KR20050062649A - Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment and management of macular degeneration - 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 USING AND COMPOSITIONS COMPRISING SELECTIVE CYTOKINE INHIBITORY DRUGS FOR TREATMENT AND MANAGEMENT OF MACULAR DEGENERATION

One. Field of invention

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

2. Background of the Invention

2.1 Pathology of Macular Degeneration

Macular degeneration (MD) is an ophthalmic disease that destroys central vision by damage to the macular. The macula is part of the retina, a thin layer of nerve cells that fill most of the interior of the eye. Nerve cells in the retina detect light and send signals to the brain about what the eye sees. The macular is near the center of the retina behind the eyeball and provides a sharp, sharp central vision that the animal uses to focus on the one in front of it. The rest of the retina provides lateral (peripheral) vision.

There are two forms of MD: atrophic ("dry") and exudative ("wet") [Riordan-Eva, P., Eye, in Current Medical Diagnosis and Treatment, 41 ed. 210-211 (2002). 90% of patients are in dry form, whereas only 10% are in wet form. However, patients suffering from a wet form 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 geographic atrophy of choroidal neovascularization (CNVM) and / or retinal pigment epithelium (RPE) in eyes with drusen [Bird, A.C., Surv. Ophthamol. 39: 367-74 (1995). Drusen are basal round pale yellow spots, located outside of neural retina. Additional symptoms of MD include RPE detachment (PED) and macular subretinal disc scar tissue (Algvere, P.V., Acta Ophthalmologica Scandinavica 80: 136-143 (2002)).

Choroidal neovascularization is associated with a wide range of retinal diseases, but is the problem most commonly associated with MD. CNVM is characterized by abnormal blood vessels stemming from the choroid (the vascular-rich tissue layer just below the retina) growing through the retinal layer. These new blood vessels are very brittle, easily rupture, and collect blood and fluid in the layers of the retina. Leakage of blood vessels can break delicate retinal tissues, worsening vision. The severity of symptoms varies with the size of the CNVM and its proximity to the macula. The patient's symptoms may be very mild, such as a blurred or distorted area of vision, or worse, such as a central blind spot.

Patients with drusen, possibly suffering from pigment abnormality, but not from CNVM or superficial atrophy, are generally diagnosed as having age-related macular disease (ARM) [supra]. Histopathological features of ARM and MD are a continuous layer of fine granular material deposited on the inner part of the Burk membrane at the bottom of RPE cells [Sarks, JP, et al., Eye 2 (Pt. 5): 552-77 (1988) )]. These bottom precipitates are believed to accumulate as waste from continuous RPE phagocytosis or photoreceptor external compartment material. The bottom precipitate thickens the Burk membrane and reduces its permeability. It has been hypothesized that reduced water permeability impairs the exchange of nutrients, blocks the flow of water and increases the incidence of soft drusen and PED, ultimately leading to atrophy of RPE cells [supra]. However, the overall understanding of ARM and MD pathogenesis is still incomplete (Cour, M., et al., Drugs Aging 19: 101-133 (2002)).

Since MD is the most prevalent among the elderly, the fastest growing class of the entire population, MD is a major economic and social problem. Macular degeneration is the most common cause of vision loss in each individual in the developed world over sixties. Macular degeneration results in loss of central vision of 1.7 million Americans, with another 11 million at risk [DuBosar, R., J. of Ophthalmic Nursing and Technology, 18: 60-64 (1998)]. Yet, no cure is known [Rhoodhooft, J., Bull. Soc. belge Ophtalmol. 276: 83-92 (2000). Therefore, effective treatment for MD is urgently needed.

2.2 Treatment of Age-Related Macular Degeneration

Until recently, laser photocoagulation has been the only common treatment used for MD and gives only moderate results. Laser photocoagulation is a type of laser surgery that uses a high density beam of light to burn small areas of the retina and abnormal blood vessels just below the macula. This burn forms scar tissue, sutures blood vessels, and keeps the blood vessels from leaking under the macula. Laser photocoagulation is only valid for patients suffering from wet MD. In addition, laser photocoagulation is a viable option for only about 13% of these patients (Joffe, L. et al., International Ophthalmology Clinics 36 (2): 99-116 (1996)). Laser photocoagulation does not treat wet MD and sometimes slows or prevents further loss of central vision. However, without treatment, vision loss from wet MD can progress until humans do not have residual central vision.

The most serious weakness of laser surgery is that some of the nerve cells are damaged in the macula, where the laser responds to light and loses some vision. Occasionally, vision loss resulting from surgery is as severe or worse than vision loss resulting from untreated treatment. In some patients, however, laser surgery initially worsens vision, but prevents more severe loss of vision over time.

Berteporphine has recently been used to treat wet MD (Cour, M., et al., Drugs Aging 19: 101-133 (2002)). Berteporphine is a vascular-blocking photoreactive dye administered via injection. The dye migrates to blood vessels causing loss of vision and is then activated by irradiating a non-imaging beam of light into the eye in the presence of oxygen. Berteporphine is preferentially transferred to plasma by lipoproteins. Activated vertoforphine produces highly reactive and short half-life singlet oxygen and reactive oxygen radicals, and causes local damage to the neovascular endothelial. This causes vascular obstruction. Damaged endothelial releases pro-coagulant and vasoactive factors through the lipo-oxygenase (leukotriene) and cyclo-oxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction It is known. Berteporphin appears to somewhat preferentially accumulate internal neovascular structures, including choroidal neovascular structures. However, animal models show that vertepofin also accumulates in the retina. Thus, vertepofin administration can secondaryly damage the retinal structure, including the retinal pigmented epithelium and the outer nuclear layer of the retina.

Another recently studied method for the treatment of MD is pharmacological antiangiogenic therapy [Cour, M., et al., Drugs Aging 19: 101-133 (2002)]. However, the first clinical trials using the anti-angiogenic agent interferon-α were not effective for the treatment of MD and resulted in a high rate of side effects [Arch. Ophthalmol. 115: 865-72 (1997).

Intravitreal injections of triamcinolone reportedly inhibit the growth of laser-induced CNVM in monkeys, but do not prevent severe vision loss over a 1-year period in patients with MD during random trials [Gillies, MC, et al. ., Invest. Ophthalmol. Vis. Sci. 42: S522 (2001). Many other antiangiogenic drugs, including hemostatic steroids (e.g., annecortave acetate, Alcon) and vasculature epidermal growth factor (VEGF) antibodies or fragments thereof, have been developed for use in patients suffering from MD. In various stages of [Guyer, DR, et al., Invest. Ophthalmol. Vis. Sci. 42: S522 (2001). One such VEGF antibody is rhuFab. Additional new drugs for the treatment of MD include EYE101 (Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant and RETISERT Implants (Bausch & Lomb). ), Which injects steroids into the eye for up to three years.

Although new and promising methods for the treatment of MD and related macular degeneration diseases are being studied, there are still no effective treatments available. Thus, there is a need in the art for effective treatment for MD.

2.3 Selective Cytokine Inhibitory Drugs

Compounds associated with SelCIDs ™ (Celgene Corporation) or selective cytokine inhibitory drugs have been synthesized and tested. The compounds strongly inhibit TNF-α production and exhibit moderate inhibitory effects on LPS induced IL1β and IL12 [LG Lorral, et al., Ann. Rheum. Dis. 58: (Suppl I) 1107-1113 (1999).

An additional feature of selective cytokine inhibitory drugs shows the efficacy of PDE4 inhibitors. PDE4 is one of the phosphodiesterase isoenzymes found in human bone marrow and lymphoid cells. The enzyme plays a critical role in regulating cellular activity by degenerating the ubiquitous secondary messenger cAMP and maintaining it at low intracellular levels [supra]. Inhibition of PDE4 activity results in an increase in cAMP levels, regulating LPS-induced cytokines, including inhibition of TNF-α production in monocytes as well as lymphocytes.

3. Summary of the Invention

The present invention provides a method for administering a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, to a patient in need thereof. It includes a method of treatment and prevention of MD, including. The invention also provides for the administration of a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, to a patient in need thereof. A method of managing (eg, prolonging the relaxation time) of the containing MD.

Other embodiments of the invention include steroids, photosensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neurotrophic factors, angiogenesis modulators, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-inflammatory compounds A selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate compound thereof, in combination with other therapeutic agents useful for the treatment or prevention of MD, including but not limited to angiogenic compounds or combinations thereof; Includes the use of prodrugs.

Another embodiment of the present invention is an effective amount of a drug in combination with conventional therapies used for the treatment or prevention of MD, including but not limited to surgical interventions (eg, laser photocoagulation therapy and photodynamic therapy). Treatment, prevention or control of MD, including administration of a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof to a patient in need of treatment, prevention or control of MD It includes a method.

The present invention provides pharmaceutical compositions suitable for use in the treatment, prevention and / or management of MD, including selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof, Further include single unit dosage forms and kits.

4. Detailed description of the invention

A first embodiment of the invention provides a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug or a pharmaceutically acceptable salt, solvate thereof in a patient (eg, a mammal such as a human) in need of treatment and prevention of MD. And methods of treating and preventing MD comprising administering hydrates, stereoisomers, clathrates or prodrugs. The invention further relates to atrophy (dry) MD, exudative (wet) MD, age-related maculopathy (ARM), choroidal neovascularization (CNVM), retinal pigment epithelial detachment (PED), and atrophy of retinal pigment epithelium (RPE). It relates to the treatment or prevention of certain types of MD and related syndromes, including but not limited to.

As used herein, the term macular degeneration (MD) includes all forms of macular degeneration disease, although some macular degeneration diseases are more common in certain age groups. It is best disease or yolk symptom (most common in patients under about 7 years old); Stargardt's disease, macular dystrophy or macular fundus (most common in patients about 5 to about 20 years old); Behr's disease, Sorsby's disease, Doyne's disease or honeycomb dystrophy (most common in patients about 30 to about 50 years old); And age-related macular degeneration (most common in patients older than about 60 years).

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

Another embodiment of the invention relates to administering a prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient in need of administration of MD. It includes the management method of the containing MD.

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 any carrier thereof.

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

Another embodiment of the present invention includes a kit comprising a selective cytokine inhibitory drug, or a pharmaceutical composition comprising a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. In addition, the present invention includes kits comprising a single unit dosage form. Kits included in the present invention may further comprise additional active agents. Certain kits include an Amsler grating useful for detecting or diagnosing MD.

Without being limited by theory, it is believed that certain selective cytokine inhibitory drugs and other agents that can be used to treat the symptoms of MD can act in a complementary or synergistic manner in the treatment or management of MD. Accordingly, one embodiment of the present invention provides a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, steric form, in a patient in need of treatment, prevention and / or management of MD. Methods of treating, preventing and / or administering MD comprising administering an isomer, clathrate or prodrug and a therapeutically or prophylactically effective amount of a second active agent.

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

The invention also encompasses 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 and a second active agent thereof. . For example, kits include compounds of the invention and steroids, photosensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neurotrophic factors, angiogenesis modulators, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti- Inflammatory compounds or anti-angiogenic compounds or combinations thereof or other drugs that can alleviate or alleviate the symptoms of MD.

It is believed that certain selective cytokine inhibitory drugs can reduce or eliminate the deleterious effects associated with the administration of a therapeutic agent used to treat MD, thereby enabling the patient to be administered a large amount of the agent and / or increasing patient compliance. . Accordingly, another embodiment of the present invention provides a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutical thereof, in a patient in need of recovering from, reducing or avoiding the deleterious effects associated with administration of a second active agent. Methods for restoring, reducing or avoiding the deleterious effects associated with the administration of a second active agent in a patient with MD, including administering an acceptable salt, solvate, hydrate, stereoisomer, clathrate compound or prodrug Include.

As discussed elsewhere herein, the symptoms of MD can be treated with light or laser therapy, radiotherapy, retinal pigment epithelial transplantation, and surgical interventions including, but not limited to, center and dislocation. Without being limited by theory, it is believed that the combination of these conventional therapies with selective cytokine inhibitory drugs can be very effective. Accordingly, the present invention provides a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion thereof, before, during or after surgical intervention or other conventional non-drug based therapy to a patient. Methods of treating, preventing and / or administering MD comprising administering a compound or prodrug.

4.1 Selective Cytokine Inhibitory Drugs

Compounds used in the present invention are racemic, stereoisomeric pure, stereoisomerically enhanced selective cytokine inhibitory drugs, stereoisomeric and enantiomerically pure compounds with selective cytokine inhibitory activity, and pharmaceuticals thereof Phase acceptable salts, solvates, hydrates, stereoisomers, clathrates and prodrugs. Preferred compounds used in the present invention are known selective cytokine inhibitory drugs (SelCIDs) from Selgin Corporation.

Unless stated otherwise, the terms "selective cytokine inhibitory drug" and "SelCIDs" as used herein refer to small organic molecules that are not small molecule drugs, such as peptides, proteins, nucleic acids, oligosaccharides or other macromolecules. Include. Preferred compounds inhibit TNF-α production. The compounds of the present invention may also have a moderate inhibitory effect on LPS induced IL1β and IL12. More preferably, the compounds of the present invention are potent PDE4 inhibitors.

Specific examples of selective cytokine inhibitory drugs include cyclic imides disclosed in US Pat. Nos. 5,605,914 and 5,463,063, US Pat. Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and The aryl amides of 6,518,281 cycloalkyl amides and cycloalkyl nitriles, US Pat. Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780 (e.g., N-benzoyl-3-amino-3- (3 '). Imides / amide ethers and alcohols disclosed in US Pat. No. 5,703,098, e.g., 3-phthalimido-3- (3 ', 4'- Dimethoxyphenyl) propan-1-ol), succinimide and maleimide (eg, methyl 3- (3 ', 4', 5 ', 6'-petrahydrophthalimido) disclosed in US Pat. No. 5,658,940 ) -3- (3 ", 4" -dimethoxyphenyl) propionate), imido and amido substitutions disclosed in US Pat. No. 6,214,857 and WO 99/06041 Alkanohydroxysamic acid, substituted phenethylsulfones disclosed in US Pat. Nos. 6,011,050 and 6,020,358, substituted imides disclosed in US Pat. No. 6,429,221 (eg, 2-phthalimido-3- (3). ', 4'-dimethoxyphenyl) propane), substituted 1,3,4-oxadiazoles disclosed in US Pat. No. 6,326,388 (eg, 2- [1- (3-cyclopentyloxy-4-meth Methoxyphenyl) -2- (1,3,4-oxadiazol-2-yl) ethyl] -5-methylisoindolin-1,3-dione, US Pat. No. 5,929,117, 6,130,226, copper Cyano and carboxy derivatives of substituted styrenes disclosed in US Pat. Nos. 6,262,101 and 6,479,554 (eg, 3,3-bis- (3,4-dimethoxyphenyl) acrylonitrile), disclosed in WO 01/34606 Isoindolin-1-one and isoindolin-1 in which the 2-position is substituted with an α- (3,4-disubstituted phenyl) alkyl group and the 4- and / or 5-positions are substituted by a nitrogen-containing group , 3-dione, and the imido and amido substituted acyls disclosed in WO 01/45702 Droxamic acid (e.g., (3- (1,3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propanoylamino) propanoate It is not limited to this. All patents and patent applications mentioned herein are incorporated by reference herein.

Additional selective cytokine inhibitory drugs belong to the group of synthetic compounds, representative examples of which include 3- (1,3-dioxobenzo- [f] isoindol-2-yl) -3- (3-cyclopentyloxy- 4-methoxyphenyl) propionamide and 3- (1,3-dioxo-4-azaisoindol-2-yl) -3- (3,4-dimethoxyphenyl) -propionamide.

Other particular selective cytokine inhibitory drugs belong to the class of non-polypeptide cyclic amides disclosed in US Pat. Nos. 5,698,579 and 5,877,200, all incorporated herein. Representative cyclic amides include compounds of the formula

In the formula,

n has a value of 1, 2 or 3;

R ⁵ is unsubstituted or is respectively nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino O-phenylene substituted with 1 to 4 substituents independently selected from the group consisting of dialkylamino, acylamino, alkyl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms and halo;

R ⁷ is (i) phenyl or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, Phenyl substituted with one or more substituents independently selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo, (ii) unsubstituted or each of nitro, cyano, trifluoromethyl, Carbuethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo Benzyl, (iii) naphthyl or (iv) benzyloxy substituted with one to three substituents;

R ¹² is —OH, alkoxy having 1 to 12 carbon atoms or ego;

R ⁸ is hydrogen or alkyl of 1 to 10 carbon atoms;

R ⁹ is hydrogen, alkyl of 1 to 10 carbon atoms, -COR ¹⁰ or -SO ₂ R ¹⁰ , wherein R ¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl.

Specific compounds of this class are

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-oxysoindolin-yl) propionic acid,

3- (4-methoxyphenyl) -3- (1-oxysoindolin-yl) propionamide,

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

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

3- (3,4-dimethoxyphenyl) -3- (1-oxysoindolin-2-yl) propionamide,

3- (3,4-diethoxyphenyl) -3- (1-oxoisoindolin-yl) propionic acid,

Methyl 3- (1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionate,

3- (1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionic acid,

3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid,

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

3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionamide,

3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionamide,

Methyl 3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionate, and

Methyl 3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionate, including but not limited to.

Other particular selective cytokine inhibitory drugs include the imido and amido substituted alkanohydroxysamic acids disclosed in WO 99/06041, which is incorporated herein by reference. Examples of such compounds include, but are not limited to, compounds having a structure of the formula: and acid addition salts of those compounds containing nitrogen atoms that can be protonated.

In the formula,

R ¹ and R ² are each independently hydrogen or lower alkyl, or together with the carbon atoms to which they are bonded, unsubstituted or are respectively nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbo Independently from the group consisting of propoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo Forms o-phenylene, o-naphthylene or cyclohexene-1,2-diyl, substituted with 1 to 4 substituents selected;

R ³ is nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, Alkoxy having 1 to 10 carbon atoms, alkylthio having 1 to 10 carbon atoms, benzyloxy, cycloalkoxy having 3 to 6 carbon atoms, C ₄ -C ₆ -cycloalkylidenemethyl, C ₃ -C ₁₀ -alkylidenemethyl, indanyloxy And phenyl substituted with 1 to 4 substituents selected from the group consisting of halo;

R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

R ^{4 '} is hydrogen or alkyl of 1 to 6 carbon atoms;

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

n has a value of 0, 1 or 2.

Specific selective cytokine inhibitory drugs for use in the present invention further include, but are not limited to, the following compounds:

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] isoindol-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) propionamide; And

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

The selective cytokine inhibitory drug used in the present invention further includes a substituted phenethylsulfone substituted with an oxoisoindine group on the phenyl group. Examples of such compounds include, but are not limited to, those disclosed in US Pat. No. 6,020,358, incorporated herein, including the following compounds.

In the formula,

Carbon atoms denoted by * represent chiral centers;

Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O;

R ¹ , R ² , R ³ and R ⁴ are each independently of each other hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 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 together with the phenylene ring form naphthylidene;

R ⁵ and R ⁶ are each independently of each other hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano or cycloalkoxy having 18 or less carbon atoms;

R ⁷ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR ^{8 ′} R ^{9 ′} ;

R ⁸ and R ⁹ are each independently of each other hydrogen, alkyl of 1 to 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 form tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ¹ CH ₂ CH _2- , wherein X ¹ is -O-, -S- or -NH-;

R ^{8 '} and R ^9' are each independently of each other hydrogen, alkyl of 1 to 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 form tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ² CH ₂ CH _2- , wherein X ² is -O-, -S -Or -NH-.

For convenience the compound is treated as phenethylsulfone, but it will be appreciated that sulfonamides are included when R ⁷ is NR ^{8 ′} R ^{9 ′} .

Particular groups of such compounds are those in which Y is C═O or CH ₂ .

A further particular group of such compounds is that R ¹ , R ² , R ³ and R ⁴ are each independently of one another hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy or -NR ⁸ R ⁹ Wherein R ⁸ and R ⁹ are each, independently of one another, hydrogen or methyl, or one of R ⁸ and R ⁹ is hydrogen and the other is —COCH ₃ .

Particular compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is —NH ₂ and the other of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

Particular compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is —NHCOCH ₃ and the other of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

Particular compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is —N (CH ₃ ) ₂ and the other of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

More preferred groups of these compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is methyl and the other of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

Particular compounds are those in which ^one of R ¹ , R ² , R ³ and R ⁴ is fluoro and the other of R ¹ , R ² , R ³ and R ⁴ is hydrogen.

Particular compounds are those in which R ⁵ and R ⁶ are each independently of one another hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentoxy or cyclohexoxy.

Particular compounds are those in which R ⁵ is methoxy and R ⁶ is monocycloalkoxy, polycycloalkoxy and benzocycloalkoxy.

Particular compounds are those in which R ⁵ is methoxy and R ⁶ is ethoxy.

Particular compounds are those wherein R ⁷ is hydroxy, methyl, ethyl, phenyl, benzyl or NR ^{8 '} R ^9' , wherein R ^{8 '} and R ^9' are each independently hydrogen or methyl.

Particular compounds are those wherein R ⁷ is methyl, ethyl, phenyl, benzyl or NR ^{8 '} R ^9' , wherein R ^{8 '} and R ^9' are each independently hydrogen or methyl.

Particular compounds are those in which R ⁷ is methyl.

Particular compounds are those wherein R ⁷ is NR ^{8 ′} R ^{9 ′} , wherein R ^{8 ′} and R ^{9 ′} are each independently hydrogen or methyl.

Other specific selective cytokine inhibitory drugs include fluoroalkoxy, found in US Provisional Application No. 60 / 436,975, filed Dec. 30, 2002, by G. Muller, which is incorporated herein by reference in its entirety. -Substituted 1,3-dihydro-isoindolyl compounds. Representative fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds include compounds of the formula: or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof.

In the formula,

Y is —C (O) —, —CH ₂ , —CH ₂ C (O) —, —C (O) CH ₂ — or SO ₂ ;

Z is ^{-H, -C (O) R 3} , - (C O-1 - alkyl) -SO ₂ - (C _1-4 - alkyl), -C _1-8 - alkyl, -CH ₂ OH, CH ₂ (O) (C _1-8 -alkyl) or -CN;

R ₁ and R ₂ are each independently —CHF ₂ , —C _1-8 -alkyl, —C _3-18 -cycloalkyl or — (C _1-10 -alkyl) (C _3-18 -cycloalkyl), 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 each independently —H, —C _1-8 -alkyl, —OH or —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 each independently -H, - halogen, - _{nitro, -NH 2, -CF 3, -C} 1-6 - alkyl, - (C _O-4-alkyl) - (C _3-6 -cycloalkyl), (C _0-4 -alkyl) -NR ⁷ R ⁸ , (C _0-4 -alkyl) -N (H) C (O)-(R ⁸ ), (C _{O -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 _O-4-alkyl) - imidazolyl, (C _0-4 - alkyl) pyrrolyl, (C _0-4 -alkyl) - oxadiazolyl or (C _{0 -4} -alkyl) -triazolyl, or two of X ₁ , X ₂ , X ₃ and X ₄ combine with each other to form a cycloalkyl or heterocycloalkyl ring (eg, 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 a 3, 4, 5, 6 or 7 membered ring which may be aromatic Thus forming a bicyclic system with isoindoleyl ring);

R ⁷ and R ⁸ are each independently 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.

Preferred compounds include, but are not limited to, the following compounds:

3- (4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)- Propionic acid;

3- (4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)- N, N-dimethyl-propionamide;

3- (4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy-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-isoindol-2-yl) -propionic acid methyl ester;

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

3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl-3- (7-nitro-1-oxo-1, 3-dihydro-isoindol-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) -propionic acid methyl ester;

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

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

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

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

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-iso Indol-4-yl} -amide;

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

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) -propionamide ;

3- (4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -N, N-dimethyl-propionamide;

3- (4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -N- Hydroxy-propionamide;

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

N- {2- [1- (4-Difluoromethoxy-3-ethoxy-phenyl) -2-methanesulfonyl-ethyl] -1,3-dioxo-2,3-dihydro-1H-iso Indol-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 7-amido-substituted isoindoleyl, found in US Provisional Application No. 60 / 454,155, filed March 12, 2003, incorporated by reference in its entirety herein. Compound is included. Representative 7-amido-substituted isoindoleyl compounds include, but are not limited to, compounds of the formula: or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or prodrugs thereof; or

(In the meal,

Y is —C (O) —, —CH ₂ , —CH ₂ C (O) — or SO ₂ ;

X is H;

Z is (C _0-4 -alkyl) -C (O) R ³ , C _1-4 -alkyl, (C _O-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 _O-4 -alkyl) -N (H) (OH) or 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);

R ⁴ 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) or C _3-6 cycloalkyl, phenyl, benzyl Or aryl)

Compounds of the formula: or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof.

(In the meal,

Y is —C (O) —, —CH ₂ , —CH ₂ C (O) — or SO ₂ ;

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

W is

ego;

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 _O-4 -alkyl) O (C _1-4 -alkyl), (C _O-4 -alkyl) SO (C _1-4 -alkyl), (C _{O-4-alkyl) NH 2, (C O-} 4 - alkyl) N (C _{1-8 -alkyl) 2, (C O-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 O} -8 - alkyl) -NR ₇ R ₈ or _{(O-C 4} - _{alkyl) -CHR 9 - (C O-} 4 - alkyl) -NR ₇ R _8, and;

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

R ₉ is C _1-4 -alkyl, (C _O-4 -alkyl) aryl, (C _O-4 -alkyl)-(C _3-6 -cycloalkyl) or (C _O-4 -alkyl) -heterocycle being)

Another selective cytokine inhibitory drug includes N-alkyl-hydroxysamic acid-found in US Provisional Application No. 60 / 454,149, filed Mar. 12, 2003, which is hereby incorporated by reference in its entirety. Isoindolyl compounds are included. Representative N-alkyl-hydroxysamic acid-isoindolyl compounds include compounds of the formula: or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof.

In the formula,

Y is —C (O) —, —CH ₂ , —CH ₂ C (O) — or SO ₂ ;

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 each 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)- NHC (O) CH (R ₈ ) (R ₉ ), (C _0-4 -alkyl) -NHC (O) N (R ₈ R ₉ ), (C _O-4 -alkyl) -NHC (O) O ( _{R 8), (C O-} 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 each 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 each independently H, C _1-9 -alkyl, C _3-6 -cycloalkyl, (C _1-6 -alkyl)-(C _3-6 -cycloalkyl), (C _O-6 -Alkyl) -N (R ₄ R ₅ ), (C _1-6 -alkyl) -OR ₅ , phenyl, benzyl, aryl, piperidinyl, piperidinyl, pyrrolidinyl, morpholino or C _3-7 Heterocycloalkyl.

Specific selective cytokine inhibitory drugs include, but are not limited to, the following compounds:

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-isoindolin-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl] -4-nitroisoindolin-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-methylisoindolin-1,3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -5-acetamidoisoindolin-1,3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-dimethylaminoisoindolin-1,3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -5-dimethylaminoisoindolin-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-methoxyisoindolin-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-dimethylaminoisoindolin-1,3-dione.

Selective cytokine inhibitory drugs include U.S. Patent Application No. 10 / 392,195, filed March 19, 2003 and International Patent Application No. PCT /, filed March 20, 2003, all of which are incorporated herein by reference. US03 / 08737; U.S. Provisional Patent Application Nos. 60 / 438,450 and 60 / 438,448, filed January 7, 2003; And pure enantiomeric compounds disclosed in U.S. Provisional Application No. 60 / 452,460, filed March 5, 2003 by Muller et al. Preferred compounds include enantiomers of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindolin-1,3-dione and 3- (3 Enantiomers of, 4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide are included.

Preferred selective cytokine inhibitory drugs for use in the present invention include 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide and Cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-1H-isoindole- As 4-yl} -amides, they are available from Selgin Corporation, Warren, New Jersey. 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) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-1H-isoindole- 4-yl} -amide has the following chemical structure:

Compounds of the invention are commercially available or may be prepared according to the methods described in the patents or patent publications disclosed herein. In addition, optically pure compositions can be asymmetrically synthesized or separated using other standard synthetic organic chemistry techniques as well as known disintegrating agents or chiral columns.

As used herein, unless otherwise specified, the term "pharmaceutically acceptable salts" includes addition salts of non-toxic acids and bases of the compound to which the term refers. Acceptable nontoxic acid addition salts include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, emvolic acid and enan Those derived from organic and inorganic acids or salts known in the art, including formic acid, and the like.

Inherently acidic compounds may form salts with various pharmaceutically acceptable bases. Bases that can be used in the preparation of pharmaceutically acceptable base addition salts of such acidic compounds are nontoxic base addition salts, ie salts containing pharmacologically acceptable cations, for example alkali metal or alkaline earth metal salts, and especially calcium salts, magnesium Salts, sodium salts or potassium salts, but are not limited to these. Suitable organic bases include, but are not limited to, N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine and procaine, and the like. It is not.

As used herein, unless otherwise specified, the term “prodrug” refers to a derivative of a compound that can be hydrolyzed, oxidized or otherwise reacted to provide a compound under biological conditions (in vitro or in vivo). Examples of prodrugs include selective hydrolyzable moieties including biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides and biohydrolyzable phosphate homologs. Derivatives of cytokine inhibitory drugs include, but are not limited to. Other examples of prodrugs include derivatives of selective cytokine inhibitory drugs comprising -NO, -NO ₂ , -ONO or -ONO ₂ residues. Prodrugs are commonly known methods such as Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995) and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985).

As used herein, unless otherwise specified, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable woo" Laid "," biohydrolyzable phosphate "may 1) impart beneficial properties to the compound in vivo, such as absorption, duration of action or onset of action without interfering with the biological activity of the compound; Or 2) amide, ester, carbamate, carbonate, ureate or phosphate, respectively, of a compound that is biologically inert but converted to a biologically active compound in vivo. Examples of biohydrolyzable esters include lower alkyl esters, lower acyloxyalkyl esters (eg, acetosylmethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (E.g. phthalidyl and thiopridyl esters), lower alkoxyacyloxyalkyl esters (e.g. methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters , Choline esters and acylamino alkyl esters (such as acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-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 polyether amines.

Various selective cytokine inhibitory drugs contain one or more chiral centers and may exist in racemic mixtures of enantiomers or mixtures of diastereomers. The present invention includes the use of pure stereoisomeric forms of such compounds and the use of mixtures of these forms. For example, mixtures comprising the same or non-equivalent amounts of enantiomers of selective cytokine inhibitory drugs can be used in the methods and compositions of the present invention. Purified (R) or (S) enantiomers of the specific compounds disclosed herein can be used in the substantial absence of another enantiomer thereof.

As used herein, unless stated otherwise, the term "stereoisomerically pure" means a composition that includes one stereoisomer of a compound but is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure composition of a compound having one chiral center will be substantially free of the relative enantiomers of that compound. Stereoisomeric pure compositions of a compound having two chiral centers will be substantially free of other diastereomers of that compound. Typical stereoisomerically pure compounds comprise greater than about 80 weight percent of one stereoisomer of the compound and less than about 20 weight percent of the other stereoisomer of the compound, more preferably greater than about 90 weight percent of one stereoisomer of the compound and other stereoisomers of the compound. Less than about 10 weight percent, even more preferably greater than about 95 weight percent of one stereoisomer of the compound and less than about 5 weight percent of the other stereoisomer of the compound, most preferably greater than about 97 weight percent of one stereoisomer of the compound and Less than about 3 weight percent of other stereoisomers.

As used herein, unless otherwise specified, the term "stereoenhanced" means more than about 60 weight percent of one stereoisomer of the compound, preferably more than about 70 weight percent of one stereoisomer of the compound, more preferably Means a composition comprising greater than about 80% by weight.

As used herein, unless otherwise specified, the term "enantiomerically pure" means a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term “stereoisotropically enhanced” means a stereoisomerically enhanced composition of a compound having one chiral center.

It should be noted that if the described structure is inconsistent with the name given to the structure, more emphasis should be placed on the described structure. In addition, when a stereochemistry of a structure or part of a structure is not indicated by a thick line or dotted line, the structure or part of the structure should be interpreted as including all stereoisomers thereof.

4.2 Second active agent

Second active agents can be used in the methods and compositions of the present invention in conjunction with selective cytokine inhibitory drugs. In a preferred embodiment, the second active agent can inhibit or alleviate the macular injury state, provide an antiangiogenic or anti-inflammatory effect or make the patient comfortable.

Examples of second active agents include steroids, photosensitizers, integrins, antioxidants, interferons, xanthine derivatives, growth hormones, neurotrophic factors, angiogenesis modulators, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-vascular Neoplastic compounds, other therapeutic agents known to inhibit or alleviate the symptoms of MD, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, prodrugs and pharmaceutically active metabolites thereof, and the like. In certain embodiments, the second active agent is vertepofin, furritin, hemostatic steroid, rhuFab, interferon-2α or pentoxifylline.

Examples of photosensitizers include, but are not limited to, vertepporpine, tin thiopurpurine, and motexapine lutetium. Berteporfin can be used to treat wet MD (Cour, M., et al., Drugs Aging 19: 101-133 (2002)). Berteporphine is a vascular-blocking photoreactive dye that can be administered via 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-methylethylidedinebis (oxy) pregna-1,4-diene-3,20-dione. It doesn't work.

Examples of prostaglandin F ₂ a derivatives include, but are not limited to, latanoprost and the like (see US Pat. No. 6,225,348, which is incorporated herein by reference in its entirety).

Examples of antibiotics include, but are not limited to, tetracyclines and derivatives thereof, rifamycin and derivatives thereof, macrolides and metronidazoles (see US Pat. Nos. 6,218,369 and 6,015,803, which are hereby incorporated by reference in their entirety). .

Examples of phytoestrogens include genistein, genistin, 6'-O-Mal genistin, 6'-O-Ac genistin, dyzein, dizin, 6'-O-Mal dizin, 6'-O-Ac Diazine, glycidin, glycidine, 6'-O-Mal glycidine, biochanin A, formmononetin and mixtures thereof, and the like (including but not limited to the United States, which is incorporated herein by reference in its entirety). Patent 6,001,368).

Examples of anti-inflammatory agents include, but are not limited to, triamcinolone acetomide and dexamethasone. (See US Pat. No. 5,770,589, which is incorporated herein by reference in its entirety).

Examples of anti-angiogenic compounds include, but are not limited to, thalidomide and immunomodulatory compounds (IMiD ™, Selgin Corporation, NJ).

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

In other embodiments, the second active agent is glutathione (see US Pat. No. 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-induced neurotrophic factor (BDNF).

Examples of angiogenesis modulators include, but are not limited to, plasminogen activator factor type 2 (PAI-2).

Additional drugs that can be used for the treatment of MD include, but are not limited to, EYE101 (Etech Pharmaceuticals), LY333531 (Eli Lily), Miravant and RETISERT Implant (Bohshu & Rom).

4.3 Treatment and Prevention Methods

The present invention includes methods for the prevention, treatment and / or management of various types of MD.

As used herein, unless otherwise indicated, the terms “MD prevention”, “MD treatment” and “MD management” include but are not limited to inhibiting or reducing the severity of one or more symptoms associated with MD. Signs and related syndromes associated with MD include drusen fundus round pale yellow spots, macular subretinal disc scar tissue, choroidal neovascularization, retinal pigment epithelial detachment, retinal pigment epithelial atrophy, choroid (vascular-rich tissue layer just below the retina). Stem-formed abnormal blood vessels, decreased vision or astigmatism, central blind spots, pigment abnormalities, continuous layers of fine granular material precipitated inside the Brueck membrane and reduced thickening and permeability of the Brueck membrane.

As used herein, unless otherwise indicated, the term "MD treatment" refers to the administration of a compound of the invention or another additional active agent after the onset of an indication of MD, while "prevention" refers to, in particular, before the onset of the indication, Administration to patients at risk of developing MD. Examples of patients at risk for MD include, but are not limited to, those older than 60 years old and those suffering from diseases such as diabetes and leprosy (eg, ENL). Patients with a family history of MD are also good candidates for prophylactic prescription. As used herein, unless otherwise indicated, the term “MD management” prevents recurrence of MD in patients with MD history and / or prolongs the time that MD remains relaxed in patients with MD history. It involves making.

The present invention is directed to various stages and specific types of diseases (wet MD, dry MD, age-related macular disease (ARM), choroidal neovascularization (CNVM), retinal pigment epithelial detachment (PED) and atrophy of retinal pigment epithelium (RPE)). Methods of treating, preventing and managing MD and related syndromes in patients suffering from, including, but not limited to, the diseases mentioned. In addition, the present invention includes methods for treating patients who have previously been treated for MD but who have not previously been treated for MD as well as patients who do not respond to standard drug and non-drug-based MD therapies. . Because MD patients have heterogeneous clinical findings and varying clinical outcomes, the treatment given to a patient may depend on his (her) prognosis. The clinician will readily be able to determine, without undue experimentation, certain second agents and therapies that can be effectively used to treat individual patients.

The methods encompassed by the present invention include one or more selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof, in patients suffering from or potentially at risk of MD. It includes administering.

In one embodiment, the recommended daily dosage range of the selective cytokine inhibitory drug is from about 1 mg to about 10,000 mg / day and is administered in a single dose once daily, or preferably in divided doses over one day. More particularly, the daily dose is administered twice daily in equally divided doses. Certain daily dosage ranges range from 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 the management of patients, the therapy is initiated at lower doses, presumably about 1 mg to about 2,500 mg, as a single or divided dose, and if necessary up to about 200 mg to about 5,000 mg / day depending on the patient's overall response Should be increased. In certain embodiments, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is 1 day in two divided doses It is administered in an amount of about 400, 800, 1,200, 2,500, 5,000 or 10,000 mg. Treatment lasts about 2 to about 20 weeks, about 4 to about 16 weeks, and about 8 to about 12 weeks until the desired therapeutic effect is achieved or the desired effect is sustained.

4.3.1 Combination Therapies Using Second Active Agents

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

The selective cytokine inhibitory drug and any second active agent can be administered to the patient simultaneously or sequentially by the same or different route of administration. The suitability of the particular route of administration used for a particular active agent will depend upon the active agent itself (eg, whether the active agent can be administered orally without degradation prior to entering the bloodstream) and the disease to be treated. Preferred routes of administration for selective cytokine inhibitory drugs are oral or ocular routes. Preferred routes of administration for the second active agents or components of the invention are known to those skilled in the art (eg, Physicians' Desk Reference (57 ^th ed., 2003)).

In one embodiment, the second active agent is from about 0.1 to about 2,500 mg, about 1 to about 2,000 mg, about 10 to about 1,500 mg, about 50 to about 1,000 mg, about 100 to about 750 mg or about 250 to about 500 mg It is administered once or twice daily by oral, intravenous, intramuscular, subcutaneous, mucosal, topical or transdermal routes.

In further embodiments, the second active agent is administered weekly, monthly, bimonthly, or yearly. The specific amount of other active agent may vary depending on the specific agent used, the type of MD to be treated or prevented, the severity or stage of the MD, the selective cytokine inhibitory drug and any other agent (s) administered simultaneously to the patient. . In certain embodiments, the second active agent is a steroid, photosensitizer, integrin, antioxidant, interferon, xanthine derivative, growth hormone, neurotrophic factor, angiogenesis modulator, anti-VEGF antibody, prostaglandin, antibiotic, phytoestrogen, anti-inflammatory Compounds or anti-angiogenic compounds, or combinations thereof.

4.3.2 Use of Surgical Intervention

The present invention relates to selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof in combination with (eg, before, during or after surgical intervention) ) Methods of treating, preventing and / or administering MD, including administering. Examples of surgical interventions include, but are not limited to, laser therapy, radiation therapy, retinal pigment epithelial transplantation, and central and dislocation.

Administering selective cytokine inhibitory drugs in parallel with surgical intervention provides a unique treatment regimen that may have unexpected effects on certain patients. While not being limited by theory, it is believed that selective cytokine inhibitory drugs can provide additional or synergistic effects when administered concurrently with surgical intervention.

In certain embodiments, the invention provides an effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or precursor thereof, in a patient in need of treatment, prevention and / or management of MD. Methods of treating, preventing and / or administering MD, including administering the drug with 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 simultaneously or sequentially with surgical intervention. In one embodiment, the selective cytokine inhibitory drug is administered prior to light or laser therapy. In other embodiments, the selective cytokine inhibitory drug is administered after light or laser therapy. In one embodiment, the selective cytokine inhibitory drug is administered during light or laser therapy. The compound may be administered for a treatment period of at least about 12 to 16 weeks in total at least 4 weeks before, 2 weeks before, 1 week before, or immediately before, or immediately after surgery.

4.3.3 Cycle therapy

In certain embodiments, the prophylactic or therapeutic agent is administered to the patient periodically. The cycle therapy involves administering the first agent and / or the second agent for one cycle and then repeating this sequential administration after administering the first agent for one cycle. Periodic therapy may reduce the deepening of resistance to one or more therapies, and / or eliminate or reduce the side effects of one of the therapies and improve the efficacy of the treatment.

In certain embodiments, the prophylactic or therapeutic agent is administered about once or twice daily, with a cycle of about 6 months. One cycle may include the administration of a prophylactic or therapeutic agent and at least one to three weeks of rest. The number of cycles administered may be about 1 to about 12 cycles, about 2 to about 10 cycles, or 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. Pharmaceutical compositions and dosage forms of the invention include selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof. Pharmaceutical compositions and dosage forms of the invention may also further comprise one or more excipients.

In addition, the pharmaceutical compositions and dosage forms of the invention may comprise one or more additional active agents. As a result, the pharmaceutical compositions and dosage forms of the present invention may comprise an active agent disclosed herein (eg, a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and Second active agent). Examples of any additional active agents are disclosed herein (see eg section 4.2).

Single unit dosage forms of the invention may be administered orally, mucosally (eg, nasal, sublingual, intravaginal, oral or rectal), or parenterally (eg, subcutaneously, intravenously, bolus injection, intramuscular or arterial) to a patient. Internal), topical (eg, eye drops), ocular, dermal or transdermal. Examples of dosage forms include tablets; Caplets; Capsules (eg, soft elastic gelatin capsules); Casein; Trocheses; Lozenges; Dispersants; Suppositories; Powder; Aerosols (eg, nasal sprays or inhalants); Liquid dosage forms suitable for oral or mucosal administration to a patient, including eye drops, gels, suspensions (eg aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs ; And 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, form and type of dosage forms of the invention will typically vary depending on their use. For example, a dosage form used for acute treatment of a disease may contain a greater amount of one or more active agents it contains than a dosage form used for chronic treatment of the same disease. Similarly, parenteral dosage forms may contain less than one or more active agents it contains than oral dosage forms used to treat the same disease. Such and other ways in which certain dosage forms included in the present invention may differ from one another will be readily understood by those skilled in the art (see, eg, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990)). ] Reference).

Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for introduction into a pharmaceutical composition or dosage form depends on a variety of factors known in the art, including but not limited to the manner in which the dosage form is administered to a patient. For example, oral dosage forms such as tablets may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of particular excipients may also depend on the particular active agent in the dosage form. For example, degradation of some active agents may be accelerated by some excipients such as lactose or when exposed to water. In particular, active agents comprising primary or secondary amines are susceptible to accelerated decomposition as described above. As a result, the present invention includes pharmaceutical compositions and dosage forms that contain little or no lactose, other monosaccharides or disaccharides. As used herein, the term "lactose-free" means that an amount of lactose is present in an amount insufficient or not at all to substantially increase the rate of degradation of the active agent.

The lactose-free compositions of the present invention may comprise excipients known in the art and are listed, for example, in USP 25-NF20 (2002). Generally, the lactose-free composition comprises the active agent, the binder / filler and the lubricant in a pharmaceutically compatible and pharmaceutically acceptable amount. Preferred lactose-free dosage forms include active ingredient, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

The present invention further includes anhydrous pharmaceutical compositions and dosage forms comprising the active agent as water may facilitate the degradation of some compounds. For example, the addition of water (eg 5%) as a method of stimulating long term storage to determine properties such as stability over time or shelf life of a formulation is widely accepted in the pharmaceutical arts (eg See, eg, Jens T. Carstensen, Drug Stablility: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In short, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on the formulation can be very important because moisture and / or humidity are typically produced during the manufacturing, handling, packaging, storage, shipping and use of the formulation.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing formulations and low moisture or low humidity conditions. If it is expected to be in substantial contact with moisture and / or humidity during the manufacturing, packaging and / or storage process, pharmaceutical compositions and dosage forms comprising one or more active agents comprising lactose and primary or secondary amines may be anhydrous. It is preferably in form.

Anhydrous pharmaceutical compositions should be prepared and stored so that their anhydrous properties are maintained. Thus, anhydrous compositions are preferably packaged using materials known to prevent exposure to water so that they can be included in the kit in a suitable manner. Examples of suitable packaging include, but are not limited to, fully sealed foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.

The invention further includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which the active agent degrades. Such compounds referred to herein as "stabilizers" include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers.

As with the amount and type of excipient, the amount and specific type of active agent in the dosage form can vary depending on factors including, but not limited to, the route administered to the patient. However, typical dosage forms comprise a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in an amount of about 1 to about 10,000 mg. Typical dosage forms comprise a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, about 1, 2, 5, 10, 25, 50, 100, 200, 400 , 800, 1,200, 2,500, 5,000 or 10,000 mg. In certain embodiments, preferred dosage forms comprise 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide at about 400, In amounts of 800 or 1,200 mg. Typical dosage forms comprise from about 0.1 to about 2,500 mg, about 1 to about 2,000 mg, about 10 to about 1,500 mg, about 50 to about 1,000 mg, about 100 to about 750 mg or about 250 to about 500 mg of the second active agent. Included in quantity. Of course, the particular dosage of the second active agent will vary depending on the particular agent used, the type of MD to be treated or administered, the selective cytokine inhibitory drug and the amount of any additional active agent administered simultaneously to the patient.

4.4.1 Oral dosage form

Pharmaceutical compositions of the invention suitable for oral administration are provided in separate dosage forms such as, but not limited to, tablets (e.g. chewable tablets), caplets, capsules and liquids (e.g., flavor syrups). Can be. Such dosage forms contain a predetermined amount of active agent and can be prepared by methods of pharmacy known to those skilled in the art (see generally Remigton's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990)). .

Typical oral dosage forms of the invention are prepared by combining the active ingredients in a well mixed mixture with one or more excipients according to conventional pharmaceutical formulation techniques. Excipients can take a wide variety of forms depending on the form of preparation desired upon administration. For example, excipients suitable for use in liquid or aerosol dosage forms for oral administration include, but are not limited to, water, glycols, oils, alcohols, flavors, preservatives and colorants. Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, capsules and caplets) include starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrants. This is not restrictive.

Because tablets and capsules are easily administered, they represent the most advantageous oral dosage unit form when solid excipients are used. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of preparation. Generally, pharmaceutical compositions and dosage forms are prepared by uniformly and well mixing the active agent with a liquid carrier, finely divided solid carrier or both, and then, if necessary, shaping the product to the desired appearance.

For example, tablets can be made by compression or molding. Compressed tablets may be prepared by compressing the active agent (optionally mixed with excipients) in a suitable machine in a free flowing form such as a powder or granules. Molded tablets may be prepared by molding in a suitable machine 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. Suitable binders for use in pharmaceutical compositions and dosage forms include corn starch, potato starch or other starches, gelatin, natural and synthetic rubbers such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, Guar gum, cellulose and derivatives thereof (e.g. ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (e.g. 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof, but are not limited thereto.

Suitable forms of microcrystalline cellulose are commercially available as Avicel-PH-101, Avicel-PH-103, Avicel RC-581, Avicel-PH-105 (FMC, American Viscose Division, Avicel Sales, Marcus Hook (Commercially available from FMC Corporation, American Viscose Division, AVICEL Sales, Marcus Hook, Pennsylvania, USA) and mixtures thereof. One particular binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose 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 disclosed herein include talc, calcium carbonate (eg, granules or powders), microcrystalline cellulose, powdered cellulose, dexrate, kaolin, mannitol, silicic acid, sorbitol , Starch, pregelatinized starch, and mixtures thereof. The binder or filler included in the pharmaceutical composition of the present invention is present in an amount of about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the present invention to provide tablets that disintegrate upon exposure to an aqueous environment. Tablets containing excess disintegrant may disintegrate during storage, but containing too little may not disintegrate under the desired conditions or at the desired rate. Therefore, a sufficient amount of disintegrant, not too much or too little, which adversely alters the release of the active agent, should be used to form the solid oral dosage form of the present invention. The amount of disintegrant used depends on the type of formulation and one skilled in the art can readily determine this. Typical pharmaceutical compositions comprise about 0.5 to about 15 weight percent of disintegrant, preferably about 1 to about 5 weight percent.

Disintegrants that can be used in pharmaceutical compositions and dosage forms include agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polyacrylic potassium, sodium starch glycolate, potato or tapioca starch, other starches, Pregelatinized starch, other starches, clays, other algins, other celluloses, rubbers and mixtures thereof, but are not limited thereto.

Lubricants that can be used in pharmaceutical compositions and dosage forms include calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenation Vegetable oils (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar and mixtures thereof. Additional lubricants include, for example, siloid silica gel (AEROSIL 200 (double oil, WR Grace Co., Baltimore, MD)), solidified aerosols of synthetic silica (de Commercially available from Degussa Co. (Plano, Texas), and CAB-O-SIL (pyrogenic silicon dioxide commercially available from Cabot Co .; Boston, Mass.) And these There is a mixture of. When used, lubricants are typically used in amounts less than about 1% by weight of the pharmaceutical composition or dosage form into which it is incorporated.

Preferred solid oral dosage forms include selective cytokine inhibitory drugs, lactose anhydrous, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin.

4.4.2 Delayed-Release Dosage Form

The active agents of the present invention can be administered by controlled release means or by delivery devices known to those skilled in the art. Examples include U.S. Pat. 5,354,556 and 5,733,566, each of which is incorporated herein by reference, but are not limited to these. Such dosage forms may, for example, use hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, particulates, liposomes, microspheres, or combinations thereof to delay the release of one or more active agents. Or by controlling it can be used to provide the desired release profile in which the ratio varies. Suitable controlled-release preparations known to those skilled in the art, including those described herein, can be readily selected for use with the active agents of the present invention. Accordingly, the present invention includes single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps and caplets suitable for controlled release.

All controlled-release medications have a common purpose to provide improved drug treatment than is achieved by their uncontrolled counterparts. Ideally, the use of controlled-release preparations best designed for medicinal treatments is characterized by the minimum amount of drug used to treat or control the symptoms in the shortest time. Advantages of controlled-release preparations include prolonging the activity of the drug, decreasing the frequency of administration and increasing patient compliance. In addition, controlled-release preparations may be used to influence other properties, such as the time of onset of action or the blood concentration of the drug, and thus may affect the occurrence of side effects (eg, adverse effects).

Most controlled-release preparations will initially release an amount of drug (active agent) that will immediately produce the desired therapeutic effect, with the remaining amount of drug gradually and continuously so that this level of therapeutic or prophylactic effect is maintained over an extended period of time. It is designed in the form of release. In order to keep this level of drug constant in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug that is metabolized and secreted from the body. Controlled-release of an active agent can be stimulated by a variety of 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 a patient by a variety of routes, including but not limited to intravitreal, subcutaneous, intravenous (including bolus injection), intramuscular and intraarterial administration. Because these administrations typically defeat the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterilized or sterilized prior to administration to the patient. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, anhydrous products that can be dissolved or suspended in pharmaceutically acceptable injectable vehicles, injectable suspensions, and emulsions.

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

Compounds that increase the solubility of one or more active agents disclosed herein may also be incorporated into the parenteral dosage forms of the invention. For example, cyclodextrins and derivatives thereof can be used to increase the solubility of selective cytokine inhibitory drugs and derivatives thereof (see, eg, US Pat. No. 5,134,127, incorporated herein by reference).

4.4.4 Topical and mucosal dosage forms

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

Suitable excipients (eg, carriers or diluents) and other materials that can be used to provide the topical and mucosal dosage forms encompassed by the present invention are known to those skilled in the art of pharmacy, and particular pharmaceutical compositions or dosage forms will be applied. It depends on your organization. Given this fact, typical excipients include water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, which form non-toxic and pharmaceutically acceptable solutions, emulsions or gels. , Isopropyl palmitate, mineral oil and mixtures thereof. Moisturizers or wetting agents can also be added to pharmaceutical compositions and dosage forms, if desired. Examples of such additional ingredients are known in the art (see, eg, Remington's Pharmaceutical Sciences, 16 ^th and 18 ^th eds., Mack Publishing, Easton PA (1980 & 1990)).

The pH of the pharmaceutical composition or dosage form may be adjusted to improve the delivery of one or more active ingredients. Similarly, delivery can be improved by adjusting the polarity of the solvent carrier, its ionic strength, or isotonicity. Compounds such as stearates may also be added to the pharmaceutical composition or dosage form to advantageously change the hydrophilicity or lipophilicity of one or more active agents to improve delivery. In this regard, stearates can be used as lipid vehicles for formulations, as emulsifiers or surfactants, and as delivery or penetration enhancers. Different salts, hydrates or solvates of the active agent can be used to further adjust the properties of the resulting composition.

4.4.5 Kit

Typically, the active agents of the invention are preferably not administered to the patient at the same time or by the same route of administration. Accordingly, the present invention includes kits that, when used by a physician, can simply administer an appropriate amount of active agent to a patient.

Typical kits of the invention include dosage forms of selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, prodrugs or clathrates thereof. Kits encompassed by the present invention may further comprise one or more additional active agents or combinations thereof. Examples of further active agents are disclosed herein (see eg section 4.2).

Kits of the present invention may further comprise a device used to administer the active agent. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers. Kits of the invention may further comprise an Amsler grating useful for the detection and diagnosis of MD.

Kits of the invention may further comprise a pharmaceutically acceptable vehicle that can be used to administer one or more active agents. For example, if a certain active ingredient is provided as a solid that must be reconstituted for parenteral administration, the kit may contain a closed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution suitable for parenteral administration. It may include. Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous vehicles such as, but not limited to, water for injection USP, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's injection; Water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; And non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

5. Example

The following examples are intended to further illustrate the invention without limiting its scope.

5.1 In vitro pharmacology study

One biological effect typically exhibited by selective cytokine inhibitory drugs is a decrease in TNF-α synthesis. Selective cytokine inhibitory drugs increase the degradation of TNF-α mRNA. TNF-α may play a pathological role in macular degeneration.

In certain embodiments, the in vitro study of pharmacological properties of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide Has been characterized. The studies examined the effect of the compound on the production of various cytokines. Inhibition of TNF-α production following LPS-stimulation of human PBMCs and human whole blood by the compounds of the present invention was investigated in vitro. In vitro studies showed that the pharmacological activity profile for 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide was stripped It was suggested to be 5 to 50 times more potent than mead. The pharmacological effect of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is as an inhibitor of the production of inflammatory cytokines. Can be inferred from its action.

5.2 Clinical Study on MD Patients

The selective cytokine inhibitory drug of the present invention is administered to macular degeneration patients in an amount of about 20 to about 1,200 mg per day. In certain embodiments, 40 macular degeneration patients were divided into two groups to conduct clinical studies. The first group received conventional treatment to close the choroidal vessels (characteristic of the disease) leaked by photodynamic therapy with vertepofin (Ophthalmol 1999 (117): 1329-1345). The second group is the adjuvant Berteporphine and (+)-2- [1- (3-ethoxy-4 methoxyphenyl) -2-methylsulfonylethyl] -4 acetylaminoisoindolin 1,3-dione Received the same conventional treatment for 20 weeks using an amount of about 20 mg / day.

In the group receiving (+)-2- [1- (3-ethoxy-4 methoxyphenyl) -2-methylsulfonylethyl] -4 acetylaminoisoindolin 1,3-dione, the angiogenic cascade was sufficiently delayed. Thus prolonging the effects of photodynamic therapy indefinitely. However, the first group not receiving (+)-2- [1- (3-ethoxy-4 methoxyphenyl) -2-methylsulfonylethyl] -4 acetylaminoisoindolin 1,3-dione was treated. Only a few weeks later they experience progressive reperfusion of the removed blood vessel. It is accompanied by progressive deterioration of vision, which requires repeated photodynamic therapy.

In another preferred embodiment, (+)-2- [1- (3-ethoxy-4 methoxyphenyl) -2-methylsulfonylethyl] -4 acetylaminoisoindolin 1,3-dione is about 1 to about A daily dosage of at least 200 mg / day, preferably about 10 to about 50 mg / day, is generally administered about 1.5 to 2.5 times every other day. Adjuvant therapy can be applied to other types of conventional therapies used to treat or prevent MD, including but not limited to surgical interventions, including laser photocoagulation therapy.

The embodiments of the invention described herein are merely to illustrate the scope of the invention. Many of the references cited herein are deemed to be incorporated by reference in their entirety.

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

Claims (22)

Treatment of macular degeneration comprising administering to a patient in need of treatment, prevention or management of macular degeneration, a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, Prevention or care method. The method of claim 1, further comprising administering a therapeutically or prophylactically effective amount of a second active agent. The method of claim 2, wherein the second active agent is a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, xanthine derivative, growth hormone, neurotrophic factor, angiogenesis modulator, anti-VEGF antibody, prostaglandin, antibiotic, phytoestrogen, anti A inflammatory compound or an angiogenic compound. The method of claim 2, wherein the second active agent is thalidomide, verteporpine, furritin, hemostatic steroid, rhuFab, interferon-2α or pentoxifylline; Or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. The method of claim 4, wherein the antiangiogenic compound is thalidomide. The method of claim 1, wherein the macular degeneration is wet macular degeneration, dry macular degeneration, age-related macular degeneration, age-related macular disease, choroidal neovascularization, retinal pigment epithelial detachment, atrophy of retinal pigment epithelium, Best disease, egg yolk Symptom, Stargardt's disease, macular dystrophy, macular fundus, Verber's disease, Thorsby's disease, man's disease, honeycomb dystrophy, or macular damage. The method of claim 1, wherein the selective cytokine inhibitory drug is stereoisomeric pure. A therapeutically or prophylactically effective amount of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindole-2 in patients in need of treatment, prevention or management of macular degeneration -Yl) -propionamide, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, for treating, preventing or managing macular degeneration. The method of claim 8, wherein 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is enantiomerically pure How to be. A therapeutically or prophylactically effective amount of cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl- for patients in need of treatment, prevention or management of macular degeneration Treatment of macular degeneration, comprising administering ethyl] -3-oxo-2,3-dihydro-1H-isoindol-4-yl-amide, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; Prevention or care method. The cyclopropanecarboxylic acid {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro of claim 10. -1H-isoindol-4-yl} -amide is enantiomerically pure. The method of claim 1, wherein the selective cytokine inhibitory drug has a structure of Formula (I) <Formula I> In the formula, n has a value of 1, 2 or 3; R ⁵ is unsubstituted or is respectively nitro, cyano, trifluoromethyl, carethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino O-phenylene substituted with 1 to 4 substituents independently selected from the group consisting of dialkylamino, acylamino, alkyl having 1 to 10 carbon atoms, alkyl having 1 to 10 carbon atoms and halo; R ⁷ is (i) phenyl or nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, Phenyl substituted with one or more substituents independently selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo, (ii) unsubstituted or each of nitro, cyano, trifluoromethyl, Carbuethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, and halo Benzyl, (iii) naphthyl or (iv) benzyloxy substituted with one to three substituents; R ¹² is —OH, alkoxy having 1 to 12 carbon atoms or ego; R ⁸ is hydrogen or alkyl of 1 to 10 carbon atoms; R ⁹ is hydrogen, alkyl of 1 to 10 carbon atoms, -COR ¹⁰ or -SO ₂ R ¹⁰ , wherein R ¹⁰ is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl. The method of claim 12, wherein the selective cytokine inhibitory drug is enantiomerically pure. The method of claim 1, wherein the selective cytokine inhibitory drug has a structure of Formula II. <Formula II> In the formula, R ¹ and R ² are each independently hydrogen or lower alkyl, or together with the carbon atoms to which they are bonded, unsubstituted or are respectively nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbo Independently from the group consisting of propoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo Forms o-phenylene, o-naphthylene or cyclohexene-1,2-diyl, substituted with 1 to 4 substituents selected; R ³ is nitro, cyano, trifluoromethyl, carboethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, Alkoxy having 1 to 10 carbon atoms, alkylthio having 1 to 10 carbon atoms, benzyloxy, cycloalkoxy having 3 to 6 carbon atoms, C ₄ -C ₆ -cycloalkylidenemethyl, C ₃ -C ₁₀ -alkylidenemethyl, indanyloxy And phenyl substituted with 1 to 4 substituents selected from the group consisting of halo; R ⁴ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R ^{4 '} is hydrogen or alkyl of 1 to 6 carbon atoms; R ⁵ is —CH ₂ —, —CH ₂ —CO—, —SO ₂ —, —S— or —NHCO—; n has a value of 0, 1 or 2. The method of claim 14, wherein the selective cytokine inhibitory drug is enantiomerically pure. The method of claim 1, wherein the selective cytokine inhibitory drug has a structure of Formula III. <Formula III> In the formula, Carbon atoms denoted by * represent chiral centers; Y is C═O, CH ₂ , SO ₂ or CH ₂ C═O; R ¹ , R ² , R ³ and R ⁴ are each independently of each other hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 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 together with the phenylene ring form naphthylidene; R ⁵ and R ⁶ are each independently of each other hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cyano or cycloalkoxy having 18 or less carbon atoms; R ⁷ is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR ^{8 ′} R ^{9 ′} ; R ⁸ and R ⁹ are each independently of each other hydrogen, alkyl of 1 to 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 form tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ¹ CH ₂ CH _2- , wherein X ¹ is -O-, -S- or -NH-; R ^{8 '} and R ^9' are each independently of each other hydrogen, alkyl of 1 to 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 form tetramethylene, pentamethylene, hexamethylene or -CH ₂ CH ₂ X ² CH ₂ CH _2- , wherein X ² is -O-, -S -Or -NH-. The method of claim 16, wherein the selective cytokine inhibitory drug is enantiomerically pure. A therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug in a patient in need of treatment, prevention or management of macular degeneration before, during or after surgical intervention associated with alleviating or eliminating the symptoms of macular degeneration in the patient, or A method of treating, preventing or managing macular degeneration, comprising administering a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 18. The method of claim 17, wherein the surgical intervention is phototherapy, laser therapy, radiotherapy, retinal pigment epithelial transplantation, or central and transposition. A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second active agent capable of alleviating or eliminating the symptoms of macular degeneration. The method of claim 20, wherein the second active agent is a steroid, photosensitizer, integrin, antioxidant, interferon, xanthine derivative, growth hormone, neurotrophic factor, angiogenesis modulator, anti-VEGF antibody, prostaglandin, antibiotic, phytoestrogen, anti-inflammatory A pharmaceutical composition that is a compound or an angiogenic compound. The method of claim 20, wherein the second active agent is thalidomide, vertoforpine, furritin, hemostatic steroid, rhuFab, interferon-2α or pentoxyphylline, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof Pharmaceutical composition.