reference in its entirety).

Examples of angiogenesis-inhibiting compounds include, but are not limited to, thalidomide and immunomodulatory compounds (IMiDs ^™ , Celgene Corp., NJ).

Examples of interferons include, but are not limited to, interferon-2α.

In another embodiment, the second active agent is glutathione (see U.S. Patent 5,632,984, which is incorporated herein by reference 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 modulators of neovascularization include, but are not limited to, plasminogen activator type 2 (PAI-2).

Other drugs that can be used to treat MD include, but are not limited to, EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant, and the RETISERT implant (Bausch & Lomb).

4.3 Treatment and prevention methods

The present invention includes methods of preventing, treating and/or managing various types of MD.

As used herein and unless otherwise stated, the term "preventing MD" includes, but is not limited to, inhibiting or lessening the severity of one or more symptoms associated with MD. Symptoms associated with MD include, but are not limited to, round white to pale yellow spots of drusen in the base, submacular discoid scar tissue, choroidal neovascularization, detachment of the retinal pigment epithelium, atrophy of the retinal pigment epithelium, abnormal vascular stems from the choroid (just Growth of the layer of rich blood vessel tissue beneath the retina), blurred vision or distortion of the visual field, central scotoma, abnormal pigmentation, continuous layer of fine granular material within Bruch's membrane, and thickening and permeation of Bruch's membrane reduced sex.

As used herein and unless otherwise stated, the term "treating MD" refers to administering a compound or other additional active agent after the onset of symptoms of MD, while "prophylaxis" refers to administering after the onset of symptoms, especially in patients with MD. Dangerous patient administration. Examples of patients at risk for MD include, but are not limited to, elderly people over the age of 60, and patients with diseases such as, but not limited to, diabetes and leprosy (eg, ENL). Patients with a family history of MD are also preferred candidates for prophylaxis regimens. As used herein and unless otherwise stated, the term "controlling MD" includes preventing recurrence of MD in a patient already suffering from MD, and/or prolonging the time a patient already suffering from MD remains in remission.

The present invention includes methods for the treatment, prevention and management of MD and related syndromes in patients with various stages and specific types of disease, including but not limited to those known as wet MD, dry MD, age-related macular degeneration (ARM), choroidal neovascularization (CNVM), retinal pigment epithelial detachment (PED) and retinal pigment epithelial (RPE) atrophy. The invention also includes methods of treating patients who have previously been treated for MD but who have not responded to standard drug therapy and non-drug-based treatments for MD, as well as patients who have not been previously treated for MD. Because patients with MD may have different clinical presentations and different clinical outcomes, the treatment given to the patient may be different according to his/her prognosis. The ordinary clinician will readily be able to determine without undue experimentation the particular second substance and treatment which will be effective in treating each patient.

The methods of the invention comprise administering to a patient suffering from or at risk of suffering from MD one or more selective cytokine inhibitory drugs or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof .

In one embodiment, the recommended daily dosage of a selective cytokine inhibitory drug is from about 1 mg to about 10,000 mg/day, administered as a once-daily dose or preferably in divided doses throughout the day. More specifically, the daily dosage is administered in divided doses twice a day. Particular daily dosages are about 1 mg to about 5,000 mg/day, about 10 mg to about 2,500 mg/day, about 100 mg to about 800 mg/day, about 100 mg to about 1,200 mg/day or about 25 mg to about 2,500 mg/day. In controlled patients, treatment should be initiated at a lower dose, approximately 1 mg to 2,500 mg, increased if necessary to approximately 200 mg to 5,000 mg/day, given in divided doses as a single dose based on the patient's systemic response medicine. In a specific embodiment, 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide Doses of about 400, 800, 1,200, 2,500, 5,000 or 10,000 mg per day are administered in 2 divided doses. Treatment is continued from about 2 to about 12 weeks, from about 4 to about 16 weeks, from about 8 to about 12 weeks, until the desired therapeutic effect is achieved, or on a longer-term basis to maintain the desired therapeutic effect.

4.3.1 Combination therapy with a second active agent

Particular methods of the invention involve administering a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with a second active agent or active ingredient. Examples of selective cytokine inhibitory drugs are disclosed herein (see, eg, Section 4.1); examples of second active agents are also disclosed herein (see, eg, Section 4.2).

The administration of the selective cytokine inhibitory drug and the optional second active agent may be by the same or different routes of administration simultaneously or sequentially. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (eg whether it can be administered orally without breaking down before entering the blood) and the disease being treated. A preferred route of administration for selective cytokine inhibitory drugs is oral. Preferred routes of administration for the second active agent or component of the invention are known to those skilled in the art, see, eg, Physicians' Desk Reference (57th Edition, 2003).

In one embodiment of the invention, the second active agent is administered orally, intravenously, intramuscularly, subcutaneously, mucosally, topically or transdermally once or twice a day at a dose of about 1- About 2,500 mg, about 1 mg to about 2,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 100 mg to about 750 mg, or about 250 mg to about 500 mg.

In another embodiment, the second active agent is administered weekly, monthly, every two months, or annually. The specific dosage of the second active agent may depend on the particular active agent used, the type of MD being treated or prevented, the severity and stage of the MD, and the selective cytokine inhibitory drug and any optional other active agents administered to the patient in combination. amount. In a specific embodiment, the second active agent is a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neurotrophic factor, a modulator of neovascularization, an anti- - VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory or angiogenesis-inhibiting compounds or combinations thereof.

4.3.2 Administering Surgical Interventions

The present invention includes a method for treating, preventing and/or controlling MD, said method comprising administering to a patient in need thereof a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, Clathrates or prodrugs and surgical intervention (eg, before, during or after surgical intervention). Examples of surgical intervention include, but are not limited to, light or laser therapy, radiation therapy, retinal pigment epithelium transplantation, and central translocation.

The combination of selective cytokine inhibitory drugs and surgical intervention offers a unique treatment option that may be unexpectedly effective in some patients. While not wishing to be bound by theory, it is believed that selective cytokine inhibitory drugs may provide additive or synergistic effects when administered in conjunction with surgical intervention.

In a specific embodiment, the present invention includes a method for treating, preventing and/or controlling MD, said method comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug or a pharmaceutically acceptable salt thereof, Solvates, hydrates, stereoisomers, clathrates or prodrugs and light or laser therapy. Examples of light or laser therapy include, but are not limited to, laser photocoagulation therapy or photodynamic therapy.

Selective cytokine inhibitory drugs can be administered concurrently or sequentially with surgical intervention. In one embodiment, the selective cytokine inhibiting drug is administered prior to light or laser treatment. In another embodiment, the selective cytokine inhibitory drug is administered after light or laser treatment. In one embodiment, the selective cytokine inhibitory drug is administered during light or laser treatment. The compounds of the invention may be administered at least 4 weeks prior to laser surgery; 2 weeks prior; 1 week prior; or immediately prior to laser treatment, or at the time of surgery or immediately following surgery, for a total of about 12-16 weeks of treatment.

4.3.3 Cycle therapy

In the following embodiments, the prophylactic or therapeutic agent is administered periodically to the patient. Cycling therapy involves administering a first therapeutic agent for a period of time, followed by that therapeutic agent and/or a second therapeutic agent for a period of time, and repeating the sequence. Cycling therapy can reduce the development of resistance to one or more therapeutic agents, avoid or reduce the side effects of a treatment, and/or increase the efficacy of the treatment.

In a specific embodiment, the prophylactic or therapeutic agent is administered about 1 or 2 times per day in a period of about 6 months. A cycle may include administration of the therapeutic or prophylactic agent and a drug rest period of at least 1 or 3 weeks. The number of administration cycles can be from about 1 to about 12 cycles, from about 2 to about 10 cycles, or from about 2 to about 8 cycles.

4.4 Pharmaceutical Compositions and Single Unit Dosage Forms

Pharmaceutical compositions can be used in the manufacture of individual, single unit dosage forms. The pharmaceutical composition of the present invention comprises a selective cytokine inhibitory drug or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug. Pharmaceutical compositions and dosage forms of the invention may also comprise one or more excipients.

Pharmaceutical compositions and dosage forms of the invention may also comprise one or more additional active agents. Accordingly, the pharmaceutical compositions and dosage forms of the present invention comprise an active agent disclosed herein (e.g., a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof and a second active agent). Optional additional active agents are disclosed herein (see, eg, Section 4.2).

The single unit dosage forms of the invention are suitable for oral, mucosal (e.g. nasal, sublingual, vaginal, buccal or rectal), or parenteral (e.g. subcutaneous, intravenous, bolus, intramuscular or intraarterial), topical (e.g. subcutaneous, intravenous, bolus, intramuscular or intraarterial) administration to a patient. such as eye drops), ophthalmic, transdermal or transdermal administration. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (such as nasal sprays or inhalants); eye drops; gels; liquid dosage forms suitable for oral or transmucosal administration to a patient, including suspensions (such as aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions) , solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (eg, crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, shape and type of dosage forms of the invention generally depend on their application. For example, a dosage form used for the acute treatment of a disease may contain greater amounts of one or more active agents than a dosage form used for the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more active agents than a customer-administered dosage form used to treat the same disease. These and other ways in which a particular dosage form of the invention can be varied from one to another will be apparent to those skilled in the art. See, eg, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known in the pharmaceutical art, non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the route by which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suitable for parenteral dosage forms. The suitability of a particular excipient may also depend on the particular active agent in the dosage form. For example, the degradation of certain active agents may be accelerated by certain excipients such as lactose when exposed to water. Active agents containing primary or secondary amines are particularly susceptible to significant accelerated degradation. Accordingly, the invention includes pharmaceutical compositions and dosage forms that contain little, if any, lactose and other mono- or disaccharides. As used herein, the term "lactose-free" means that lactose, if any, is present in an amount insufficient to significantly increase the rate of degradation of the active agent.

Lactose-free compositions of the present invention may comprise excipients well known in the art and listed, for example, in U.S. Pharmacopeia (USP) 25-NF20 (2002). Lactose-free compositions generally comprise active agents, binders/fillers and lubricants in pharmaceutically compatible and pharmaceutically acceptable amounts. A preferred lactose-free dosage form comprises active agent, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing active agents, since water may facilitate the degradation of some compounds. For example the addition of water (eg 5%) is widely accepted in the pharmaceutical arts to simulate long term storage to determine formulation properties over time such as shelf life or stability. See, eg, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat can accelerate the degradation of some compounds. Thus, the effect of water on formulations can be severe, as moisture and/or humidity are frequently encountered during production, handling, packaging, storage, transport, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture content components and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active agent comprising a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging and/or storage is expected.

Anhydrous pharmaceutical compositions should be prepared and stored while maintaining their anhydrous nature. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to moisture such that they can be included in suitable prescribed kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.

The present invention also includes pharmaceutical compositions and dosage forms that contain one or more compounds that modify the rate of degradation of the active agent. Such compounds, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or buffer salts.

Like the amount and type of excipients, the amount and specific type of active agent in a dosage form can vary depending on factors such as, but not limited to, the route by which it will be administered to the patient. However, typical dosage forms contain from about 1 to about 10,000 mg of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. Typical dosage forms contain about 1, 2, 5, 10, 25, 50, 100, 200, 400, 800, 1,200, 2,500, 5,000, or 10,000 mg of selective cytokine inhibitory drug or pharmaceutically acceptable salts, solvates, hydrates thereof compounds, stereoisomers, clathrates or prodrugs. In a specific embodiment, preferred dosage forms comprise about 400, 800 or 1,200 mg of 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro- isoindol-2-yl)-propionamide. Typical dosage forms contain about 1 to about 2,500 mg, about 1 mg to about 2,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 1,000 mg, about 100 mg to about 750 mg, or about 250 mg to about 500 mg of the second active agent. The specific amount of the second active agent will, of course, depend on the particular active agent used, the type of MD being treated or managed, and the amount of the selective cytokine inhibitory drug and any optional additional active agent administered to the patient in combination.

4.4.1 Oral dosage forms

Pharmaceutical compositions of the invention suitable for oral administration may be presented in discrete dosage forms such as, but not limited to, tablets (eg, chewable tablets), caplets, capsules, and liquids (eg, flavored syrups). Such dosage forms contain predetermined amounts of active agent and may be prepared by methods of pharmacy well known to those skilled in the art. See Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

Typical oral dosage forms are prepared by intimately admixing the active agent with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a variety of different forms depending on the form of preparation desired for administration. For example, suitable excipients for oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents. Examples of excipients suitable for solid oral dosage forms such as powders, tablets, capsules and caplets include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders agents and disintegrants.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms using a solid excipient. If administered, tablets may be coated by standard aqueous or non-aqueous techniques. Such dosage forms may be prepared by any of the methods of pharmacy. Pharmaceutical compositions and dosage forms are generally prepared by uniformly and intimately admixing the active agent with liquid carriers, finely divided solid carriers or both, and then, if necessary, shaping the product into the desired shape.

For example, tablets may be made by compression or molding. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth powder , guar gum, cellulose and its derivatives (such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized Starch, hydroxypropylmethylcellulose (eg nos. 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ^™ and Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, cellulose powder, dextrate, kaolin, mannitol, silicic acid, sorbitol Alcohols, starches, pregelatinized starches and mixtures thereof. The binder or filler in the pharmaceutical composition of the present invention is present in an amount of about 50 to about 99% by weight of the pharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. A tablet with too much disintegrant may disintegrate on storage, while a tablet with too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Accordingly, a sufficient amount of disintegrant that is neither too large nor too small to decisively alter the active agent should be used to form a solid oral dosage form of the invention. The amount of disintegrant used varies with the type of formulation and is readily determined by one skilled in the art. Typical pharmaceutical compositions contain from about 0.5 to about 15% by weight disintegrant, preferably from about 1 to about 5% by weight disintegrant.

The disintegrants that can be used in the pharmaceutical composition and dosage form of the present invention include but are not limited to agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, povidone potassium , sodium starch glycolate, potato or sweet potato starch, other starches, pregelatinized starches, clays, other alginates, other celluloses, gums and mixtures thereof.

Lubricants that may be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, Stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (such as peanut oil, cottonseed oil, sunflower oil, castor oil, olive oil, cottonseed oil, and soybean oil), zinc stearate, zinc oleate, ethyl oleate esters, ethyl laurate, agar and mixtures thereof. Additional lubricants include, for example, syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), solidified aerosol gel of synthetic silica (sold by Degussa Co. of Plano, TX), CAB-O-SIL (Cabot Co. .of Boston, MA marketed sintered silica products) and mixtures thereof. If used at all, lubricants are generally used in amounts of less than about 1% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

A preferred solid oral dosage form comprises a selective cytokine inhibitory drug, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide and gelatin.

4.4.2 Sustained-release dosage forms

The active agents of the invention may be administered by controlled release or delivery devices well known to those skilled in the art.实例包括但不限于在以下专利中描述的那些：U.S.专利3,845,770；3,916,899；3,536,809；3,598,123；和4,008,719、5,674,533、5,059,595、5,591,767、5,120,548、5,073,543、5,639,476、5,354,556和5,733,566，其分别引入本文以供参考。 Such dosage forms may be used to provide sustained or controlled release of one or more active agents using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, isotonic systems, multilayer Coatings, microparticles, liposomes, microspheres or combinations thereof to provide the desired release profile with different properties. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active agents of the invention. The invention thus includes single unit dosage forms suitable for oral administration which are adapted for sustained release, including, but not limited to, tablets, capsules, gelcaps, and caplets.

All controlled-release drug products share the common goal of improving drug therapy over that achieved through its non-controlled-release counterparts. Ideally, the use of optimally designed controlled-release formulations in medicine is characterized by the use of the least amount of drug for the least amount of time to cure or control a condition. Advantages of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and improved patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thereby affect the incidence of side effects (eg, adverse side effects).

Most controlled-release formulations are designed to initially release the amount of drug (active agent) that rapidly produces the desired therapeutic effect, and to gradually and continuously release other amounts of drug to maintain that level of therapeutic or prophylactic effect over an extended period of time . In order to maintain a constant level of drug in the body, the drug must be released from the dosage form at such a rate as to replace the amount of drug that is metabolized and excreted from the body. Controlled release of an active agent can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

4.4.3 Parenteral dosage forms

Parenteral dosage forms can be administered to patients by a variety of routes including, but not limited to, intravitreal, subcutaneous, intravenous (including bolus injection), intramuscular and intraarterial. Since their administration generally bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile, or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions for injection, dry products for injection dissolved or suspended in pharmaceutically acceptable carriers, suspensions for injection, and emulsions.

Suitable carriers that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; Aqueous carriers such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; Water-miscible carriers such as, but not limited to, ethanol , polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, castor oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active agents disclosed herein can also be incorporated into the parenteral dosage forms of the invention. For example, cyclodextrins and their derivatives can be used to increase the solubility of selective cytokine inhibitory drugs and their derivatives. See, eg, U.S. Patent 5,134,127, which is incorporated herein by reference.

4.4.4 Topical and transmucosal dosage forms

Topical and transmucosal dosage forms of this invention include, but are not limited to, eye drops, sprays, aerosols, solutions, emulsions, suspensions or other dosage forms known to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 16th and 18ths., Mack Publishing, Easton PA (1980 &1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity may be formulated as mouthwashes or oral gels.

Suitable excipients such as carriers and diluents and other materials useful in providing topical and transmucosal dosage forms of the invention are well known to those skilled in the pharmaceutical art and depend on the particular tissue to which the pharmaceutical composition or dosage form is administered. In fact, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and Mixtures to form non-toxic and pharmaceutically acceptable solutions, emulsions or gels. Wetting agents or wetting agents can also be added to pharmaceutical compositions and dosage forms, if desired. Examples of important additional components are well known in the art. See, eg, Remington's Pharmaceutical Sciences, 16 ^th and ¹⁸ eds., Mack Publishing, Easton PA (1980 & 1990).

The pH of a pharmaceutical composition or dosage form can also be adjusted to improve delivery of one or more active agents. Similarly, the polarity of a solvent carrier, its ionic strength or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active agents so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, an emulsifying agent or surfactant, and a delivery-enhancing or penetration-enhancing agent. It is also possible to use different salts, hydrates or solvates of the active agents to adjust the properties of the resulting composition.

4.4.5 Medicine box

It is generally preferred that the active agents of the invention are not administered at the same time or by the same route of administration. Accordingly, the present invention includes kits which, when used by a medical practitioner, simplify the administration of appropriate amounts of active agents to a patient.

A typical kit of the invention comprises a dosage form of a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The dosage forms of the present invention may also comprise one or more additional active agents or combinations thereof. Examples of additional active agents are disclosed herein (see, eg, Section 4.2).

Kits of the invention may also comprise devices for administering the active agent. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalants. The kit of the invention may also comprise an Amsler grid for detecting or diagnosing MD.

Kits of the invention may also comprise a pharmaceutically acceptable carrier useful for administering one or more active agents. For example, if the active agent is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable carrier in which the active agent can be dissolved to form a suitable Particle-free sterile solution of medicine. Examples of pharmaceutically acceptable carriers include, but are not limited to: Water for Injection, USP; aqueous carriers such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, castor oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

5. Example

The following examples are intended to illustrate the invention. not intended to limit the scope of the invention.

5.1 Pharmacological test in vitro

One biological effect commonly exerted by selective cytokine inhibitory drugs is to reduce the synthesis of TNF-[alpha]. Specific and selective cytokine inhibitory drugs promote the degradation of TNF-α mRNA. TNF-α may play a pathological role in macular degeneration.

In a specific embodiment, 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl )-Pharmacological properties of propionamide. The assay measures the effect of the compound on the production of different cytokines. The inhibitory effect of this compound on LPS-stimulated TNF-[alpha] production in human PBMC and whole blood was assessed in vitro. In vitro tests showed that 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide was more pharmacologically active than Ridomide is 5-50 times stronger. The pharmacological effects of 3-(3,4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide may be derived from its role as Inhibitors of inflammatory cytokine production.

5.2 Clinical Trials in MD Patients

The selective cytokine inhibitory drug of the present invention is administered to patients with macular degeneration at a dose of about 20 to about 1,200 mg/day. In a specific embodiment, a clinical trial is conducted with forty macular degeneration patients divided into two groups. The first group received conventional treatment by photodynamic therapy with verteporfin to close leaky choroidal vessels, a feature of this disease (Ophthalmol. 1999 117: 1329-1345). The second group was treated with (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetyl at a dose of about 20 mg/day Aminoisoindoline-1,3-dione as an adjuvant for 20 weeks received the same conventional treatment with verteporfin.

Accept (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3 - The neovascular cascade of the diketone group is sufficiently blocked to indefinitely prolong the effect of the photodynamic therapy. However, after several weeks of treatment, (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylamino The first group of isoindoline-1,3-diones will undergo asymptotic reperfusion of the removed vessel. The progressive loss of vision that accompanies it necessitates repetition of said photodynamic therapy.

In another preferred embodiment, (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4- Acetylaminoisoindoline-1,3-dione is administered at a dose of about 1 to about 200 mg/day, preferably about 10 to about 50 mg/day or higher, usually about 1.5 to 2.5 times the daily dose . Reference to adjuvant therapy also applies to other types of conventional therapy used to treat or prevent MD, including but not limited to surgical interventions including laser photocoagulation.

The embodiments of the invention described herein are only illustrative of the scope of the invention. Various references cited herein are hereby incorporated by reference in their entirety.

Claims (22)

1. treat or prevent the method for degeneration of macula, described method comprises selective cytokine inhibitory drugs or its officinal salt, solvate or the stereoisomer to patient's administering therapeutic that these needs are arranged or prevention effective dose.

2. the process of claim 1 wherein that described method also comprises second kind of activating agent to patient's administering therapeutic or prevention effective dose.

3. the method for claim 2, wherein said second kind of activating agent is steroid, photosensitizer, integrin, antioxidant, interferon, xanthine derivative, growth hormone, neurotrophic factor, neovascularization regulator, anti-VEGF antibodies, prostaglandin, antibiotic, phytoestrogen, anti-inflammatory compound or angiogenesis inhibitor compound.

4. the method for claim 2, wherein said second kind of activating agent is Thalidomide, Verteporfin, purlytin, angiogenic growth inhibition steroid, rhuFab, IF2 α or pentoxifylline; Or its officinal salt, solvate or stereoisomer.

5. the method for claim 4, wherein said angiogenesis inhibitor compound is a Thalidomide.

6. the process of claim 1 wherein that described degeneration of macula is moist degeneration of macula, dryness degeneration of macula, the degeneration of macula relevant with the age, maculopathy, choroidal neovascularization, retinal pigment epithelium detachment, retinal pigment epithelium atrophy, best's disease, vitelliform macular degeneration, Si Tajiateshi disease, teenager macular dystrophy, fundus flavimaculatus, Bell, Sorsby ' s disease, Doyne ' s disease, cellular malnutrition or the macula lutea infringement disease relevant with the age.

7. the process of claim 1 wherein that described selective cytokine inhibitory drugs is that stereoisomer is pure.

8. the method for treatment, prevention or control degeneration of macula, described method comprises the 3-(3 to patient's administering therapeutic of this treatment of needs, prevention or control or prevention effective dose, 4-dimethoxy-phenyl)-3-(1-oxo-1,3-dihydro-iso-indoles-2-yl)-propionic acid amide. or its officinal salt, solvate or stereoisomer.

9. the method for claim 8, wherein (1-oxo-1,3-dihydro-iso-indoles-2-yl)-propionic acid amide. is an enantiomer-pure to 3-(3,4-dimethoxy-phenyl)-3-.

10. the method for treatment, prevention or control degeneration of macula; described method comprise to patient's administering therapeutic of this treatment of needs, prevention or control or the prevention effective dose cyclopropane-carboxylic acid 2-[1-(3-ethyoxyl-4-methoxyl group-phenyl)-2-mesyl-ethyl]-3-oxo-2,3-dihydro-1H-iso-indoles-4-base-amide or its officinal salt, solvate or stereoisomer.

11. the method for claim 10, wherein cyclopropane-carboxylic acid 2-[1-(3-ethyoxyl-4-methoxyl group-phenyl)-2-mesyl-ethyl]-3-oxo-2,3-dihydro-1H-iso-indoles-4-yl)-amide is an enantiomer-pure.

12. the process of claim 1 wherein that described selective cytokine inhibitory drugs is formula (I) chemical compound:

Wherein n is 1,2 or 3;

R ⁵Be adjacent phenylene, described phenylene is unsubstituted or is independently selected from following substituent group respectively by 1-4 and replaces: nitro, cyano group, trifluoromethyl, carbethoxyl group, methoxycarbonyl group, the third oxygen carbonyl, acetyl group, carbamoyl, acetoxyl group, carboxyl, hydroxyl, amino, alkyl amino, dialkyl amido, acyl amino, the alkyl with 1-10 carbon atom, the alkyl with 1-10 carbon atom and halogen;

R ⁷Be (i) phenyl or be independently selected from the phenyl that following group replaces respectively: nitro by one or more, cyano group, trifluoromethyl, carbethoxyl group, methoxycarbonyl group, the third oxygen carbonyl, acetyl group, carbamoyl, acetoxyl group, carboxyl, hydroxyl, amino, alkyl with 1-10 carbon atom, alkoxyl and halogen with 1-10 carbon atom, (ii) replace or be selected from the benzyl that following group replaces: nitro by 1-3, cyano group, trifluoromethyl, carbethoxyl group, methoxycarbonyl group, the third oxygen carbonyl, acetyl group, carbamoyl, acetoxyl group, carboxyl, hydroxyl, amino, alkyl with 1-10 carbon atom, alkoxyl and halogen with 1-10 carbon atom, (iii) naphthyl and (iv) benzyloxy;

R ¹²Be-OH, have 1-12 carbon atom alkoxyl or

R ⁸Be hydrogen or alkyl with 1-10 carbon atom; And

R ⁹Be hydrogen, have 1-10 carbon atom alkyl ,-COR ¹⁰Or-SO ₂R ¹⁰, R wherein ¹⁰Be hydrogen, have an alkyl or phenyl of 1-10 carbon atom.

13. the method for claim 12, wherein said selective cytokine inhibitory drugs is an enantiomer-pure.

14. the process of claim 1 wherein that described selective cytokine inhibitory drugs is formula (II) chemical compound:

Wherein, when independently of one another, R ¹And R ²Be respectively hydrogen, low alkyl group, perhaps when with the carbon atom of their institute's bondings together the time, R ¹And R ²Be adjacent phenylene, adjacent naphthylene or cyclohexene-1 together, 2-two bases, it does not replace or is independently selected from following substituent group respectively by 1-4 and replaces: nitro, cyano group, trifluoromethyl, carbethoxyl group, methoxycarbonyl group, the third oxygen carbonyl, acetyl group, carbamoyl, acetoxyl group, carboxyl, hydroxyl, amino, alkyl amino, dialkyl amido, acyl amino, have the alkyl of 1-10 carbon atom, have the alkoxyl and the halogen of 1-10 carbon atom;

R ³Be phenyl, described phenyl does not replace or is selected from following substituent group by 1-4 and replaces: nitro, cyano group, trifluoromethyl, carbethoxyl group, methoxycarbonyl group, the third oxygen carbonyl, acetyl group, carbamoyl, acetoxyl group, carboxyl, hydroxyl, amino, the alkyl with 1-10 carbon atom, the alkoxyl with 1-10 carbon atom, the alkylthio group with 1-10 carbon atom, benzyloxy, the cycloalkyloxy with 3-6 carbon atom, C ₄-C ₆-cycloalkylidene methyl, C ₃-C ₁₀-alkylidene methyl, indanyl oxygen base and halogen;

R ⁴Be hydrogen, have alkyl, phenyl or a benzyl of 1-6 carbon atom;

R ^{4 '}Be hydrogen or alkyl with 1-6 carbon atom;

R ⁵Be-CH ₂-,-CH ₂-CO-,-SO ₂-,-S-or-NHCO-;

N is 0,1 or 2.

15. the method for claim 14, wherein said selective cytokine inhibitory drugs is an enantiomer-pure.

16. the process of claim 1 wherein that described selective cytokine inhibitory drugs is formula (III) chemical compound:

Wherein constitute chiral centre with the * marked carbon atoms;

Y is C=O, CH ₂, SO ₂Or CH ₂C=O;

Each R ¹, R ², R ³And R ⁴Independently of one another for hydrogen, halogen, alkyl, alkoxyl, nitro, cyano group, hydroxyl with 1-4 carbon atom with 1-4 carbon atom or-NR ⁸R ⁹The perhaps R on adjacent carbon atom ¹, R ², R ³And R ⁴In any two with shown in phenyl ring be naphthylene; Each R ⁵And R ⁶Be hydrogen independently of one another, have the alkyl of 1-4 carbon atom, alkoxyl, cyano group or have the cycloalkyloxy that is up to 18 carbon atoms with 1-4 carbon atom;

R ⁷Be hydroxyl, have alkyl, phenyl, benzyl or a NR of 1-8 carbon atom ^{8 '}R ^{9 '}

Each R ⁸And R ⁹Be hydrogen, alkyl, phenyl or benzyl, perhaps R independently of one another with 1-8 carbon atom ⁸And R ⁹In have one to be hydrogen, and another is-COR ¹⁰Or-SO ₂R ¹⁰, perhaps R ⁸And R ⁹Be together tetramethylene, pentamethylene, hexa-methylene or-CH ₂CH ₂X ¹CH ₂CH ₂-, X wherein ¹Be-O-,-S-or-NH-; And

Each R ^{8 '}And R ^{9 '}Be hydrogen, alkyl, phenyl or benzyl, perhaps R independently of one another with 1-8 carbon atom ^{8 '}And R ^{9 '}In have one to be hydrogen, and another is-COR ^{10 '}Or-SO ₂R ^{10 '}, perhaps R ^{8 '}And R ^{9 '}Be together tetramethylene, pentamethylene, hexa-methylene or-CH ₂CH ₂X ²CH ₂CH ₂-, X wherein ²Be-O-,-S-or-NH-.

17. the method for claim 16, wherein said selective cytokine inhibitory drugs is an enantiomer-pure.

18. the method for treatment, prevention or control degeneration of macula, described method comprise patient to this treatment of needs, prevention or control before surgical intervention, during or afterwards the selective cytokine inhibitory drugs of administering therapeutic or prevention effective dose or its officinal salt, solvate or stereoisomer to alleviate or to prevent degeneration of macula symptom among the patient.

19. the method for claim 17, wherein said surgical intervention are light treatment, laser therapy, radiotherapy, retinal pigment epithelium transplanting or center transposition.

20. pharmaceutical composition, described compositions comprise selective cytokine inhibitory drugs or its officinal salt, solvate or stereoisomer and can alleviate or prevent second kind of activating agent of degeneration of macula symptom.

21. the pharmaceutical composition of claim 20, wherein said second kind of activating agent is steroid, photosensitizer, integrin, antioxidant, interferon, xanthine derivative, growth hormone, neurotrophic factor, neovascularization regulator, anti-VEGF antibodies, prostaglandin, antibiotic, phytoestrogen, anti-inflammatory compound or angiogenesis inhibitor compound.

22. the pharmaceutical composition of claim 20, wherein said second kind of activating agent are Thalidomide, Verteporfin, purlytin, angiogenic growth inhibition steroid, rhuFab, IF2 α or pentoxifylline; Or its officinal salt, solvate or stereoisomer.