TW200423936A - Methods of using and compositions comprising immunomodulatory compounds 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 an immunomodulatory compound, 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

200423936 发明 Description of the Invention: This application claims the rights and interests of US Provisional Application No. 60 / 422,899 filed on October 31, 2002, the contents of which have been fully incorporated herein by reference. [Technical field to which the invention belongs] The present invention relates to a method for treating, preventing and treating macular degeneration (MD) and related syndromes, which comprises administering an immunomodulatory compound, which can be administered alone or in combination with known therapies. The invention also relates to medicinal compositions and medications. In particular, the invention includes the use of immunomodulatory compounds in combination with surgical intervention and / or other standard therapies for macular degeneration. [Previous Technology] 2.1 Pathology of Macular Degeneration Macular Degeneration (MD) is an eye disease that damages central vision by harming the macula. The macula is part of the retina and is a thin layer of nerve cells located mainly inside the eyeball. The nerve cells in the retina detect the light and send it to the brain to tell the brain what the eyes see. The macula is close to the center of the retina behind the eyeball, and the animal uses it to focus on what is in front of it. Get the clear center image. The rest of the retina provides side (peripheral) images. There are two types of MD: atrophic ("dry") and exudate (,, wet).

Eva, P.5 Eye5 in Current Medical Diagnosis and Treatment, 41 ed_ 210-21 1 (2002). 90% of patients are dry. Only 10% are wet. However, up to 90% of wet patients may be blind. DuBosar, R., Jof Ophthalmic Nursing and Technolgy, 18: 6-64 (μ%). Patchy degeneration causes choroidal neovascularization (CNVM) and / or geometric atrophy of retinal pigment epithelium (RpE) in eyes with choroidal warts. Bid, 89178 200423936 A.C., Surv. 0phtham 01 39: 367 74 (i995). Choroid minor warts are round white-yellow dots located in the basement outside the neural retina. Other symptoms of md include RPE dissection (PED) and discoid scar tissue under the macula.

Algvere, P.V., Acta Ophthalmologica Scandinavica 80: 136-143 (2002). Choroidal neovascularization is a problem related to a variety of retinal diseases, but it is still mainly related to MD. CNVM is characterized by abnormal blood vessels growing from the choroid (the vascular-rich tissue layer immediately below the retina) to the retinal layer. These new blood officials are extremely fragile and easily rupture, causing blood and body fluids to flow into the retinal layer. When the blood vessel leaks, it will interfere with the precise retinal tissue, which will cause vision damage. The severity of its symptoms depends on the size of the CNVM and how close it is to patches. The patient's symptoms may be very mild, such as blurred vision or visual field distortion 'or more severe, such as a central blind spot. Patients with choroid warts and possibly pigmented abnormalities but without CNVM or geometric atrophy are usually diagnosed with age-related macular degeneration (Arm). See above. The histopathological features of the arm and MD are a continuous gradation of fine particles inside the Bruch's membrane at the base of the rpe cell. Sarks, J.P., etal., Eye2 (Pt.5): 5 52_77 (198 8). These basal deposits are considered to be the result of continuous RPE phagocytosis or accumulation of waste from the outer layers of photoreceptors. Basement deposits cause the Bruch membrane to deplete and reduce permeability. Youfan said #tolerance ’decreased water permeability combined with damage to the nutrient exchange in the scrotum, accumulating water, and promoting the development of soft choroidal fatigue and pED, which eventually caused RPE cells to shrink. See above. However, the current overall understanding of arm and MD pathology is not complete, Cour,%, et al > 5 Dl > ugs 89178 200423936

Aging 19: 101-133 (2002) 〇 Because MD occurs in old age, this ethnic group grows fast, so MD becomes a major economic and social issue. Macularity is the most common cause of vision loss in people over the age of 60 in developing countries. Macular degeneration makes! 700,000 Americans have lost sight, and another 11 million are in danger. DuBosar, R, j 〇f 〇phthaimic

Nursing and Technology, 18: 60-64 (1998). There is no known cure. Rhoodhooft, J., Bull. Soc. Beige Ophtalmol. 276: 83-92 (2000). Therefore, there is an urgent need for an effective treatment ... ^. 2.2 Treatments for age-related macular degeneration Until now, the 'laser-induced coagulation method is the only treatment routinely used for Md, which only provides a moderate therapeutic effect. Laser photocoagulation is a type of laser surgery that uses a focused beam to burn small areas of the retina and abnormal blood vessels beneath the macula. Cauterization causes scar tissue and seals blood vessels to keep the underside of the macula from leaking. Laser photocoagulation is effective only for patients with wet type] ^ 〇 In addition, laser photocoagulation is only available to about 13% of their patients. Joffe, L. et al., International Ophthalmology Clinics 36 (2): 99-1 16 (1996). Laser photocoagulation does not cure wet MD, but it sometimes slows or prevents central vision loss. However, without treatment, vision loss due to wet MD will continue to develop until the patient's residual vision is lost. The most serious disadvantage of laser surgery is that it can damage some of the macular nerves that react with light and cause some vision loss. Occasionally, vision loss due to surgery is as severe or more severe than untreated vision loss. However, some patients have worse vision in the initial period after laser surgery, but can prevent vision deterioration over time. Verteporfin has recently been used to treat wet MD. Cour, M,: Heart Drugs Aging 19: 101-133 (2002). Fitphen is a blood's official blocking photoreactive dye, which is administered via injection. The dye migrates to blood vessels that cause vision loss, and is activated by non-cauterizing flashes that enter the eye in the presence of oxygen. Fettphene is mainly delivered to humans via lipoproteins. ^ Fettphene produces extremely reactive, short-lived monooxygen and reactive milk: the base's cause local damage to the neovascular endothelium. As a result, the blood vessels are closed. It is known that the injured endothelium will pass lipid-oxidase (leukotriene) and epoxidation, and (metabolism-like acids such as prostastin) releases procoagulant and angiogenic factor I, causing platelets to coagulate and form blood. Fibrin clot and vasoconstriction. Fitphen seems to tend to accumulate in new blood vessels, including choroidal new blood vessels. However, the animal model shows that Fitterfin will also accumulate in the retina. "Therefore, the administration of Fitterfin may damage the retinal structure, including the retinal pigment epithelium and the outer nuclear layer of the retina." Another type currently used to treat MD Methods: Drug-resistant anti-angiogenic therapy. Corn., M., et al., Drugs Aging 19: 101-133 (2002). However, the first anti-angiogenic agent: interferon- Clinical trials of 〇〇 are not effective in treating MD and have a high degree of side effects. Arch 〇phthalm〇i ΐ 5: 865-72 (1997). Intravitreal injection of triamcin〇ne is said to inhibit thunder in monkeys Radiation-induced CNVM, but cannot prevent patients from severely losing vision within one year in randomized trials. Gillies, Mc, et al, Invest

Ophthalmol. Vis. Sci · 42: S522 (2〇〇υ. Many other antiangiogenic agents 89178 200423936 Zengle has reached different stages of development for patients with MD, including vasostatic steroids (eg, Ankerta acetate (Anecortave acetate), Alcon Pharmaceuticals) and vascular epithelial growth factor (VEGF) antibodies or fragments thereof. Guyer, DR., Et al., Invest. Ophthalmol. Vis. Sci. 42: S522 (2001). One of the VEGF antibodies RhuFab. Other new drugs for MD include EYE101 (Eyetech Pharmaceuticals), LY33353 1 (Eli Lilly Pharmaceuticals), Miravant and Retisert Implants (Bausch &

Lomb), which allows steroids to penetrate the eyes for up to three years. Although new and effective therapies for MD and related macular degeneration are being explored, there are no effective treatments. Therefore, there is a need in the art for an effective treatment for MD. 2-3 Immunomodulatory Compounds Some compounds have been explored for their ability to strongly inhibit TNF_a production by stimulating PBMCs with LPS. l.G. Corral, et al., Ann. Rheum. Dii

58: (Suppl I) li07_1U3 (1999). These compounds are called & IMiDsTM (Celgene) or immunomodulatory drugs, which not only strongly inhibit TNF-α, but also significantly inhibit the production of monocytes induced by LPS. LPS-induced IL6 is also suppressed by immunomodulatory compounds, but only partially. These compounds are potent stimulators of IL10 induced by LPS. See the literature above. [Summary of the Invention] The present invention includes a method for treating and preventing MD, which comprises administering to a patient in need thereof a medically or prophylactically effective amount of an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, Hydrates, stereoisomers, clathrates 89178 200423936 hydrates or prodrugs. The present invention also includes methods of treating MD (eg, prolonged remission days), which includes administering to a patient in need of such treatment an immunomodulatory compound or a pharmaceutically acceptable salt, fusion thereof that is medically or prophylactically effective Compounds, hydrates, stereoisomers, clathrates or prodrugs. Another specific embodiment of the present invention includes an immunomodulatory compound or a commercially acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and other suitable Combination of agents for treating or preventing MD, such as (but not limited to): steroids, photosensitizers, integrins, antioxidants, interferons, lutein derivatives, growth hormone, neutrophil factor, neovascularization Modulators of action, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds, or combinations thereof. Another embodiment of the present invention includes a method for treating, preventing, or treating MD, which comprises administering to a patient in need thereof a medically or prophylactically effective amount of an immunomodulatory compound or a pharmaceutically acceptable salt thereof, and a fusion Compounds, hydrates, stereoisomers, clathrates or prodrugs, in combination with therapies traditionally used to treat or prevent MD, such as (but not limited to): surgical interventions such as: laser-induced / kink Therapy and photodynamic therapy). -The present invention also includes pharmaceutical compositions, single-unit dosage forms and kits suitable for the treatment, prevention and / or treatment of MD, which comprise immunomodulatory compounds or pharmaceutically acceptable salts, solvates, hydrates thereof , Stereoisomers, clathrates or prodrugs. [Embodiment] The first-specific embodiment of the present invention includes a method for treatment and prevention, which includes 89178 -10-200423936, including administering to patients in need (for example, a therapeutic or prophylactically effective amount of immune animals such as humans). And medical class, human-friendly, or sexually acceptable compounds or pharmaceutically acceptable. The right isomers, dragon-shaped inclusion compounds or prodrugs of the present invention include (but are not limited to, m dMD and related diseases; the first method, aging has I dry type) MD, leak type ( Wet type), aging-related plaque degeneration (arm retina $ I), pulse, ..., 血 new blood organ formation (CNVM), visual acuity, and membrane epithelium detachment ^ ^ ^ Atrophy (RPE). = So: The term "macular degeneration" or "help" includes sexual diseases regardless of the patient's age, but some macular degeneration diseases are more common in certain years :; · (Shovel in patients under 7 years old); Stargardt's (stargardt, s,) juvenile plaque dystrophy or basal macula (most common in people aged 5 to 20 years), Bell's disease ⑺ ^^ € Ca 6), Swsby (s ^ sease), Downey's disease (Doyne, s heart calyx or honeycomb dystrophy (first seen in, spoon 30 to about 50 years old) Patients); macular degeneration associated with aging (most commonly in patients around 60 years of age or older). The causes of MD include (but are not limited to): genetics, physical trauma, diseases such as diabetes, malnutrition and infections, such as bacterial infections (E.g., leprosy, specifically ENL >. Another specific embodiment of the present invention includes a method of treating MD, which comprises administering a prophylactically effective amount of an immunomodulatory compound or a medicament to a patient in need of such treatment. Acceptable salts, solvates, hydrates, stereoisomers Shaped inclusion compound or prodrug. Another specific embodiment of the present invention includes a pharmaceutical composition comprising 89178 • 11-200423936 immunomodulatory compound compound, stereoisomer carrier. Salts, lysates, water, cage-opening clathrates or prodrugs, and optionally the present invention also includes a single unit dosage form, which contains immunomodulatory compounds or: pharmaceutically acceptable salts, solvents Compounds, hydrates, stereoisomers, i-shaped clathrates, or trioxane, and optional carriers as needed. Another specific embodiment of the present invention includes _ species of sets, which include ... Or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The present invention also includes a kit comprising a single unit dosage form. The present invention Included kits, and may contain other active agents. Specific kits include Amsler grids suitable for the detection or diagnosis of MD. Without being limited by theory, believe in certain immunomodulatory compounds With others that can be used to treat MD The medicine can treat or treat MD in a complementary or stimulating manner. Therefore, 'a specific embodiment of the present invention includes a method for treating, preventing and / or treating MD', which includes administering medical treatment to patients in need: A prophylactically effective amount of an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof: a second active with a medically or prophylactically effective amount Examples of the second active agent include (but are not limited to) agents traditionally used to treat or prevent MD, such as: steroids, photosensitizers, integrins, antioxidants, interferons, yellow-voxelin derivatives, growth hormones ,% Neutrophilic factor, regulator of new blood-forming effects, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds, 89178-12-200423936, others can be found in, for example, Physieian, s Desk Ref 咖 _ 中 中药: Specific examples of 帛 a active agents include (but are not limited to) Fettven, PUrlytin, angiostatic steroids, rhuFab, interferon_ 2α, integrin, antioxidants and pentoxifylline. The present invention also includes pharmaceutical compositions, single unit doses, types, and kits, including immunomodulatory compounds or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, and clathrates thereof. Or a prodrug with a second active agent. For example, the kit may contain a compound of the present invention and a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a yellow throat derivative, a growth hormone, a neutralizing agent: a hematopoietic factor, a regulator of neovascularization, Anti-bile anti-Blestone, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-blood = amplifying compounds' or combinations thereof, or other pleasures that can relieve or alleviate symptoms. It is believed that certain immunomodulatory compounds can reduce or eliminate the side effects associated with the administration of pharmaceuticals, in order to improve the dosage to patients and / or improve the patient's adaptability. Therefore, other specific embodiments of the present invention include a method for transferring, reducing, or avoiding MD patients related to receiving the first: active agent administration = effects include administering a medically or prophylactically effective amount of an immunomodulatory compound to patients in need Or a pharmaceutically acceptable salt, hydrate hydrate, stereoisomer, clathrate or prodrug thereof. As discussed elsewhere in this article, MD symptoms can be treated with surgical interventions such as (but not limited to) light or laser therapy, radiation therapy, retinal pigment epithelial transplantation, and omental center displacement. Without being bound by theory, it is believed that the combination of these traditional therapies with immunomodulatory compounds is 89178-13 · 200423936. At the same time, the present invention includes a method for treating, preventing and / or treating MD, It includes administration of immunomodulatory compounds or their pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates before, during, or after surgical intervention or other traditional non-drug therapy. Or prodrug. 4.1 Immunomodulatory compounds The compounds used in the present invention include racemic, high stereoisomeric or pure stereoisomeric immunomodulatory compounds and their pharmaceutically acceptable salts, solvates, hydrates , Stereoisomers, clathrates and prodrugs. The compounds more suitable for the present invention are small organic knives having a molecular weight of less than about 500,000 to 1 and are not protein, belly, riboic acid, oligosaccharides or straight macromolecules. As used herein and unless otherwise indicated, the composition contains one stereoisomer of the compound and is substantially free of the other stereoisomer of the 1 compound. For example: a compound with a pure stereo :: The pure stereoisomer composition of a compound does not substantially contain the relative i-enantiomer of the compound. The pure stereofluorene composition of a compound with two opposing centers is essentially free of other diastereomers of the compound. A typical 'stereoisomeric compound contains about 80% by weight or more of the compound, a' stereoisomer ', and about 20% by weight or less of the compound: ⑴ ⑴' is more preferably about 90% by weight Among the above compounds, one kind of ... structure 'and other stereoisomers of the compound below about 10% by weight; more preferably about 95% by weight of one of the compounds in the stereostructure 4, =: weight . "Other stereoisomers of this compound. The best is $ y / weight 3: more than the compound of this compound Φ ^ 籾 籾 具 具 with one of the stereoisomers, and about 3 weight 1 89178 -14- 200423936 % The following other stereoisomers of the compound. As used herein and unless otherwise stated 'the term " high stereoisomerism' refers to the composition: one of the stereoisomers containing about 60% by weight or more of the compound The "soil" is about 70% by weight or more, and more preferably about one of the stereoisomers of the compound. As used herein and unless otherwise stated, the term, purely enantiomeric "refers to the pure stereoisomeric composition of a compound having a solid center of palmity.

"Enantiomerism" refers to a highly stereoisomeric composition of a compound having an antagonism center. As used herein and unless otherwise specified, the term f, immunomodulatory compound "or" IMiDsTM "( Celgene Corporation, NJ) includes small organic molecules that significantly inhibit the production of TNF_a and LPS-induced monocytes IL1 ^ 12 and partially inhibit 乩 6. Specific immunomodulatory compounds are described below. TNF-α is a compound Inflammatory cytokines produced by macrophages and monocytes during acute inflammation. TNF-α is responsible for a variety of signal responses in cells. Without being limited by theory, the biological effect of specific immunomodulatory compounds is to reduce TNF_a synthesis. Specificity Immunomodulatory compounds can enhance the degradation of TNF-amRNA. Without being limited by theory, the immunomodulatory compounds used in the present invention can also be powerful co-stimulators of T-cells, which can greatly increase cell proliferation with dose changes. Immunity Regulatory compounds also have a greater co-stimulatory effect on CD8 + T cell subpopulations than on CD4 + T cell subpopulations. Exact examples include (but are not limited to): substituted cyano and carboxy derivatives of Benzen, such as: those disclosed in US Patent 89178-15-200423936 No. 5,929,117; i • oxo_ 2_ (2,6_dioxo_3_fluorohexaaza0-3-yl) isoindoline and 丨, 3_dioxo_2_ (2,6_dioxo_3_fluorohexahydropyridine -3-yl) isoindoline, such as: they are disclosed in US Patent Nos. 5,874,448 and 5,955,476; the tetra-substituted 2_ (2,6_dioxohexahydropyridine_3_yl) Berberyl isoindolino, as described in U.S. Patent No. 5,798,368; ^ oxo and 1,3-dioxo-2- (2,6-dioxohexahydropyridine_3_yl) isoindole Indoline (for example: 4-methyl derivative of thalidomide and eM-12), including (but not limited to): they are disclosed in US Patent Nos. 5,635,5 i7 and 6,403,613; indole Substituted ^ oxo and 丨,% dioxoisoindolinoline at the 4- or 5-position of the ring (for example: 4- (4-amino-1,3-dioxoisoindolinoline-2-yl ) -4-aminoformamidine butyric acid), which is described in US Patent No. 6,38,0,239, 2-position via 2,6-monooxo-3-via hexa The difference between p and σ is -5 -group substitution. Introduce sigma-dolin and isoindoline _ 丨, 3_dione (for example: 2_ (2,6_dioxoyl-5-fluorohexahydropyridine- 5-yl) -4-aminoisoindololine-1 -one), which is described in US Patent No. 6,458,810; a non-peptide cyclic amidine, which is disclosed in US Patent Nos. 5,698,579 and 5,877,200; Analogs and derivatives of thalidomide, including hydrolysates, metabolites, derivatives and precursors, as disclosed in U.S. Pat. Nos. 5,593,99, 5,629,327 and M7 1,948 (issued to D1 Amato ); Aminosalidomalide and its analogs, hydrolysates, metabolites, derivatives and precursors with substituted 2- (2,6_dioxohexahydro? Ratio ° -3-yl) @ 太 随 EImine and substituted 2- (2,6-dioxohexahydroxanthidine-3-yl) -1-oxoisoindole, as described in U.S. Patent Nos. 6,281,230 and 6,316,471; and isoindoleimine compounds, such as: they are described in U.S. Patent Application η 09 / 972,487 (October 5, 2001, 89178-16) -200423936 application), U.S. Patent Application No. 10 / 032,286 (filed on December 21, 2001) and International Application No. PCT / US01 / 50401 (International Publication No. WO 02/05 9106) By. The disclosures of each patent case and patent application specified herein are incorporated herein by reference in their entirety. Immunomodulatory compounds do not include thalidomide. Other specific immunomodulatory compounds include (but are not limited to) ... 1-oxo- and 1,3 dioxo_2_ (2,6_dioxohexahydropyridine- 3-yl) isoindoline, which is described in the U.S. patent, the disclosure of which is fully incorporated herein by reference. These compounds have the structure I:

One of X and Y is C = 〇, the other of X and γ-and R2 is hydrogen or a lower carbon number alkyl group, specifically the nail beauty compounds include (but are not limited to): one is C = 0 or CH2 ,. Definitive immunoregulation-Lice generation_2_ (2,6-dioxohexahydropyridine- 2- (2,6-monooxohexahydropyridine 1-oxo-2_ (2,6-dioxo Hexahydropyridine 1-oxo_2_ (2,6-dioxohexahydropyridine L3-dioxo-2- (2,6-dioxohexaminyl-yl) -4-aminoisoindoleline ; -Yl) -5-aminoisoindoline; -yl) -6-aminoisoindole π-droline; 'yl) -7-aminoisoisomer | σdorpyl; ) -4-Aminoisoindoleline. Milk generation (2,6--lactation hexapyridin-3-yl) -5-aminoisoindole 89178 -17- 200423936 Other clear immunomodulatory compounds belong to a substituted 2_ (2,6_ dioxo Hexahydropyridin-3-yl) phthalimide and substituted 2_ (2,6_dioxo /, hydropyridin-3-yl) -1-oxoisoindole, as described in the United States Patent Nos. 6'281'230 '6'316,471; 6,335,349; and 6,476,052 and International Patent Application No. PCT / US97 / 13375 (International Publication No. wo 98/03502), the disclosures of which are respectively cited by reference This approach is fully incorporated into this article. Such representative compounds are as follows:

Wherein R1 is fluorene or methyl. In another embodiment, the invention includes the use of pure enantiomeric forms of these compounds (e.g., pure optical (R) or (S) enantiomers). Other clear immunomodulatory compounds belong to the class of isoindoleimines, which are disclosed in U.S. patent applications nos. 10 / 〇32,286 and 09 / 972,487, and National Application No. PCT / US01 / 50401 (International Publication No. W089178-18-200423936 〇2 / 〇591〇6), the disclosure of which has been fully incorporated herein by reference. Its representative compound is as follows:

Instead of its pharmaceutically acceptable gi to g. Λ according to the salt hydrazone, hydrate, solvate, clathrate, enantiomer, diastereomer Rizo. F 了 呀 吴 structure, A mixture of #Rotary and its stereoisomers, where: one of X and Y is (> 〇, the other is decanted or (: >〇; R1 is h, (Ci-c8) alkyl, c3_C7) cycloalkyl, (cvc8) dialkynyl, benzyl, aryl, (c0_C4) alkyl_ (Ci_D heterocycloalkyl, alkyl_ (C2_C5) heteroaryl, C (0 ) R3, c (s) r3, c (〇) 〇r4, (C1-C8) alkyl-N (R6) 2, (Cl-C8) alkyl-0R5, (Cl_c8) alkyl_c (〇) 〇r5 , C (〇) NHR3, C (S) NHR3, C (0) nr3r3 ', c (s) nr3r3, or (Ci C8) alkyl_0 (C0) R5; R2 is H, F, phenylfluorenyl , (Ci-Cs) alkyl, (c2_c8) alkenyl, or (C2_C8) alkynyl; R3 and Rv are independently (CVC8) alkyl, (CVC7) cycloalkyl, (C2_C8) alkenyl, (c2- c8) fastyl, phenylfluorenyl, aryl, (c0_c4) alkyl_ (Ci C6) heterocycloalkyl, (C0-C4) alkyl- (C2-C5) heteroaryl, (cq- c8) alkyl-N (R6) 2, (Ci-Cs) alkyl-OR5, (Ci-Cs) alkyl-C (〇) 〇5, (Ci-C8) alkane Radical-0 (C0) R5 or C (0) 0R5; R4 is (Ci-Cs) alkyl, (C2-C8) diluted, (c2, c8): ^, (CVC4) :): END 89178- 19- 200423936 group-OR5, benzyl, brass (C0-C4) alkyl_ (c2-C5) / aryl; 04) alkylcycloheteroxyl or R5 is (CVC8), and (C2_C8 ) Alkyl, f aryl or (c2-c5) heteroaryl; A) alkynyl, benzene f, each occurrence of R6 is independently H, ir r wr r ^, rC8) alkyl, (c2- c8) Alkenyl (c2-c8) bulk, benzyl, aryl M T? 5+ _ 5 miscellaneous or (CQ-C8) alkyl C (0) 〇_R μ groups can be combined to form hetero Cyclic radical; η is 0 or 1; and soil * represents a palmar carbon center. Specifically, in the compound of formula Π, when it is called, R ^ (C3_C7) cycloalkyl, (c2-c8) alkenyl, (C2-C8) alkynyl, benzyl, aryl, (c0_c4) alkyl -(G-C6) heterocycloalkyl, (c0_c4) morpho_ (CVC5) heteroaryl, c⑼r3, C (〇) OR4, (Cl-C8) alkyl_n (r6) 2, (Ci_C8) alkyl-〇r5, (C1_C8) alkyl-C (0) OR5, C (S) NHR3, or (Ci C8) alkyl_〇 (c〇) r5; R is H or (Ci-Cg ) Alkyl; and R is (C ^ Cs) alkyl, (C3-C7) cycloalkyl, (C2-C8) alkenyl, (C2-C8) fastyl, phenylfluorenyl, aryl, (C0-C4 ) Alkyl- (Cl-c6) heterocycloalkyl, (CVC4) alkyl_ (C2-C5) heteroaryl, (C5_c8) alkyl-N (R6) 2; (cvc8) alkyl-NH-C (〇) 〇-R5; (Ci-Cs) alkyl-OR5; (CpCO alkyl-C (〇) 〇R5; (Ci-C8) alkyl-0 (C0) R5 or C (〇) 〇R5, The other codes are the same as defined above. In other compounds of the formula II, R2 is fluorene or (Ci-CJ alkyl. In other compounds of the formula II, R1 is (Ci-Cs) alkyl or phenylfluorenyl. Others In the compound of formula II, R1 is fluorene, (C ^ Cs) alkyl, benzyl 89178-20-200423936, ch2och3, ch2ch2och3 or compound of formula II Another embodiment, R1 is R7 R7

Wherein Q is 0 or S, each occurrence of R7 is independently Η, (Ci-CJ alkyl, benzyl, CH2OCH3 or CH2CH2OCH3. In other compounds of formula II, R1 is C (0) R3. Others are clear In the compound of formula II, R3 is (C ()-C4) alkyl- (c2-c5) heteroaryl, (Ci-Cg) alkyl, aryl, or (C0_C4) alkyl-OR5. Others In the compound of the specific formula II, the heteroaryl group is pyridyl, furyl or pyrenyl. In other compounds of the specific formula II, R1 is C (0) 0R4. Among the other compounds of the specific formula II, C (0) NHC (0) can be replaced by (CVC4) alkyl, aryl, or benzyl groups. Other definite immunomodulatory compounds belong to an isoindoleimine class, which is disclosed in US Patent Application No. 09/78 ^ 7 ^ International Publication No. WO98 / 54i70 and U.S. Patent No. 6,395,754, the disclosures of which have been fully incorporated herein by reference. Representative compounds are as follows:

ΠΙ 89178 -21-200423936 and its fc · pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates and their stereoisomers A mixture of substances, wherein: one of X and Y is c = 0, the other is 〇112 or 〇〇, R is Η or CH20COR ,; (1) each R, R, R3 or R4 independently halo, 1 An alkyl group of 4 carbon atoms or an alkoxy group of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 or R4 is nitro or _NHR5, and the remaining R1, R2, R3 or R4 is hydrogen Is hydrogen or an alkyl group of 1 to 8 carbon atoms; R6 is chlorine, an alkyl group of 1 to 8 carbon atoms, benzoyl, chlorine or fluorine; R 'is R7-CHR10-N (R8R9); R7 is M-phenylene or p-phenylene or _ (CnH2n)-, where the value is 0 to 4; each R and R9 is independently hydrogen or an alkyl group of 1 to 8 carbon atoms, or 8 and R9 together form a four Methylene, pentamethylene, hexamethylene or 弋 h2Ch2 [x] XiCH2CH2 'where [X] Xi is -0-, -S- or -NH-; R10 is hydrogen, 1 to 8 carbon atoms Alkyl or phenyl; and * represents a palmar carbon center. The best immunomodulatory compound is 4_ (amino) -2- (2,6-dioxo (3-hexahydropyridyl))-isoindololine- 丨,% dione and 3- (analamine The basic oxo group, 3-dihydro group, hexahydropyridinyl group, hexahydropyridine group, 2-dione. This compound can be prepared via standard synthetic methods (see, e.g., U.S. Pat. No. 5,635,5 17, which discloses that the valley is fully incorporated herein by reference). The chemical structure of 4- (amino) _2_ (2,6-dioxo (3-hexahydrotolyl)) _ isoindole · 丨, 3-dione (actimidTM) 89178 -22- The structure is as follows * :

Amino small oxo 4 3 one two two dicaffeine, the chemistry of the :: configuration, two two 2: yl) hexahydro ..., 6-

The compounds of the present invention can be purchased from commercial products. U_ 从 ， 丄 厶 〇 木 所 is Ling I prepared. In addition, pure optics, soil-enterment, and shangyuzhuang compounds can be prepared by asymmetric synthesis 30% or using a known resolving agent A pair of fist columns and other standard synthetic organic chemistry techniques. 〇 As used herein and unless otherwise stated, a Θ, the term "pharmaceutically acceptable salts" includes non-toxic acids and base addition salts of the compounds referred to in the term ° acceptable non-toxic acids Addition salts include organic and inorganic acids or salts derived from known techniques, including, for example, hydrochloric acid, nitrous acid, linolenic acid, sulfuric acid, formic acid, acetic acid, acetonitrile , Tartaric acid, lactic acid, succinic acid, citric acid, picolinic acid, maleic acid, sorbic acid, aconitic acid (ticacid), salicylic acid, g taric acid, pamoic acid, heptanoic acid, etc. It is acidic in nature The compounds can form salts with a variety of pharmaceutically acceptable bases. The pharmaceutically acceptable base addition salts that can be used in the preparation of these acidic compounds are bases that can form non-toxic bases such as salts, That is, medicine containing 89178 -23- 200423936 :: cation: cation salts, such as ... (but not limited to) alkali metal or alkaline earth salts' specific H sodium or potassium salts. Suitable organic tests include ( But not limited to ...- diphenylinylethylenediamine, chloroprocaine, bile test, Yihui, 7 mu 1 amine, methyl glucosamine (N-methyl glucosamine), _ amino acid and procaine. As used herein and unless otherwise stated, the term "anterior" means that it can be used in Biological conditions (in vivo or in vitro) under hydrolysis, oxidation or other reactions to produce derivatives of the parent compound. Examples of prodrugs include (but are not limited to): biohydrolyzable groups such as · 可Immune regulation of biohydrolyzed amidines, biohydrolyzable esters, biohydrolyzable carbamic acid vinegars, biohydrolyzable carbonic acid moieties, biohydrolyzable ureas, and biohydrolyzable phosphate analogs Biology of biological compounds. Examples of other prodrugs include derivatives of immunomodulatory compounds containing _N〇, _n〇2, _〇NO, or -〇N〇2 partial groups. These prodrugs are mainly used Prepared by known methods, as described in i Burger, s Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (edited by Manfred E. Wolff, 5th edition, 1995), and Design 〇f Prodrugs (edited by Η · Bundgaard , Elselvier, New York 1 985). The terms "biohydrolyzable amidoamines", "biohydrolyzable esters", "biohydrolyzable amidoamines", and "biobiohydrolyzable carbonates", unless otherwise stated, Type "," biohydrolyzable ureas "and" biohydrolyzable phosphates "refer to the compounds amines, esters, amino acids, carbonates, ureas, or phosphates, respectively. The compound ·· 丨) does not interfere with the biological activity of the compound, but imparts beneficial in vivo properties to the compound, such as 89178 -24- 200423936. Absorptivity, duration of action or time of onset of action; or 2) no biological activity, but can be In vivo conversion into biologically active compounds. Examples of biohydrolyzable esters include (but are not limited to): low carbon number alkyl vinegars, low carbon number alkoxy ^ alkyl vinegars (such as: acetamidine, acetamidine ethyl acetate, aminocarbonyl Oxymethyl ^ purpose, pentamidine oxymethyl vinegar, pentamidine oxyethyl brewing), lactone-based vinegar (such as: phthaloacetate and thiophthaloyl ester), low-carbon alkoxy alkoxyalkyl ester ( For example, methoxycarbonyl ^ methyl ester, ethoxyquinyloxyethyl and isopropyloxyphenyloxyethyl (§1), makorin vinegar, cholestyramine and amidinoyl group sl (such as acetamidine) Aminomethyl § intent). Examples of biodegradable amidoamines include (but are not limited to): low carbon number alkylamidoamines, amidoamidoamidoamines, oxoamidoamidoamines, and alkanylaminoalkylamino amines. Examples of biohydrolyzable urethanes include (but are not limited to): low carbon number amines, via: ethylenediamine, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines and Polyetheramines. Fang Yuexian understands that if the structural formula shown does not match the specified name, the structural formula will be the main one. In addition, if the stereo-part of the structural formula is not represented by, for example, a thick line or a dashed line, the result = = of the formula: the part will include all its stereoisomers. I structure 4.2 even two live materials ^ No .: active radiation and ㈣iH ± compound to make patients comfortable, anti-angiogenic effect or anti-inflammatory effect, or two examples of two live agents include (but not limited to): steroids, Photosensitizers, sensitizers, interferons, lutein derivatives, growth hormone 89178 • 25-200423936 Neutrophil, regulator of neovascularization, anti-VEGF antibodies, prostaglandins, antibiotics, plants Estrogen, anti-inflammatory compounds, anti-hematurinary amplification compounds, other agents known to inhibit or relieve MD symptoms, and their pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, i-shaped inclusions Substances, prodrugs and pharmaceutically active metabolites. In some specific embodiments, the first sigma agent is phenoxyphene, purlytin, vasodilator, and alcohol. The interferon-2α or hexag is the same as cocoa (pentoxifyiHne). ). Examples of photosensitizers include, but are not limited to, phentermine, tin etiop Urpurin, and motexafin iutetium. Fitphen is used to treat wet MD. Cour, M., et al., Drugs Aging 19 ·· 10b 133 (2002). Fett is classified as a vascular blocking photoreactive dye and can be administered via injection. Examples of derpurin derivatives include, but are not limited to, pentoxifylline. Anti-VEGF antibodies include (but are not limited to): rhuFab. Examples of steroids include, but are not limited to, 9i_u, 21_dihydroxymethylethylenebis (oxy) pregnant_M_diene_3,2__dione. Examples of derivatives of uracillin F] a include (but are not limited to): iatan〇pr〇st (see U.S. Patent No. 6,225,348, the disclosure of which is fully incorporated herein by reference) . Examples of antibiotics include (but are not limited to): tetracycline and its derivatives, dfamycin and its derivatives, macrolides and metronidazole (see U.S. Patent Nos. 6,218,369 and 6, 〇15,8 () 3 'The content of this disclosure has been fully incorporated into this text by reference). Examples of phytoestrogens include, but are not limited to: genistein, genistein 89178 -26- 200423936 glucosides, 6'-0-Mal genistein, 6f-〇-Ac genistein, lignin isoflavones, daidzein (Daidzin), heart ~ ... "daidzein, 6, _〇Ac daidzein, daidzin, glycidin, 6'_mal Maldoxin, biochanin A, Anthocyanin and its mixture (see U.S. Pat. No. 6,001,368, the disclosure of which has been fully incorporated by reference herein) Examples of Xiao tablets include (but are not limited to) ) Triarncinolone and dexamethasone (see US Patent No. 5,770,589, the disclosure of which is fully incorporated herein by reference). Amplifying compounds include (but are not limited to): Salidomide and selective cytokine inhibitory drugs (SelCIDsTM Celgene corp., Nj). Examples of interferons include (but are not limited to): interferon_2 (χ In another specific embodiment, the second active agent is glutathione ( See U.S. Patent No. 5,632,984, the disclosure of which is fully incorporated herein by reference.) Examples of growth hormones include (but are not limited to): basic fibroblast growth factor (bFGF) and transforming growth factor b ( TGF-b). Examples of neutrophilic factor include (but not limited to): brain-derived neutrophilic factor (BDNF). Examples of modulators of neovascularization include (but not limited to) · type 2 fibrin Lysogen Activating Factor (PAI-2). Other drugs that can be used to treat MD include (but are not limited to): eye 1 〇1 (Eyetech Pharmaceutical Factory), LY33353 1 (EliLilly Pharmaceutical Factory), Miravant and Lily RETISERT implants (Bausch & Lomb Pharmaceuticals). 89178 -27- 200423936 4 · 3 Methods of prevention ^ This month contains methods to prevent, treat, and / or manage multiple MDs. As used herein, and Unless otherwise stated, the terms "prevention of MD", "treatment of MD", and "treatment of MD" include, but are not limited to, suppressing or reducing the severity of one or more symptoms related to investigations. Symptoms related to radon and Related symptoms T includes (but is not limited to) ·· Choroidal fatigue around white and yellow spots in the base, discoid necrosis tissue under the macula, choroidal neovascularization, retinal pigment epithelial detachment, retinal pigment epithelial atrophy, and from the choroid (close to the retina The vascular-rich tissue layer below) grows abnormal blood vessels, blurred vision or distorted vision, middle: blind spots, abnormal pigmentation, continuous deposition in Bruch, smembr—internal layers of fine-grained matter and Bruch membrane Thickness and reduced permeability. As used herein and unless otherwise stated, the term "treating md" refers to the administration of a compound or other active agent of the invention after the onset of symptoms of MD, where "prevention" means before the onset of symptoms (especially in patients at risk of MD) ) Dosing. Examples of patients at risk for MD include (but are not limited to): seniors over 60 years of age and sufferers such as (but not limited to): diabetes and leprosy (for example: £ 1 ^ 1 ^. MD Patients with a Dai history are also good candidates for preventive therapy. As used herein and unless otherwise stated, the term "treating MD" includes preventing the patient's MD from recurring and / or prolonging the duration of remission. The present invention includes Methods for the treatment, prevention and treatment of MD and related symptoms in patients with different stages and specific disease types, including (but not limited to): they are called dry MD, wet MD, age-related macular Degeneration (ARM), choroidal neovascularization (CNVM), retinal pigment epithelium detachment (PED), and retinal pigment epithelial atrophy (RPE). These further include treatments 89178 -28-200423936 to treat Patients with MD who have not responded to standard drugs and non-drug-based md treatment, and patients who have not received MD treatment in the past. Because md patients have many different clinical symptoms and different clinical results, the treatment of patients can be It varies with its prognosis. Clinical experts who are familiar with this technique can determine the specific second agent and the treatment method that can be used to effectively treat individual patients. Patients with MD are administered one or more immunomodulatory compounds or their pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or prodrugs. A specific implementation of this task In the example, the immunomodulatory compound is administered orally, which is administered in a single dose or in small doses within a day, the dosage is 10 to about 15 Gmg / day. In a specific embodiment, 4- (amino) 基(2, Bu = oxo (3-octahydropyridine)) _ isoindololine_ 丨, 3 • dione (AWmidTM) is about 0.1 to about 1, or every- About 0.1 to about 5 mg per day. Preferred embodiments The dosage of 3, amine-based small oxo ei, 3_m dongyi hexahydroepian-2,6-di- (RevimidTM) is about i to §, § or about 10 to about 50 mg per day. The treatment can last from about 2 to about 20 weeks, about 4 dollars a year, and Tian au 1 H for about 12 weeks, until the desired effect is achieved or it can be maintained chronically. 4-3 1 i 用 弟 二The group of live tinctures is the age-defining method of the present invention. Pregnancy # s administers the administration of an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, human skin ^ ,,,-物 水 5 Substances, stereoisomers, clathrates or uranium, and the second active .. _ _ 戍 active ingredient. Examples of immunomodulatory drugs are disclosed herein (dry moxibustion (see, for example, section 4.1); and examples of second active 89178-29-29200423936 are also disclosed herein (see section 4.2). The immunomodulatory compound administered to the patient and the second active agent component selected as needed can be administered sequentially in the same or different routes at the same time. The suitability of the specific administration route for the specific active agent depends on the active agent itself (for example: Whether it can be administered orally without breaking down before entering the bloodstream) depends on the disease being treated. The preferred route for administering an immunomodulatory compound is oral or ocular administration. The second active agent of the present invention The preferred route of administration is known to those skilled in the art. See, for example, Physicians, Desk Ref ^ en% 594-597 (56th edition, 2002). In a specific embodiment, the second active agent is Orally, intravenously, intramuscularly, subcutaneously, transmucosally, topically or transdermally, once or twice a day, the dosage is about (M mg to about 2,500 mg, about! Mg to about 2, _ mg, about 10 mg to about 1,500 mg, about 50 mg About 1,000 mg, about 100 mg to about 7500 mg 'or about 250 mg to about 500 mg. In another specific embodiment, the second active agent is weekly, monthly, bimonthly, or Dosing once a year. The specific dosage of other active agents depends on the specific agent used, the type of 2MD to be treated or prevented, the severity and stage of the disease, and the immunomodulatory compounds currently used by the patient and any other agents selected as needed. The amount depends on the amount. In a specific embodiment, the second active agent is a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthin derivative, a growth hormone, a neutrophil +, a new blood vessel formation Modulators of action, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds, or combinations thereof. 89178 -30-200423936 4.3.2 Surgical intervention-The present invention includes a treatment, A method for preventing and / or treating MD, which comprises administering an immunomodulatory compound or a pharmaceutically acceptable salt thereof, a soluble compound, a hydrate, a stereoisomer, a clathrate, or a prodrug. Drugs and use (for example: before, during, or after) surgical interventions. Examples of surgical interventions include (but are not limited to) light or laser therapy, radiation therapy, retinal pigment epithelium transplantation, and omental center displacement. Immunomodulatory compounds The combined use with surgical intervention provides a unique course of treatment that can bring unexpected results to some patients. Without being bound by theory, the belief that immunomodulatory compounds, when used in conjunction with surgical intervention, can provide a bonus In the specific embodiment of the invention, "the present invention includes a method for treating, preventing, and / or treating MD" which includes administering an effective amount of an immunomodulatory compound or a medicament to a patient in need thereof. Acceptable salts, solvates' hydrates, stereoisomers, clathrates or prodrugs, and use light or laser therapy. Examples of light or laser therapy include, but are not limited to: laser photocoagulation therapy or photodynamic therapy. Immunomodulatory compounds can be taken on the same day as a surgical intervention or sequentially. In the case of one member, the immunomodulatory compound is administered before light or laser therapy. In other specific embodiments, the immunomodulatory compound is performed after light or laser therapy. In a specific embodiment, the immunomodulatory compound is performed during light or laser therapy. The compound can be administered for at least 4 weeks before laser surgery at least 4 weeks, two weeks ago, ~ β, or immediately before surgery, at the same time, or after surgery 'for a total of about 12.6 weeks. 89178 -31-200423936 4 · 3 · 3 裒 Therapy In some embodiments, it is too patient. Circulation therapy involves "two! After the therapeutic agent is cyclically administered and / or the second agent-some days; ^ and 7Γ period of time, the administration of this cycle therapy can reduce its pair-species :: sub-repeat this continuous administration process Developed resistance by following the low I medium box anesthesia treatment to avoid or reduce the side effects of one of the two therapies and / or improve the treatment effect. Specific embodiments of the month φ ^ ^ ^ 〇_ ^ ^ t ^ Circulation, about 2 to about i. A cycle number T can be about 1 to about 12 oral quilts, or about 2 to about 8 cycles. 4,4 Houses and pharmaceutical compositions can be used in individual single unit dosage forms. This Hair, and compounds and dosage forms include immunomodulatory compounds or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or pharmaceutical compositions and dosage forms of the present invention. Contains one or more excipients. The pharmaceutical compositions and dosage forms of the present invention may also include one or more other active agents. Therefore, the pharmaceutical compositions and dosage forms of the present invention include the active agents disclosed herein (eg, immunomodulatory Sex compounds or pharmaceutically acceptable salts, solvates, hydrates, Stereoisomers, clathrates or prodrugs and a second active agent). Examples of other active agents selected as needed are disclosed herein (see, eg, Section 4.2). The single unit dosage form of the present invention is suitable for oral administration , Mucosa (for example: nasal, sublingual, vaginal, intrabuccal, or rectal), or parenteral (for example: subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), local (for example: eye Medicine 89178 -32- 200423936 water), eye, transdermal or transdermal injection to patients. Examples of dosage forms include (but are not limited to) ... lozenges; film-coated tablets' capsules, such as ... Capsules; sugar-coated tablets; buccal tablets; dispersed liquids; suppositories; powders; aerosols (such as nasal sprays or inhalants); eye drops; gels; suitable for oral or mucosal administration to patients Liquid dosage forms, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil emulsions), solutions and brews; liquid dosage forms suitable for parenteral administration to patients; and sterile solids (eg : Crystalline or amorphous solid) It can be reconstituted into a liquid dosage form suitable for parenteral administration to patients. The composition, shape, and type of the dosage form of the present invention mainly depend on its use. For example, a dosage form for acute treatment may include one or more active agents, which contains Here, the content of the dosage form used in the same disease for the treatment of AIDS is similar. Similarly, the content of one or more active agents in the parenteral dosage form can be lower than the content of the oral dosage form for the same disease. The difference between these and other means included in the invention is that those who know about this and other ways are those who are familiar with this technology. See, for example: Remington's Pharmaceutical…

Mack Publishing, Easton PA (1990). Typical pharmaceutical compositions and dosage forms include one or more excipients. Suitable excipients are known to those skilled in the art of pharmacy. Examples of suitable excipients are those provided herein. Whether a particular excipient is suitable for addition to a medical composition or dosage form depends on a variety of factors known to the relevant art, including (but not limited to) dosage form approval * + only market-oriented, . For example ... If a lozenge: The excipients contained in a dosage form may not be suitable for parenteral dosage forms. w The suitability of the disintegrant also depends on the specific active agent in the dosage form. For example: 89178 -33-200423936 can be extensively degraded by some excipients (eg lactose) or when exposed to water. Active agents containing primary or secondary amines are particularly susceptible to rapid degradation. Therefore, the pharmaceutical compositions and compounds included in the present invention include: in addition to early hearing or double hearing, may contain (if included) a small amount of lactose. As used herein The term "yichuan 丨 sugar ,, ## ,,", and the right amount of any lactose may not be sufficient to increase the degradation rate of the active agent on the babe. The lactose-free composition of the present invention may include related techniques Known excipients, 1 t ^ (US Pharmacopeia) (USP) 25-NF20 (2002) ^ general and g, the lactose-free composition contains a pharmaceutically compatible and pharmaceutically acceptable active ingredient, Binders / fillers, and lubricants. Preferred lactose-free "type containing agents, microcrystalline cellulose, pregelatinized powder and stearic acid. The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing active agents. Because $ f will promote the degradation of certain compounds. For example, the addition of water (eg: 5%) is a method widely accepted in medical technology for simulating long-term storage conditions to determine the shelf life or stability of formulations over time. Changes. See example Jens T. Carstensen, Drug Stability: Principles & Practice, 2d · Ed., Marcel Dekker, Nγ, ny, 1995, pp 379-8. In fact, water and heat will accelerate the degradation of certain compounds. Therefore, water pairs formulations The shadow ¥ is very important because moisture and / or humidity are often encountered during the manufacture, operation, packaging, storage, transportation and use of the formulations. The anhydrous pharmaceutical composition and dosage form of the present invention can use anhydrous or low water content Preparations, and conditions of low moisture and low humidity. When pharmaceutical compositions and dosage forms contain lactose and at least one active agent containing primary or secondary amines, they may be substantially encountered during manufacturing, packaging, and / or storage if possible When it reaches moisture, 89178 -34- 200423936 is best to be anhydrous. The preparation and storage of anhydrous pharmaceutical compositions should maintain its anhydrous nature. Therefore, 'anhydrous compositions are best packaged with known water-resistant materials so that and can include In the set of appropriate formulations. Examples of suitable packaging include, but are not limited to, sealed tin cases, plastic, unit-dose containers (eg, vials), blister packs, and The present invention also includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of active agent degradation. These compounds are referred to herein as "stabilizers" and include, but are not limited to, antioxidants, For example, ascorbic acid, pH buffers, or salt buffers. As with the use and type of excipients, the amount of active agent in the dosage form and the specific type may vary according to factors such as' Example # ·· The way of administration to patients However, a typical dosage form of the present invention comprises an immunomodulatory compound or a pharmaceutically acceptable salt thereof, a solvate, a hydrate, a stereoisomer, a clathrate or a curazone, and the amount is about 0. · 10 to about 150 mg. Typical dosage forms include immunomodulatory compounds or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs, and their content is about 0.1, 1, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, or 200 mg. In a specific embodiment, the preferred dosage form comprises 4_ (amino group) _2_ (2,6_ • monooxo (3- /, p ratio ° fluorenyl group))-iso 11 linden wood lin forest-1, 3-two g is the same (ActiniidTM), and its content is about 1, 2, 5, 5, 10, 25 or 50 mg. In the specific embodiment, the 'preferred dosage form contains 3- (4-amino_1-oxo], 3-dihydro-isoindol-2-yl) -hexahydropyridine-2,6 · dione (RevimidTM ) And its content is about 1, 25, 5, 10, 25 or 50 mg. A typical dosage form contains a second active agent in an amount of about 1 to 89178 -35- 200423936 about 2,500 mg 'about 1 mg to about 2,000 mg, about 10 mg to about 1,500 mg' about 50 mg to about 1,000 mg, about 100 mg to about 750 mg, or about 250 mg to about 500 mg. Of course, the exact amount of the second active agent will depend on the specific agent used, the treatment, or The type of MD and immunomodulatory compound to be treated and the amount of any other active agent that is administered to the patient concurrently may be different. 4.4.1 The pharmaceutical composition of the present invention suitable for oral administration may be in a separate dosage form, such as (but not Limited) • Lozenges (for example: chewable tablets), film-coated tablets, capsules and liquids (for example: flavored syrup). These dosage forms contain a predetermined amount of active agent and can be prepared according to methods known to those skilled in the pharmaceutical arts. See generally Remingt〇n, s

Pharmaceutical Sciences, 18th ed. 5 Mack Publishing, Easton PA (1990) 〇 Typical oral dosage forms are prepared by mixing the active agent with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a variety of forms depending on the type of formulation required. For example: • Excipients suitable for oral liquids or creams include (but are not limited to) + water, glycols, oils, alcohols, flavors, preservatives and coloring agents. • Grilled two I > ten 丨 ”a, for solid oral dosage forms (such as • tertiary, lozenges, capsules and film-coated tablets) ·, machine L, shaped clams include (but are not limited to) · version Private tablets, sugars, microcrystalline cellulose, binding agents and disintegrating agents. Heart-coated granules and lubricants are easy to administer due to tablets and capsules. Therefore, solid excipients are used at this time. Table 1: Advantageous oral administration A unit of water-based or non-aqueous technology coating. This: To b '1 tincture can be standard, back i can be any pharmaceutical method 89178 * 36-200423936 method to uniformly mix the active agent or both' then if Prepared as necessary. Generally, pharmaceutical compositions and dosage forms with liquid carriers, uniformly dispersed solid carriers, 'make the product into the desired formulation. For example: the preparation of tablets can be compressed or molded. Suitable machine, compression free-flowing form Active agent, == granules, which can be mixed with excipients as needed. Moulded tablets: granules, powdered compounds can be used in an inert liquid diluent wet / dipper. Excipients that can be used in the oral dosage form of the present invention include ( (But not limited to): surname agent, filler Disintegrants and lubricants. Suitable for pharmaceutical compositions and dosage forms: Binding agents include (but are not limited to): corn starch, potato starch, or potash starch, natural gums and synthetic gums ... acacia gum, sodium alginate, Alginic acid, other alginates, powdered tragacanth gum, guanhua bean gum, cellulose and its derivatives (for example: ethyl cellulose, cellulose acetate, carboxymethyl, truncated, and arsenic Sodium methylcellulose), Polyvinylpyrrolidone ag, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose (e.g. · 〇s. 22〇8, 29〇6, 29 1 0), microcrystalline cellulose and its mixtures. Suitable forms of microcrystalline cellulose include (but are not limited to) aAVICEL- PH-101, AVICEL-PH-103, AVICEL RC-5 8 and materials sold under the name AVICEL-PH-105 (From FMC, American Viscose Division, Avicel Sales, Marcus Hook, PA) and its mixture. The specific binding agent is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, which is named as AVICEL RC-5 81 For sale. Suitable anhydrous or low moisture excipients or additives include AVICEL_PH-103TM And starch 1500 LM. Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include 89178-37- 200423936 (but not limited to) ... talc, calcium carbonate (for example ... granules or powder), microcrystalline fibers f, Cellulose powder, dextran, kaolin, mannitol, light, sorbitol, starch, pregelatinized starch and mixtures thereof. The typical content of the binder or filler in the pharmaceutical composition of the present invention accounts for about 50 to about 99% by weight. The tablet formed by using a disintegrant in the composition of the present invention will disintegrate when exposed to water-based clothing. Bonding agents containing too much disintegrant may disintegrate during storage, while too little may disintegrate at the required rate or under the required conditions. Therefore, the amount of disintegrant should be enough, not too much or too little, so as not to negatively modify the active agent used in the formation of solid oral dosage forms. The amount of disintegrant varies with the type of formulation, and it is easily understood by those who are familiar with this technology. A typical pharmaceutical composition contains from about 0.5 to about 15 weight percent disintegrant, preferably from about 1 to about 5 weight percent disintegrant. Disintegrating agents that can be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, amaranth, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, general Potassium carboline (pollacriHn), sodium starch glycolate, potato or cassava starch, other starches, pregelatinized starch, other rice flour, clay, other alginic acid, other cellulose, gums and mixtures thereof. Lubricants that can be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hard moon gg text, stearic acid town, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol Alcohols, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (such as 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. Other lubricants 89178 -38- 200423936 include, for example: Silicate Silicate (AEROSIL200, manufactured by W.R. Grace Co., of Baltimore, MD), Condensing aerosol of synthetic silica (Degussa Co. of Plano, TX (Sold), CAB_0-SIL (pyrolytic silica products, sold by Cabot Co. 〇f Boston, MA) and mixtures thereof. If used, the typical amount of lubricant is less than about 1% by weight of the pharmaceutical composition or dosage form. Preferred solid oral dosage forms of the present invention include immunomodulatory compounds, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin. 4.4.2 Sustained-release fast-food 丨 剞 This miscellaneous ✓ The tongue agent can be administered by controlled release methods or delivery devices known to those skilled in the art. Examples include (but are not limited to): they are described in US Patent Nos .: 3,845,770; 3,916,899; 3,53 6,809; 3,598,123; and 4,00,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548 , 5,073,543, 5,639,476, 5,3 54,556 and 5,73 3,566, the disclosures of which have been fully incorporated herein by reference. These dosage forms can be used, for example, hydroxypropyl methylcellulose, other polymer masterbatches, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof. In providing a sustained or controlled release of one or more active agents, a desired release pattern can be provided in different proportions. Those skilled in the art know that suitable controlled release formulations (including those disclosed herein) can be easily selected for use with the active agents of the present invention. The present invention therefore encompasses controlled release single unit dosage forms suitable for oral administration such as, but not limited to, lozenges, capsules, gelcaps, and film-coated tablets. All controlled release medicinal products have a common goal, which is to improve their use of the equivalent of 89178 -39- 200423936 uncontrolled release. The company ... Imagine that the medical treatment method = take: ... ten controlled release The formulation is characterized by the shortest time to cure or control the condition. The advantages of controlling the release of the formulation include: Γ, reducing the frequency of administration, and improving patient adaptability. The formulation released by the "heart" can be used to influence the onset time of the effect or its concentration in the blood of the animal, so it can affect the occurrence of side effects). Bu Minji Most of the controlled release formulations are designed to release a certain amount of sex agent first) to promote the effect of oral therapy, and then gradually release other amounts in order to hold the therapeutic or preventive effective amount of the drug for a period: in The body maintains a constant dose of this drug, and the drug is deleted: The drug must be replaced in the body and excreted in the body. Control of Active Agents: It can be stimulated by a variety of conditions, including (but not limited to), pH, temperature, fermentation, water, or other physiological conditions or compounds. 4. · 4 · 3 Parenteral dosage forms can be administered to patients in a variety of different ways, including: intravitreal, subcutaneous, intravenous (including intravenous guanidine (including bolus injection), intramuscular = intramuscular. Because of its The administration method mainly bypasses the patient's defense against foreign objects: the system, so parenteral dosage forms are preferably sterile or can be sterilized before administration. Examples of parenteral dosage forms include (but not limited to) ): Available now; Shooting / Cereals, ready-made can be used for bathing or suspending in medicine can be connected to a: dry product of shooting vehicle, ready-made suspension for injection ,: milk 2 :: for Suitable vehicles for providing parenteral dosage forms of the present invention are those skilled in the art. Examples include (but are not limited to): Water for injection 89178 200423936 USP; aqueous vehicles such as (but not limited to (Ringer , S) injection, right, / / main injection, Ringer's, and Ringer's injection with lactic acid; ,, right: take sugar and sodium chloride injection. B ^, Xia, /, Shuiluoluo Vehicles such as (but not limited to) • Ethyl alcohol, polyethylene glycol and polypropylene — .τ ^ 1%, and non-aqueous vehicles such as ( But it is not limited to) aa ^ / yin, sesame oil 'ethyl oleate, nutmeg I isopropyl ester and benzyl benzoate. The parenteral dosage form of the present invention ^ can also be added to 4 feet to improve one A combination of the solubility of multiple active agents. Μ1 For example ...% dextrin and its derivatives can be used to increase the solubility of immunoregulatory compounds such as daggers and other organisms. See, for example, US Patent No. 5,134 127, Gan Zhi- ', 27 The content of this disclosure has been fully incorporated into this article by reference. 4.4 · 4 · 4 stars j 卩 and the mucosal part 丨 ψ Including (but not limited to): eye drops, spray suspension or practice Those skilled in the art Local and mucosal dosage forms, aerosols, solutions, emulsions, and other known forms of the present invention. See, for example, RemingtQn, sphaeeeutical Sciences, 16thik i8th eds. 5 Mack Publishing, Easton PA (1980 199 〇), and Introduction to Pharmaceutical Dosage Forms, 4th ed · 'Lea & Febiger, Philadelphia (1985). Formulations suitable for treating oral mucosal tissue can be formulated into mouthwash or oral gel. A suitable excipient ( Such as: carriers and diluents) and other substances that can be used to form the topical and mucosal dosage forms covered by this hair month are known to those skilled in this medical technology and depend on the specific tissues to which the specified pharmaceutical composition or dosage form will be applied Examples of typical excipients include, but are not limited to, non-toxic and pharmaceutically acceptable water, acetone, ethanol, ethyl 89178 • 41-200423936 glycols, propylene glycols, butanes that form solutions, emulsions, or gels 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures thereof. If necessary, wetting agents or humectants can also be added to pharmaceutical compositions and dosage forms. These other examples are known to those skilled in the art. See, for example: Remington, Pharmaceutical Sciences, 16th and 18th Eds., Mack Publishing, Easton PA (1980 & 1990). The pH of a pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more ingredients. Sex. Similarly, the polarity of the solvent carrier, its ionic strength or isotonicity can be adjusted, and the money transfer property can be adjusted. It is also possible to add compounds such as stearates to pharmaceutical compositions or dosage forms, which is beneficial to change the hydrophilicity or lipophilicity of one or more active agents to improve the transportability. In this case, stearates can be used as a lipid vehicle, emulsifying ingredient or surfactant for the formulation, and as an added transport or penetration enhancer. Different salts' hydrates or solvates can be used to further adjust the properties of the resulting composition. 4.4_5 Set of interest, one in this hair, a small% take π avenues to administer medicine. Therefore, the set of sets covered by the present invention is operated by medical personnel; the process of administering an appropriate amount of active agent to a patient can be simplified. A typical kit of the present invention includes a dosage form of an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomeric inclusion compound thereof. The kit of the present invention may further include one: =: active agent or a combination thereof. Examples of other active agents have been disclosed herein (see, for example, section 4.2). f The kit of the present invention may further include a device for administering an active agent. 89178 -42- and other device examples include (but not limited to #. The kit of the present invention can be further advanced pack ^^ medicine bag, patch and inhaler grid (Amsler grid). 3. Used to detect or diagnose MD The set of the present invention can be further # 1 ^ ^ Μ ^ -r-can be used to administer one or more active brake moxibustion acceptable music agents 1 soil, ^ ^ ^ ^, 1 such as ... If the active agent is in a solid form ^ ^ ^ _ _ The commercial 'set can include a fork valley sealer containing a suitable vehicle, wherein the active agent,

.§ ^ / combined solution to form a granule-free solution of A for parenteral administration. Examples of medicinal materials that can be used as…,., And other vehicles include (but are not limited to) • USP for injection; aqueous vehicles such as (, ren are not limited to): sodium chloride injection, Ringer's injection , Liuxun M. Xunzhuangzhuang injection, dextrose and sodium chloride / main injection, and Linzhi's Wyatt's injection with lactic acid; the solvents that are miscible with water are not limited to ethanol and polyethylene Alcohols and polypropylene glycols; and non-aqueous vehicles: limited to). Yuwei oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate. 5. Examples The following examples are further illustrations, but do not limit the scope of the invention. 5-1 Applicability_ One of the biological effects of in vitro pharmacological & immunomodulatory compounds is to reduce the synthesis of τΝρ_α. Immunomodulatory compounds can enhance TNF_amRNA reduction. TNF_a may play a certain pathological role in macular degeneration. In the specific embodiment, 3_ (4-amino small oxo-1,3-dihydro-isoindole_2-yl) _hexahydropyridine_2,6_dione, (Amine) -2- (2,6-dioxo- (3-hexahydropyridine)) _ isoindone'3_dione or thalidomide inhibits TNF_ai induced by LPS in human PBMC and human whole blood fruit. 89178 -43- 200423936 4- (Amino) -2- (2,6-dioxo_ (3_hexahydropyridyl))-isoindolino-i, 3-dione inhibits LPS-stimulated human PBMC IC5q with human whole blood to produce TNF-α is about 24 ηM (6.55 ng / mL) and about 25 nM (6.83 ng / mL), respectively. 3- (4-Amine_l-oxo-l53-dihydro-iso-sigma 2-do) _hexahydro P ratio a_256-di i¾ Inhibits PB S stimulated human PB MC and human whole The IC50 of tnF-a produced by blood was about 100 nM (25.9 ng / mL) and about 480 nM (103.6 ng / mL), respectively. In contrast, the IC50 of thalidomide inhibiting LPS-stimulated production of TNF-a in human PBMCs was about 194 μM (50.1 pg / mL). In vitro tests show that 3- (4-amino-1-oxo-1,3_dihydro-iso-sound | Hou_2_yl) -hexahydro p ratio 唆 _2,6 -di_ or 4- ( Amino group) -2 '(2,6-dioxo- (3-hexahydroerbino))-isoinduodol'3-dione is also 50 to 2,000 times more potent than saristine. Also 'known 3- (4-amino small oxo_1,3_dihydro-isoindolyl) _hexahydropyridine-2,6_dione or 4- (amino) -2- (2 , 6-dioxo- (3-hexahydropyridyl)) _ iso'sullin-1,3-dione is more potent in primary T-cell proliferation than T-cell receptor (TCR) activation Sally Douglas is about 50 to 100 times. The compound is also about 50 to 100 times more potent in enhancing the production of IL2 and IFN-γ by TCR-activated PBMCs (IL2) or T-cells (IFN_Y) than salidol. In addition, the compound inhibited LPS-stimulated production of proinflammatory cytokines TNF_a, ILlp, and IL6 'by PBMCs with dose change, and increased production of anti-inflammatory cytokines IL10. The Linqing test in 5.2 MD patients. The dose of immunomodulatory compounds in macular degeneration is from about 25 mg per day. In specific embodiments, clinical trials are performed by detaining patients with macular degeneration and divided into two groups. The first group was treated with the traditionally used photodynamic therapy of Pfisterphene to seal leaky choroidal vessels (a characteristic of this disease) 89178 -44- 200423936 therapy. Ophthalmol 1999 (1 17): i 329-1345. The second group received the same traditional therapies using phenanthrene and about 10 mg / day of Hiro-Amine-, oxo-1,3-a-iso-isosophylline_2_yl) _hexahydropyridine _2,6_ dione as an adjuvant therapy for 20 weeks. … The test group that accepted 3- (4-amino- ^ oxo_ 丨, 3_dihydro_isotendol_2_yl) _hexahydroton bite -2,6-di_ was fully stopped-a series of Neovascular response, extending the effects of photodynamic therapy indefinitely. However, the test group that did not use 3_ (4_amino small oxo 1'3 monochloro_iso „initiator_2 • yl) _hexahydropyridine_2,6_dione was treated several weeks after treatment. The treated blood f experienced reperfusion. After that, it gradually lost vision and required repeated photodynamic therapy. In other preferred embodiments, 3_ (4_amino small oxoyihong dihydro_isoindole- The dosage of 2-yl) -hexahydropyridine-2,6_dione is from about 丄 to about 1 day, or higher doses, usually about 2 to 5 times the daily dose every other day. Adjuvant therapy is applicable to other traditional therapies for the treatment or prevention of MD, including (but not limited to): surgical interventions' including laser-induced coagulation. The specific embodiments of the invention described herein are merely illustrative of the scope of the invention. The disclosures of many documents extracted from this article have been fully incorporated herein by reference.

Claims (1)

200423936 Patent application scope 1. A method for treating, preventing or treating macular degeneration, which comprises administering a therapeutically or preventively effective amount of an immunomodulatory compound, or a medicine thereof, to a patient in need of such treatment, prevention or treatment Acceptable salts, solvates or stereoisomers. 2. The method according to item 1 of the scope of patent application, which further comprises administering a therapeutically or prophylactically effective amount of a second active agent. 3. The method according to item 2 of the scope of patent application, wherein the second active agent is a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrophil factor, Regulators of neoangiogenesis, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds. 4. The method according to item 2 of the patent application, wherein the second active agent is thalidomide, verteporfin, purlytin, angiostatic steroids, rhuFab, interferon μ, or pentoxifyiline, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 5. Method of claim 4 in the patent scope, # 中 抗The vasodilator compound is salidomide. 6. According to the method in the scope of patent application No. 1 and only < Wan Li, of which the macular degeneration is wet macular degeneration, dry macular degeneration, and the right Macular degeneration, aging-related macular degeneration, venom, underamine κ, total muscle, osteomalacia, neoretinal formation, retinal pigment epithelial peeling, retinal pigment ancient smile, broad spear epithelium contraction, Best disease (Best, s disease), yolk type, stargardt.s disease, juvenile 89178 200423936 type macular dystrophy, basal macula, Behr (sdisease), Sorsby (s disease), Downey Disease (Doyne, s disease), bee-table dystrophy, or macular impairment 7. The method according to item i of the patent application scope, wherein the immunomodulatory compound is pure stereoisomerism. 8. A treatment, prevention or treatment A method of macular degeneration comprising administering a therapeutically or preventively effective amount of 4_ (amino) -2- (2,6-dioxo (3-hexahydropyridyl) to a patient in need of such treatment, prevention or treatment ) ≫ Isoindoline_, 3-monoketone or its hundred-acceptable salts, solvates, or stereoisomers. 9. Method according to item δ of the scope of patent application, where 4- ( Amine) · 2_ (2,6_ — lice (3-hexahydropyridyl)) _ isoindololine_, 3_dione is pure enantiomeric conformation. ^ 10 · A treatment, prevention or A method for treating macular degeneration comprising administering a therapeutically or prophylactically effective amount (amino-small oxo_ 丨, 3 · dihydro-isoindole_2_yl) to a patient in need of such treatment, prevention or treatment Hexahydropyridine = ketone, or a pharmaceutically acceptable salt, solvate, or stereoisomerism thereof, the method of Kangshenming's patent No.! 0, in which 3_ (4 Amino small oxo-1,3 _ dihydro · is called 丨 one bow 1 ° wood-2-yl) -hexahydropyridine-2,6-difluorene is also pure enantiomer., 1 2 · According to the method of applying nasal collection W > J Ganweidi 1 item, wherein the immunoregulatory eight substances are as shown in formula (I): σ 89178 -2- ^ 0423936 13. 14. where one of x and Y is c = 0, the other of X and Y is 0 or Ch 2, and R 2 is hydrogen or a lower carbon alkyl group. The method according to item 12 of Shen Yan's patent, wherein the immunomodulatory compound is pure enantiomer. The method according to item 1 of the scope of patent application, wherein the immunomodulatory compound is represented by formula (II): Where: one of X and Y is c = o, the other is CH24C = 0; R1 is H, (Ci-Cs) alkyl, (c3, c7) cycloalkyl, (c2_c8) alkenyl, (c2- c8) alkynyl, benzyl, aryl, (C0-C4) alkyl- (CVC6) heterocycloalkyl, (C0-C4) alkyl- (c2-c5) heteroaryl, C (0) R3, C (S) R3, C (0) 0R4, (CVC8) alkyl-N (R6) 2, (CVC8) alkyl-OR5, (Ci-CO alkyl-C (0) 0R5, C (0 ) NHR3, C (S) NHR3, C (0) NR3R3 ·, C (S) NR3R3 ·, or (C 「C8) alkyl-〇 (CO) R3; R2 is H, F, phenylfluorenyl, (CrCO Alkyl, (C2-C8) alkenyl, or 89178 200423936 (Cz-Cs) fast group, R3 and R3_ are independently (CrCs) alkyl, (C3-C7) cycloalkyl, (C2-C8) ene ((: 2 < 8) alkynyl, benzyl, aryl, (c0-c4) alkyl- (Ci-C6) heterocycloalkyl, (C0-C4) alkyl- (C2-C5 ) Heteroaryl, (C0-C8) alkyl-N (R6) 2, (CVC8) alkyl_OR5, (Ci_c8) alkyl-C (0) OR5, (CVC8) alkyl-0 (C0) R5 or C (0) 〇R5; R4 is (Ci-Cs) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (Ci-C4) alkyl-OR5, benzyl, aromatic , (CVC4) alkyl-((VC6) heterocycloalkyl, or (C0-C4) alkyl- (C2-C 5) Heteroaryl; R5 is (CVC8) alkyl, (c2-c8) alkenyl, (c2-c8) alkynyl, benzyl, square or (C2_C5) heteroaryl; each occurrence of R6 is respectively Independently, fluorene, (Ci-C: 8) alkyl, (C2-C8) alkenyl, (C ^ Cs) alkynyl, benzyl, aryl, (C2_c5) heteroaryl, or (C0-Cs) Alkyl-C (〇) 〇_R5 or R6 groups can be combined to form a heterocycloalkyl group; n is 0 or 1; and * represents a palmar carbon center .: According to the method in the scope of patent application No. 14, Among them, immunomodulatory compounds are pure enantiomers. 1 6. The method of the first and second patent scope of Cai Gencai, in which the immunomodulatory compound 2 is a cyano group of disubstituted styrene Or carboxy derivative, oxo-oxo 3 -fluorohexahydro-p ratio bite -3 -yl) isoamidine α-dolin, 1,3-dioxo, oxo-3 -fluorohexahydroedian-3- Base) isoindolin or four-of-two 2- (2 6-preparation, 17 · according to the application,-hexahydropyridin_3_yl) -1-oxoisoindolin. Patent pending The method of the sixth item, wherein the immunomodulatory compound 89178-4-200423936 is pure enantiomer. 18. A method for the treatment, prevention or treatment of macular degeneration, which comprises administering to a patient in need of such treatment, prevention or treatment medical treatment before, during or after receiving a surgical intervention for reducing or avoiding the symptoms of macular degeneration in the patient A prophylactically effective amount of an immunomodulatory compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 19. The method according to item 18 of the application, wherein the surgical intervention method is phototherapy, laser therapy, radiation therapy, retinal pigment epithelium transplantation or omental center displacement. 20. A pharmaceutical composition comprising an immunomodulatory compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a second active agent capable of reducing or avoiding the symptoms of macular degeneration. 21. The pharmaceutical composition according to item 20 of the scope of the patent application, wherein the second active agent is a steroid, a photosensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, and a neutrophil. Factors, modulators of neovascularization, anti-VEGF antibodies, prostaglandins, antibiotics, phytoestrogens, anti-inflammatory compounds or anti-angiogenic compounds ^ 22. A pharmaceutical composition according to item 20 of the scope of patent application, wherein The second active agent is thalidomide, vertep (Jfin, purlytin), angiostatic steroid, rhuFab, interferon 々a, or pentoxifyiline, Or its pharmaceutically acceptable species, solvates, or stereoisomers. 89178 200423936 柒. Designated representative map: (1) The designated representative map in this case is: None. (2) The component representative symbols in this representative map are simply explained. : 捌. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: None 89178