MXPA06004998A - Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of asbestos-related diseases and disorders - Google Patents

Abstract

Methods of treating, preventing and managing an asbestos-related disease or disorder 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 chemotherapy, surgery, or radiation therapy. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in the methods of the invention are also disclosed.

Description

METHODS OF UTILIZATION AND COMPOSITIONS THAT INCLUDE IMMUNOMODULATORIQS COMPOUNDS FOR TREATMENT AND HANDLING OF DISEASES AND DISORDERS RELATED TO ASBESTOS FIELD OF THE INVENTION This invention relates to methods for treating, preventing and managing an asbestos-related disease or disorder, which comprise the administration of an immunomodulatory compound alone or in combination with known therapeutics. The invention also relates to pharmaceutical compositions and dosage regimens. In particular, the invention encompasses the use of an immunomodulatory compound in conjunction with surgery or radiation therapy and / or other standard therapies for diseases associated with asbestos poisoning. 2. BACKGROUND OF THE INVENTION 2.1 DISEASES OR TRANSTORNES RELATED TO ASBESTOS Several million individuals around the world were exposed to asbestos in the exploitation of minerals or the manufacture and use of asbestos products. D.R. Aberle, Seminars in Roentgenology, 24 (2): 118, 1991. Given the extensive "latency time" for the development of many pathological consequences of asbestos, diseases related to asbestos will probably dominate the field of occupational and environmental diseases for some time. The diseases and disorders related to benign asbestos include asbestosis, pleural effusion, pleural plaques, diffuse pleural thickening and rounded atelectasis. AC Staples, Radiologic Clinics of North America, 30 (6): 1191, 1992. Diseases related to malignant asbestos include malignant pleural effusion, pleural or peritoneal mesothelioma and bronchogenic carcinoma. Merck Index, 1999 (17th ed.), 645 and 651. Asbestosis (interstitial fibrosis) is defined as diffuse pulmonary fibrosis due to the inhalation of asbestos fibers. AC Staples, Radiologic Clinics of North America, 30 (6): 1195, 1992. This is one of the major causes of professionally related lung damage. Merck Index, 1999 (17th ed.), 622. Asbestosis characteristically occurs after a latent period of 15-20 years, with disease progression even after the exposure has ended, but rarely occurs in the absence of plaques. Pleural C. Peacock, Clinical Radiology, 55: 425, 2000. Fibrosis first develops in and around the respiratory bronchioles, predominating in the subpleural portions of the lung in the lower lobes, and then progresses centrally. AC Staples, Radiologic Clinics of North America, 30 (6): 1195, 1992. Asbestosis can cause an insidious onset of progressive dyspnea in addition to dry cough. The incidence of lung cancer increases in smokers with asbestosis, and a dose response relationship has been observed. Merck Index, 1999 (17th ed.), 623. Another disorder related to asbestos is the pleural effusion. Pleural effusions are often the earliest manifestation of an asbestos-related disease. AC Staples, Radiologic Clinics of North America, 30 (6): 1192, 1992. Persons exposed to asbestos may develop an exudative pleural effusion five to 20 years after exposure. Merck Index, 1999 (17th ed.), 645; C. A. Staples, Radiologic Clinics of North America, 30 (6): 1192, 1992; and C. Peacock, Clinical Radiology, 55: 427, 2000. The effusion may follow a short exposure, but more often follows an intermediate exposure of approximately 10 to 15 years. The clinical picture in the pleural effusion related to benign asbestos varies from asymptomatic patients to patients with an acute episode of pleuritic chest pain and pyrexia. Id., 426. The mechanism is unknown, but it is assumed that the fibers migrate from the lungs to the pleura and induce an inflammatory response. In most people, spills clear up after three to four months, but they can persist or recur for several years. Id. When the effusion clears, many develop diffuse pleural thickening. Id.

Pleural plaques are a common manifestation of exposure to asbestos, usually occurring after a latent period of approximately 20-30 years. C. A. Staples, Radiologic Clinics of North America, 30 (6): 1191, 1992; and C. Peacock, Clinical Radiology, 55: 423, 2000. Histologically, pleural plaques consist of bundles of acellular collagen that form a radiating ligament pattern, which involves almost exclusively the parietal pleura. AC Staples, Radiologic Clinics of North America, 30 (6): 1191, 1992. The precise pathogenesis of pleural plaques remains undetermined, although some have assumed that they are caused by the mechanical effect of asbestos fibers that perforate the visceral pleura. C. Peacock, Clinical Radiology, 55: 425, 2000. Currently, however, it is believed that the fibers are transported to the parietal pleura through lymphatic channels, where they stimulate an inflammatory response. Id. Plates grow slowly over time, even after cessation of exposure, but they are not considered pre-malignant. Jd. Calcification occurs later, frequently 30-40 years after exposure. Jd. 424; and C.A. Staples, Radiologic Clinics of North America 30 (6): 1191, 1992. Although there is a significant correlation between the severity of pleural disease and that of asbestosis, pleural plaques tend to occur in isolation without any other manifestations of diseases related to asbestos. C. Peacock, Clinical Radiology, 55: 425, 2000. Another common manifestation of exposure to asbestos is diffuse pleural thickening. AC Staples, Radiologic Clinics of North America, 30 (6): 1193, 1992. Usually, the latent period is approximately 15 years. Diffuse pleural thickening is less specific for asbestos exposure than the presence of pleural plaques, since thickening can also be observed after TB pleuritis, hemothorax, and empyema. C. Peacock, Clinical Radiology, 55: 427, 2000. The most common symptom is dyspnea. The pathogenesis is not clear, but it is thought to be due to inflammation and fibrosis of visceral lymphatics, and it has been considered an extension of parenchymal fibrosis. Jd. The development of diffuse pleural thickening has a similar time course as plaque formation. Thickening is a concomitant finding common to asbestosis, with a reported reported incidence of 10%. Jd. Another disease associated with asbestos exposure is rounded atelectasis, which refers to atelectatic lung adjacent to pleural thickening with collapsed features of bronchi and blood vessels. T. Wallace, Diagnostic Cytopathology, 8 (6): 617, 1992; C. Peacock, Clinical Radiology, 55: 429, 2000; and C.A. Staples, Radiologic Clinics of North America, 30 (6): 1193, 1992. also known as refolded lung, pseudotumor pulmonar, pleuroma or Blesovsky syndrome. Jd. The presence of the effusion has been postulated to cause passive atelectasis, with narrowing of the lung resulting in the intussusception of the adjacent pleura. Jd. This process causes captivity, which prevents the re-expansion of the lung in the resolution of the effusion and which causes rounded atelectasis. Jd. An alternative explanation is that an assault on the pleura leads to localized inflammation and fibrosis, which results in volume loss and subsidence of the underlying lung. Jd. The lingula is the most common site, followed by the middle and then the lower lobes, although the lesions can be multiple and bilateral. Jd. Mesothelioma is a malignant pleural or peritoneal neoplasm which is usually associated with occupational exposure to asbestos. Merck Index, 1999 (17th ed.) 645. The clinical latency period between asbestos exposure and the development of mesiotelioma is normally 15-40 years. Jd., 623; and C. Peacock, Clinical Radiology, 55: 427, 2000. As a result, the number of patients with mesothelioma has continued to rise despite the decreased production of asbestos. JM van Haarst et al. , Bri tish Journal of Cancer, 86: 342, 2002. Common symptoms are chest pain, dyspnea, cough, weight loss, weakness and increased sputum production. Merck Index, 1999 (17th ed.), 645. The The tumor gradually lines the lungs, invades the chest wall and produces pleural effusion in approximately 75% of patients. Jd. The prognosis is depressing, with slow response to radial surgery, chemotherapy or radiation therapy, Jd. The causal relationship between bronchogenic carcinoma and asbestos exposure is well accepted. Merck Index, 1999 (17th ed.), 651; and D.R. Aberle, Seminars in Roentgenology, 24 (2): 124, 1991. This shows a dose response at occupational exposure levels. Jd. The relative risk of lung cancer in asbestos workers increases multiplicatively with combined smoking, and interstitial disease related to asbestos is frequently associated with this. Jd. Lung cancer has also been reported in individuals without interstitial lung disease who are exposed to asbestos. Jd. 2. 2 CONVENTIONAL TREATMENTS The main strategy for dealing with asbestos-related diseases or disorders is prevention, with the worldwide elimination of the use of asbestos and the replacement of asbestos with safe synthetic products. No treatment for asbestosis is known to be effective. Mesothelioma is very difficult to treat, and no standard therapy for its treatment exists currently. Kaiser LR., Semin Thorac Cardiovasc Surg. Oct . , 9 (4): 383-90, 1997. Methods of chemotherapy, radiation therapy and surgery have all been used with little improvement in survival 'in general, although trimodality therapy involving a combination of all three treatments has demonstrated that it improves survival in selected patients. Jd. The two main surgical interventions used to treat mesothelioma are pleurectomy and extrapleural pneumonectomy (PPE). Pleurectomy is usually a palliative procedure to relieve chest wall pain and prevent recurrent pleural effusions by dissolving the visceral and parietal pleura. C. Turton, Bri tish Journal of Hospi tal Medicine, 23 (3): 249, 1980. PPE is a group resection of the parietal and mediastinal pleura, the lung, the hemi-diaphragm and the ipsilateral pericardium to remove all diseases in general. Sugarbaker DJ. Ann Surg. , 224 (3): 288-94, 1996. EPP is indicated for stage I tumors without the involvement of mediastinal lymph nodes. PPE is a technically demanding surgery with significant morbidity. Complications of surgery for pleurectomy and PPE include pneumonia, bronchopleural fistulas, bronchial leaks, empyema, chylothorax, respiratory failure, myocardial infarction, congestive heart failure, hemorrhage, cardiac volvulus, subcutaneous emphysema, incomplete tumor removal, and vocal cord paralysis. Jd. Radiation therapy is usually a palliative or a supplement for surgery. C. Turton, British Journal of Hospi- tal Medicine, 23 (3): 249, 1980. Brachytherapy, intrapleural implantation of radioactive isotopes, delivers high-dose radiation locally to the pleural space and is used for recurrent pleural effusions. Jd. Post-operative radiation therapy can prevent recurrence within the incision sites of the chest wall. Radiation therapy complications include nausea and vomiting, radiation hepatitis, esophagitis, myelitis, myocarditis, and pneumonitis with impaired lung function. Photodynamic therapy is an adjuvant treatment in patients with surgically treated pleural malignancies. P. Baas, Br. J. Cancer. , 76 (6): 819-26, 1997. A light-activated photosensitive drug is instilled intrapleurally and stimulated with light of a certain wavelength that produces oxygen free radicals that cause tumor necrosis. Jd. The response to chemotherapy has been disappointing because it has been difficult to compare chemotherapies. Intrapleural instillations of antibiotics such as mepacrine, thiotepa and tetracycline have been reported sometimes successful. C. Turton, British Journal of Hospi tal Medicine 23 (3): 247, 1980. Several cytotoxic drugs including mustine have been instilled into the pleural cavity. Jd. Medications currently used during the treatment of mesothelioma include GM-CSF, doxorubicin, gemcitabine, cisplatin, vinblastine, adriamycin, bleomycin, hyaluronidase, methotrexate and mitomycin. JMW van Haarst et al. , Bri tish Journal of Cancer, 86: 342-345, 2002. However, patients rarely get complete relief. Chemotherapy results in less than 20% response and has not yet shown to improve survival in patients with mesothelioma. Jd. Therefore, there remains a need for safe and effective methods to treat and manage mesothelioma and other diseases associated with asbestos exposure. 2. 3 IMMUNOMODULATORY COMPOUNDS A group of compounds selected for their ability to potently inhibit the production of TNF-a by PBMC stimulated by LPS have been investigated. L.G.

Corral, et al. , Ann. Rheum. Dis. 58: (Suppl I) 1107-1113 (1999) . These compounds, which are referred to as IMiDs ™ (Celgene Corporation) or Immunomodulatory Drugs, show not only the potent inhibition of TNF-α, but also the marked inhibition of IL1 / 3 and IL12 production of monoOcitos induced by LPS. IL6 induced by LPS is also inhibited by immunomodulatory compounds, although partially. These compounds are potent stimulators of IL10 induced by LPS. Jd. 3. SUMMARY OF THE INVENTION This invention encompasses methods for treating, preventing and / or managing diseases or disorders related to asbestos, which comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a salt, pharmaceutically acceptable solvate, hydrate, stereoisomer, clathrate or prodrug thereof. Another embodiment of the invention encompasses the use of one or more immunomodulatory compounds in combination with other therapeutics typically used to treat or prevent diseases or disorders related to asbestos such as, but not limited to anti-cancer agents, antibiotics, anti-inflammatory agents, cytokines, steroids, immunomodulatory agents, immunosuppressive agents and other known therapeutics. Yet another embodiment of the invention encompasses the use of one or more immunomodulatory compounds in combination with conventional therapies used to treat, prevent or manage diseases or disorders related to asbestos. including, but not limited to chemotherapy, surgery, radiation therapy and photodynamic therapy. The invention further encompasses pharmaceutical compositions, unique unit dosage forms, and equipment suitable for use in the treatment, prevention and / or management of diseases or disorders related to asbestos, which comprise one or more immunomodulatory compounds, or a salt, pharmaceutically acceptable solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and one or more additional active agents. 4. DETAILED DESCRIPTION OF THE INVENTION A first embodiment of the invention encompasses methods for treating, preventing or managing diseases or disorders related to asbestos, which comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. As used herein, the terms "disease, disorder or syndrome related to asbestos", "disease or disorder associated with the exposure of asbestos" and "disease or disorder associated with "Asbestos poisoning" means any disease, disorder, syndrome or abnormality associated with, or related to, exposure to asbestos or asbestos poisoning.The terms encompass benign and malignant diseases or disorders, and include, but are not limited to, mesothelioma, asbestosis, malignant pleural effusion, benign exudative effusion, pleural plaques, pleural calcification, diffuse pleural thickening, rounded atelectasis, fibrotic masses, and lung cancer. In a specific modality, the terms do not cover lung cancer. In a certain modality, the disease, disorder or syndrome related to asbestos does not include malignant mesothelioma or mesothelioma syndrome of malignant pleural effusion. Another embodiment of the invention encompasses a pharmaceutical composition suitable for the treatment, prevention or management of diseases or disorders related to asbestos comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and an optional carrier. Also encompassed by the invention are simple unit dosage forms suitable for use in the treatment, prevention or management of diseases or disorders related to asbestos comprising an immunomodulatory compound, or a salt, solvate, hydrate, stereoisomer, clathrate or pharmaceutically acceptable prodrug thereof and an optional carrier. Another embodiment of the invention encompasses equipment suitable for use in the treatment, prevention or management of diseases or disorders related to asbestos comprising: a pharmaceutical composition comprising an immunomodulatory compound, or a salt, solvate, hydrate, stereoisomer, clathrate or pharmaceutically acceptable prodrug. The invention also encompasses equipment comprising simple unit dosage forms. Without being limited by theory, it is believed that an immunomodulatory compound can act in complementary or synergistic ways with certain second active agents in the treatment, prevention or management of diseases or disorders related to asbestos. Therefore, one embodiment of the invention encompasses a method for treating, preventing and / or managing an asbestos-related disease or disorder, which comprises administering to a patient in need thereof a therapeutically or prophylactically active amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and a therapeutically or prophylactically effective amount of a second active agent. Examples of the second active agents include, but are not limited to conventional therapeutics used to treat or prevent mesothelioma such as anti-cancer agents, antibiotics, anti-inflammatory agents, steroids, cytokines, immunomodulatory agents, immunosuppressive agents and other therapeutic drugs capable of alleviating or mitigating a symptom of diseases or asbestos-related disorders which may be found, for example, in the Physician's Desk Reference, 2003. It is further believed that an immunomodulatory compound can reduce or eliminate adverse effects associated with the administration of conventional therapeutic agents used to treat diseases or disorders. related to asbestos, so that the administration of larger quantities of conventional agents to patients and / or the increasing obedience of the patient is allowed. Accordingly, another embodiment of the invention encompasses a method for reversing, reducing or avoiding an adverse effect associated with the administration of a second active agent in a patient suffering from an asbestos-related disease or disorder, which comprises administering to a patient with need therefor a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The invention also encompasses compositions Pharmaceuticals, unique unit dosage forms, and kits comprising an effective amount of an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof and a second active agent. As discussed elsewhere herein, the symptoms of asbestos-related diseases or disorders can be treated with chemotherapy, surgery, radiation therapy, photodynamic therapy, immunotherapy and / or gene therapy. Without being limited by theory, it is believed that. combined use of such conventional therapies and an immunomodulatory compound can provide an exceptionally effective treatment of diseases or disorders related to asbestos. Therefore, this invention encompasses a method for treating, preventing and / or managing diseases or disorders related to asbestos, which comprises administering to a patient (e.g., a human being) an effective amount of an immunomodulatory compound, or a salt , solvate, hydrate, stereoisomer, clathrate or pharmaceutically acceptable prodrug thereof, before, during or after chemotherapy, surgery, radiation therapy, photodynamic therapy, immunotherapy, gene therapy and / or other therapies based on conventional drugs. 4. 1 IMMUNOMODULATORY COMPOUNDS The compounds of the invention can be purchased or prepared commercially according to the methods described in the patents or patent publications described herein. In addition, optically pure compositions can be synthesized or resolved asymmetrically using known solution agents or chiral columns as well as other standard synthetic organic chemistry techniques. The compounds used in the invention may include immunomodulatory compounds that are racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable salts, solvates, stereoisomers, clathrates and prodrugs thereof. The preferred compounds used in the invention are small molecules having a molecular weight less than about 1,000 g / moles, and they are not proteins, peptides, oligonucleotides, oligosaccharides or other macromolecules. As used herein and unless otherwise indicated, the terms "immunomodulatory compounds" and "IMiDs ™" (Celgene Corporation) encompass small organic molecules that markedly inhibit TNF-α, the IL1 / 3 monocyte and IL12 induced by LPS, and partially inhibit the production of IL6. Specific immunomodulatory compounds are discussed later.

TNF-a is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF-a is responsible for a diverse range of signaling events within cells. Without being limited by theory, one of the biological effects exerted by the immunomodulatory compounds of the invention is the reduction of synthesis of TNF-α. The immunomodulatory compounds of the invention improve the degradation of TNF-α mRNA. Furthermore, without being limited by theory, the immunomodulatory compounds used in the invention can also be potent co-stimulators of T cells and increase cell proliferation dramatically in a dose-dependent manner. The immunomodulatory compounds of the invention may also have a greater co-stimulatory effect in the subset of CD8 + T cells than in the subset of CD4 + T cells. In addition, the compounds preferably have anti-inflammatory properties, and efficiently co-stimulate the T cells. Furthermore, without being limited by particular theory, the immunomodulatory compounds used in the invention may be able to act both indirectly through the activation of the cytokine and directly in Natural Exterminating Cells ("NK") and the increased ability of NK cells to produce beneficial cytokines such as, but not limited to, IFN- ?.

Specific examples of immunomodulatory compounds include, but are not limited to, cyano and carboxy derivatives of substituted styrenes such as those described in U.S. Patent No. 5,929,117; 1-oxo-2- (2,6-dioxo-3-fluoropiperidin-3-yl) isoindolines and 1,3-dioxo-2- (2,6-dioxo-3-fluoropiperidin-3-yl) isoindolines such as those described in the North American patents Nos. 5,874,448 and 5,955,476; the tetra substituted 2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolines described in U.S. Patent No. 5,798,368; 1-oxo and 1,3-dioxo-2- (2,6-dioxopiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of thalidomide), including, but not limited to, those described in US Pat. Nos. . 5,635,517, 6,476,052, 6,555,554 and 6,403,613; 1-oxo and 1,3-dioxoisoindolines substituted at the 4 or 5 position of the indole ring (eg 4- (4-amino-1,3-dioxoisoindolin-2-yl) -4-carbamoylbutanoic acid) described in the patent North American No. 6,380,239; isoindolin-1-one and isoindoline-1,3-dione substituted at the 2-position with 2,6-dioxo-3-hydroxypiperidin-5-yl (for example, 2- (2,6-dioxo-3-hydroxy) -5-fluoropiperidin-5-yl) -4-aminoisoindolin-l-one) described in US Pat. No. 6,458,810; a class of non-polypeptide cyclic amides described in U.S. Patent Nos. 5,698,579 and 5,877,200; aminothalidomide, as well as analogs, hydrolysis products, metabolites, derivatives and precursors of aminothalidomide, and substituted 2- (2,6-dioxopiperidin-3-yl) phthalimides and substituted 2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindoles such as those described in the patents North American Nos. 6,281,230 and 6,316,471; and isoindol-imide compounds such as those described in U.S. Patent Application No. 09 / 972,487, filed October 5, 2001, U.S. Patent Application No. 10 / 032,286 filed on December 21, 2001, and International Application No. PCT / US01 / 50401 (International Publication No. WO 02/059106). The totalities of each of the patents and patent applications identified herein are incorporated herein by reference. The immunomodulatory compounds do not include thalidomide. Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo- and 1,3-dioxo-2- (2,6-dioxopiperidin-3-yl) isoindolines amino-substituted on the benzo ring as described in U.S. Patent No. 5,635,517, which is incorporated herein by reference. These compounds have structure I: wherein one of X and Y is C = 0, the other of X and Y is C = 0 or CH2, and R2 is hydrogen or lower alkyl, in particular methyl. Specific immunomodulatory compounds include, but are not limited to: l-oxo-2- (2,6-dioxopiperidin-3-yl) -4-aminoisoindoline; l-oxo-2- (2,6-dioxopiperidin-3-yl) -5-aminoisoindoline; l-oxo-2- (2,6-dioxopiperidin-3-yl) -6-aminoisoindoline; l-oxo-2- (2,6-dioxopiperidin-3-yl) -7-aminoisoindoline; 1,3-dioxo-2- (2,6-dioxopiperidin-3-yl) -4-aminoisoindoline; and 1,3-dioxo-2- (2,6-dioxopiperidin-3-yl) -5-aminoisoindoline. Other specific immunomodulatory compounds of the invention belong to a class of substituted 2- (2,6-dioxopiperidin-3-yl) phthalimides and substituted 2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindoles, such as those described in US Pat. 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), each of which is incorporated herein by reference. The representative compounds are of the formula: where: one of X and Y is C = 0 and the other of X and Y is C = 0 or CH2; (i) each of R1, R2, R3 and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 and R 4 is -NHR 5 and the remainder of R 1, R 2, R 3 and R 4 are hydrogen; R5 is hydrogen or alkyl of 1 to 8 carbon atoms; R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl or halo; provided that -R6 is different from hydrogen if X and Y are C = 0 and (i) each of R1, R2, R3 and R4 is fluoro or (ii) one of R1, R2, R3 or R4 is amino. The representative compounds of this class are of the formulas: wherein R1 is hydrogen or methyl. In a separate embodiment, the invention encompasses the use of enantiomerically pure forms (e.g., optically pure (R) or (S) enantiomers) of these compounds. Still other specific modulatory compounds of the invention belong to a class of isoindolimides described in US Patent Application Publication Nos. US 2003/0096841 and US 2003/0045552, and International Application No. PCT / USOl / 50401 (Publication International No. WO 02/059106), each of which is incorporated herein by reference. Representative compounds are of formula II: and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates and mixtures of stereoisomers thereof, wherein: one of X and Y is C = 0 and the other is CH2 or C = 0; R 1 is H, (C 1 -C 8) alkyl, (C 3 -C 7) cycloalkyl, (C 2 -C 8) alkenyl, (C 2 -C 8) alkynyl, benzyl, aryl, (C 1 -C 4) -heterocycloalkyl (C_-C_), (C0-C_) alkyl-heteroaryl of (C2-C5), C (0) R3, C (S) R3, C (0) 0R4, (C_-C8) alkyl -N ( R6) 2, (C? -C8) -OR5 alkyl, (C? -C8) alkyl -C (0) 0R5, C (0) NHR3, C (S) NHR3, C (0) NR3R3 ', C (S) NR3R3 'or alkyl of (C_-CB) -0 (CO) R5; R2 is H, F, benzyl, (C_-C8) alkyl, (C2-C8) alkenyl or (C2-C8) alkynyl; R3 and R3 'are independently alkyl of (C_-C_), cycloalkyl of (C3-C7), alkenyl of (C2-C8), alkynyl of (C2-C8), benzyl, aryl, alkyl of (C0-C4) - (C 1 -C 6) heterocycloalkyl, (C 0 -C) alkyl -heteroaryl (C 2 -C 5) alkyl, (C 0 -C 8) -N (R 6) 2 alkyl, (C 1 -C 8) -0 R 5 alkyl, alkyl of (C? -Cβ) -C (0) 0R5, (Cx-C8) -0 (CO) R5 alkyl or C (0) 0R5; R 4 is (C 1 -C 8) alkyl, (C 2 -C 8) alkenyl, (C 2 -C 8) alkynyl, benzyl, aryl, (C 1 -C 4) -heterocycloalkyl (C 1 -C 6) alkyl or (C0-C4) -heteroaryl of (C2-C5); R5 is (C? -C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, benzyl, aryl or (C2-Cs) heteroaryl; each case of R6 is independently H, alkyl of (C? -C8), (C2-C8) alkenyl, (C2-C8) alkynyl, benzyl, aryl, (C2-C5) heteroaryl or (C0-C8) alkyl-C (0) 0-R5 or the R6 groups can be joined to form a heterocycloalkyl group; n is 0 or 1; and * represents a chiral carbon center. In the specific compounds of the formula II, when n is 0, then R1 is (C3-C7) cycloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, benzyl, aryl, (C0-) alkyl C4) -heterocycloalkyl of (C? -C5), (C0-C4) alkyl-heteroaryl of (C2-C5), C (0) R3, C (0) 0R4, (C_-C8) alkyl -N ( R6) 2, (C? -C8) -0R5 alkyl, (C_-C8) alkyl -C (0) 0R5, C (S) NHR3 or (CrC8) -0 (CO) R5 alkyl; R2 is H or (C? -C8) alkyl; and R3 is (C? -C8) alkyl, (C3-C7) cycloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, benzyl, aryl, (C0-C4) alkyl -heterocycloalkyl (C? -C6), (C0-C) alkyl- (C2-C5) heteroaryl, (C5-C8) -N (R6) 2 alkyl; (C0-C8) alkyl -NH-C (O) 0-R5; (C? -C8) -OR5 alkyl, (C? -C8) -C (0) OR5 alkyl, (C? -C8) alkyl-O (CO) R5 or C (0) OR5; and the other variables have the same definitions. In other specific compounds of the formula 'II, R2 is H or (C_-C) alkyl. In other specific compounds of formula II, R1 is (C? -C8) alkyl or benzyl. a i '> u_ I - • - - • • • • - ~ ''. - -. '?. ". - '"---. -".-.-', aJ < "In other specific compounds of formula II, R1 is H, (C_-C8) alkyl, benzyl, CH2OCH3, CH2CH2OCH3, or In another embodiment of the compounds of the formula II, R1 is wherein Q is 0 or S, and each case of 'R7 is independently H, (C? ~ C8) alkyl, (C3-C7) cycloalkyl, alkenyl of. (C2-C8), (C2-C8) alkynyl, benzyl, aryl, halogen, (C0-C4) alkyl -heterocycloalkyl of (C? -C6), (C0-C4) alkyl -heteroaryl of (C2- C5), (C0-C8) alkyl -N (R6) 2, (C! -C8) -OR5 alkyl, (C? -8) alkyl-C (O) OR5, (C? -8) alkyl ) alkyl-0 (CO) R5 or C (0) OR5, or the cases Adjacent R7 can be taken together to form a bicyclic alkyl or an aryl ring. In other specific compounds of formula II, R1 is C (0) R3. In other specific compounds of formula II, R3 is (C0-C4) alkyl-heteroaryl of (C2-C5), alkyl of (C? -8), aryl or (C0-C4) alkyl-OR5. In other specific compounds of the formula II, the heteroaryl is pyridyl, furyl or thienyl. - In other specific compounds of the formula II, R1 is C (0) 0R4. In other specific compounds of the formula II, the H of C (0) NHC (0) can be replaced with (C_-C4) alkyl, aryl or benzyl. Additional examples of the compounds in this class include, but are not limited to: [2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-lH-isoindol-4 -ylmethyl] -amide; (2- (2, β-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-lJ-isoindol-4-ylmethyl) -carbamic acid tert-butylester; 4- (aminomethyl) -2- (2, β-dioxo (3-piperidyl)) -isoindolin-1,3-dione; N- (2- (2,6-dioxo-piperidin-3-yl) -1,3-dioxo-2,3-dihydro-l-isoindol-4-ylmethyl) -acetamide; N-. { (2- (2, ß-dioxo (3-piperidyl) -1, 3-dioxoisoindolin-4-yl) methyl J-cyclopropyl-carboxamide; 2-chloro-N-. {(2- (2,6-dioxo (3 -piperidyl)) -1, 3-dioxoisoindolin-4-yl) methyl.} acetamide, N- (2- (2,6-dioxo (3- piperidyl)) -1,3-dioxoisoindolin-4-yl) -3-pyridylcarboxamide; 3- . { l-oxo-4- (benzylamino) isoindolin-2-yl} piperidin-2,6-dione; 2- (2,6-dioxo (3-piperidyl)) -4- (benzylamino) isoindoline-1,3-dione; N-. { (2 - (2,6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) methyl} propionamide; N-. { (2- (2,6-dioxo (3-piperidyl)) -1,3-dioxoisoindolin-4-yl) methyl} -3-pyridylcarboxamide; N { (2- (2,6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) methyl} heptanamide; N-. { (2- (2,6-dioxo (3-piperidyl)) -1,3-dioxoisoindolin-4-yl) methyl} -2-furylcarboxamide; acetate. { ? - (2- (2,6-dioxo (3-piperidyl)) -1,3-dioxoisoindolin-4-yl) carbamoyl} methyl; N- (2- (2,6-dioxo (3-piperidyl)) -1,3-dioxoisoindolin-4-yl) pentanamide; N- (2 - (2,6-dioxo (3-piperidyl)) -1,3-dioxoisoindolin-4-yl) -2-thienylcarboxamide; ? -. { [2- (2,6-dioxo (3-piperidyl)) -1,3-dioxoisoindolin-4-yl] methyl} (butylamino) carboxamide; ? -. { [2- (2,6-dioxo (3-piperidyl)) -l, 3-dioxoisoindolin-4-yl] -methyl} (octylamino) carboxamide; Y ?-. { [2- (2,6-dioxo (3-piperidyl)) -1,3-dioxoisoindolin-4-yl] methyl} (benzylamino) carboxamide. Still other specific immunomodulatory compounds of the invention belong to a class of isoindolimides described in US Patent Application Publication Nos. US 2002/0045643, International Publication No. WO 98/54170, and US Patent No. 6,395,754, each one of which is incorporated in the present for reference. Representative compounds are of formula III: and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereoisomers, racemates and mixtures of stereoisomers thereof, wherein: one of X and Y is C = 0 and the other is CH2 or C = 0; R is H or CH20C0R '; (i) each of R1, R2, R3 or R4 independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 or R 4 is nitro or -NHR 5 and the remainder of R 1, R 2, R 3 or R 4 are hydrogen; R5 is hydrogen or alkyl of 1 to 8 carbons R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro; R 'is R7-CHR10-N (R8R9); R7 is m-phenylene or p-phenylene or - (CnH2n) - wherein n has a value of 0 to 4; each of R8 and R9 taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene or -CH2CH2X1CH2CH2- wherein X_ is -O-, -S- or -NH-; R10 is hydrogen, alkyl of 8 carbon atoms or phenyl; and * represents a chiral carbon center. Other representative compounds are of the formula: where: one of X and Y is C = 0 and the other of X and Y is C = 0 or CH2; (i) each of R1, R2, R3 or R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 and R 4 is -NHR 5 and the rest of R 1, R 2, R 3 and R 4 are hydrogen; R5 is hydrogen or alkyl of 1 to 8 carbon atoms; R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro; R7 is m-phenylene or p-phenylene or - (CnH2n) - wherein n has a value of 0 to 4; each of R8 and R9 taken independently of another is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene or -CH2CH2 X1CH2CH2- wherein X1 is -0-, -S- or -NH-; R10 is hydrogen, alkyl of 8 carbon atoms or phenyl. Other representative compounds are of the formula: where one of X and Y is C = 0 and the other of X and Y is C = 0 or CH2; each of R1, R2, R3 and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 and R4 is nitro or protected amino and the rest of R1, R2, R3 and R4 are hydrogen; and R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro. Other representative compounds are of the formula: where: one of X and Y is C = 0 and the other of X and Y is C = 0 or CH2; (i) each of R1, R2, R3 and R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3 and R4 is -NHR5 and the rest of R1, R2, R3 and R4 are hydrogen; R5 is hydrogen, alkyl of 1 to 8 carbon atoms, or CO-R7-CH (R10) NR8R9 wherein each of R7, R8, R9 and R10 is as defined herein; and R6 is alkyl of 1 to 8 carbon atoms, benzo, chloro or fluoro. Specific examples of the compounds are of the formula: where: one of X and Y is C = 0 and the other of X and Y is C = 0 or CH2; R6 is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, chloro or fluoro; R7 is m-phenylene, p-phenylene or - (CnH2n) - wherein n has a value of 0 to 4; each of R8 and R9 taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene or -CHCH2X: 1CH2CHa- wherein X1 is -O-, -S - or -NH-; and R10 is hydrogen, alkyl of 1 to 8 carbon atoms or phenyl; Preferred immunomodulatory compounds of the invention are 4- (amino) -2- (2,6-dioxo (3-piperidyl)) -isoindolin-1,3-dione and 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione. The compounds can be obtained by synthetic, standard methods (see, for example, U.S. Patent No. 5,635,517, incorporated herein by reference). The compounds are available from Celgene Corporation, Warren, NJ. 4- (Amino) -2- (2,6-dioxo (3-piperidyl)) -isoindolin-1,3-dione has the following chemical structure: The compound 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione has the following chemical structure: In another embodiment, specific immunomodulatory compounds of the invention encompass polymorphic forms of 3- (4-amino-1-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione such as Form A, B, C, D, E, F, G and H, described in the North American provisional application No. 60 / 499,723 filed on September 4, 2003, which is incorporated herein by reference. For example, Form A of 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione is a crystalline, unsolvated material obtainable from non-aqueous solvent systems. Form A has an X-ray powder diffraction pattern comprising significant peaks at about 8, 14.5 16, 17.5, 20.5, 24 and 26 degrees 2 ?, and has a maximum differential scanning calorimetry melting temperature of about 270 ° C. Form A is weak or non-hygroscopic and appears to be the most thermodynamically stable anhydride polymorph of 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione discovered Until now . Form B of 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione is a crystalline material, hemihydrate, which can be obtained from various solvent systems, including, but not limited to, hexane, toluene and water. Form B has an X-ray powder diffraction pattern that comprises significant peaks at approximately 16, 18, 22 and 27 degrees 2 ?, and has endotherms of the DSC curve of approximately 146 and 268 ° C, which are dehydration identified and fusion by microscopy experiments in stages of heat. Interconversion studies show that Form B converts to Form E in aqueous solvent systems, and converts to other forms in acetone and other anhydrous systems. Form C of 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione is a hemisolvated crystalline material obtainable from solvents such as , but not limited to, acetone. Form C has an X-ray powder diffraction pattern comprising significant peaks at approximately 15.5 and 25 degrees 2 ?, and has a maximum differential scanning calorimetry melting temperature of approximately 269 ° C. Form C is not hygroscopic below approximately 85% RH, but can convert to Form B at higher relative humidity. Form D of 3- (4-amino-1-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione is a crystalline, solvated polymorph prepared from a mixture of acetonitrile and Water. Form D has a dust diffraction pattern of X-rays that comprise significant peaks at approximately 27 and 28 degrees 2? and has a maximum differential scanning calorimetry melting temperature of about 270 ° C. Form D is either weakly or non-hygroscopic, but will normally convert to Form B when accentuated at higher relative humidities. Form E of 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione is a crystalline material dihydrate, which can be obtained by suspension of 3- ( 4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione in water and by slow evaporation of 3- (4-amino-1-oxo-1, 3 dihydro-isoindol-2-yl) -piperidin-2,6-dione in a solvent system. with a ratio of approximately 9: 1 acetone: water. Form E has an X-ray powder diffraction pattern comprising significant peaks at approximately 20, 24.5 and 29 degrees 2 ?, and has a maximum differential scanning calorimetry melting temperature of approximately 269 ° C. Form E can be converted to Form C in an acetone solvent system and Form G in a THF solvent system. In aqueous solvent systems, Form E appears to be the most stable form. The desolvation experiments performed in Form E show that until heating at approximately 125 ° C for about five minutes, Form E can be converted to Form B. Until heating at 175 ° C during For approximately five minutes, Form B can be converted to Form F. Form F of 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione is an unsolvated crystalline material obtainable from the dehydration of Form E. Form F has an X-ray powder diffraction pattern comprising significant peaks of approximately 19, 19.5 and 25 degrees 2 ?, and has a temperature Maximum differential scanning calorimetry fusion temperature of approximately 269 ° C. Form G of 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione is an unsolvated crystalline material, which can be obtained from a suspension of the forms B and E in a solvent such as, but not limited to, tetrahydrofuran (THF). Form G has an X-ray powder diffraction pattern that comprises significant peaks at approximately 21, 23 and 24.5 degrees 2? and has a maximum differential scanning calorimetry melting temperature of about 267 ° C. Form H of 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione is a partially hydrated crystalline material that can be obtained by exposing Form E to 0% relative humidity. Form H has an X-ray powder diffraction pattern comprising significant peaks at approximately 15, 26 and 31 degrees 2 ?, and has a differential scanning calorimetry melting temperature of approximately 269 ° C. Other specific immunomodulatory compounds of the invention include, but are not limited to l-oxo-2- (2,6-dioxo-3-fluoropiperidin-3-yl) isoindolines and 1,3-dioxo-2- (2,6-dioxo- 3-fluoropiperidin-3-yl) isoindolines such as those described in U.S. Patent Nos. 5,874,448 and 5,955,476, each of which is incorporated herein by reference. The representative compounds are of the formula: wherein Y is oxygen or H2 and each of R1, R2, R3 and R4, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or amino. Other specific immunomodulatory compounds of the invention include, but are not limited to the tetra substituted 2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindolines described in U.S. Patent No. 5,798,368, which is incorporated herein by reference. for reference. The representative compounds are of the formula: wherein each of R1, R2, R3 and R4 independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms. Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo and 1,3-dioxo-2- (2,6-dioxopiperidin-3-yl) isoindolines described in US Patent No. 6,403,613, which is incorporated herein by reference. incorporated in the present for reference. The representative compounds are of the formula: wherein Y is oxygen or H2, a first of R1 and R2 is halo, alkyl, alkoxy, alkylamino, dialkylamino, cyano or carbamoyl, the second of R1 and R2, independently of the first, is hydrogen, halo, alkyl, alkoxy, alkylamino , dialkylamino, cyano or carbamoyl, and R3 is hydrogen, alkyl or benzyl.

Specific examples of the compounds are of the formula: wherein a first of R1 and R2 is halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, dialkylamino wherein each alkyl is 1 to 4 carbon atoms, cyano or carbamoyl, the second of R1 and R2, independently of the first, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino wherein the alkyl is 1 to 4 carbon atoms, dialkylamino wherein each alkyl is from 1 to 4 carbon atoms, cyano or carbamoyl, and R3 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl. Specific examples include, but are not limited to l-oxo-2- (2,6-dioxopiperidin-3-yl) -4-methylisoindoline. Other representative compounds are of the formula: wherein a first of R1 and R2 is halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, dialkylamino wherein each alkyl is 1 to 4 carbon atoms, cyano or carbamoyl, the second of R1 and R2, independently of the first, is hydrogen, halo, alkyl from 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylamino wherein alkyl is 1 to 4 carbon atoms, dialkylamino wherein each alkyl is 1 to 4 carbon atoms, cyano or carbamoyl, and R3 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl. Specific examples include, but are not limited to l-oxo-2- (2,6-dioxopiperidin-3-yl) -4-methylisoindoline and enantiomers thereof, which is described in US Pat. No. 6,403,613, which is incorporated herein by reference. Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo and 1,3-dioxoisoindolines substituted at the 4 or 5 position of the indoline ring described in US Pat. No. 6,380,239, and the co-pending North American application. 10 / 900,270, filed July 28, 2004, which is incorporated herein by reference. The representative compounds are of the formula: wherein the carbon atom designated C * constitutes a chiral center (when n is not zero and Rx is not the same as R2); one of X1 and X2 is amino, nitro, alkyl of one to six carbons or NH-Z, and the other of X1 or X2 is hydrogen; each of R1 and R2 independently of the other, is hydroxy or NH-Z; R3 is hydrogen, alkyl of one to six carbons, halo, or haloalkyl; Z is hydrogen, aryl, alkyl of one to six carbons, formyl, or acyl of one to six carbons; and n has a value of 0, 1 or 2; with the proviso that if X1 is amino, and n is 1 or 2, then R1 and R2 are not both hydroxy; and the salts thereof. Additional representative compounds are of the formula: wherein the carbon atom designated C * constitutes a center of chirality (when n is not zero and R1 is not R2, one of X1 and X2 is amino, nitro, alkyl of one to six carbons or NH-Z, and the other of X1 or X2 is hydrogen; one of R1 and R2 independently of the other, is hydroxy or NH-Z; R3 is alkyl of one to six carbons, halo or hydrogen; Z is hydrogen, aryl or an alkyl or acyl of one to six carbons; and n has a value of 0, 1 or 2. Specific examples include, but are not limited to 2- (4-amino-1-oxo-l, 3-dihydro-isoindol-2-yl) -4-carbamoyl-butyric acid and 4- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -4-carbamoyl-butyric acid, which have the following structures, respectively, and salts, solvates, prodrugs and stereoisomers pharmaceutically acceptable thereof.

Other representative compounds are of the formula: wherein the carbon atom designated C * constitutes a center of quarity when n is not zero and R1 is not R2; one of X1 and X2 is amino, nitro, alkyl of one to six carbons, or NH-Z, and the other of X1 or X2 is hydrogen; each of R1 and R2 independently of the other, is hydroxy or NH-Z; R3 is alkyl of one to six carbons, halo or hydrogen; Z is hydrogen, aryl or an alkyl or acyl of one to six carbons; and n has a value of 0, 1 or 2; and the salts of it. Specific examples include, but are not limited to, 4-carbamoyl-4 acid. { 4- [(furan-2-yl-methyl) -amino] -1,3-dioxo-1,3-dihydro-isoindol-2-yl} -butyric, 4-carbamoyl-2- acid. { 4- [(furan-2-yl-methyl) -amino] -1,3-dioxo-l, 3-dihydro-isoindol-2-yl} -butyric, acid 2-. { 4- [(furan-2-yl-methyl) -amino] -1,3-dioxo-1,3-dihydro-isoindol-2-yl} -4-phenylcarbamoyl-butyric acid and 2- [4- [(furan-2-yl-methyl) -amino] -1,3-dioxo-l, 3-dihydro-isoindol-2-yl acid} -pentandioic, which have the following structures, respectively, and pharmaceutically acceptable salts, solvates, prodrugs and stereoisomers thereof.

Other specific examples of the compounds are of the formula: where one of X1 and X2 is nitro or NH-Z, and the other of X1 or X2 is hydrogen; each of R1 and R2, independently of the other is hydroxy or NH-Z; R3 is alkyl of one to six carbons, halo or hydrogen; Z is hydrogen, phenyl, an acyl of one to six carbons, or an alkyl of one to six carbons; and n has a value of 0, 1 or 2; with the proviso that if one of X1 and X2 is nitro, and n is 1 or 2, then R1 and R2 are different from hydroxy; and if -COR1 and - (CH2) _COR2 are different, the carbon atom designated C * constitutes a center of chirality. Other representative compounds are of the formula: where one of X1 and X2 is alkyl of one to six carbons; each of R1 and R2, independent of the other, is hydroxy or NH-Z; R3 is alkyl of one to six carbons, halo or hydrogen; Z is hydrogen, phenyl, an acyl of one to six carbons, or an alkyl of one to six carbons; and n has a value of 0, 1 or 2; and if -COR1 and - (CH2) nCOR2 are different, the carbon atom designated C * constitutes a center of chirality. Still other specific immunomodulatory compounds of the invention include, but are not limited to, isoindolin-1-one and isoindoline-1,3-dione substituted at the 2-position with 2,6-dioxo-3-hydroxypiperidin-2-yl described in U.S. Patent No. 6,458,810, which is incorporated herein by reference. The representative compounds are of the formula: wherein: the designated carbon atoms * constitute centers of chirality; X is -C (O) - or -CH2-; R1 is alkyl of 1 to 8 carbon atoms or -NHR3; R2 is hydrogen, alkyl of 1 to 8 carbon atoms 0 halogen; And R3 is hydrogen, alkyl of 1 to 8 carbon atoms, substituted or unsubstituted with alkoxy of 1 to 8 carbon atoms, halo, amino or alkylamino of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, substituted or unsubstituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino or alkylamino of 1 to 4 carbon atoms, benzyl, substituted or unsubstituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino or alkylamino of 1 to 4 carbon atoms or -COR4 wherein R 4 is hydrogen, alkyl of 1 to 8 carbon atoms, substituted or unsubstituted with alkoxy of 1 to 8 carbon atoms, halo, amino or alkylamino of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, substituted or unsubstituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino or alkylamino of 1 to 4 carbon atoms, or benzyl, substituted or unsubstituted with alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, halo, amino or alkylamino of 1 to 4 carbon atoms. The compounds of the invention can be purchased or prepared commercially according to the methods described in the patents or patent publications described herein. In addition, the optically pure compounds can be synthesized or resolved asymmetrically using known solution agents or chiral columns as well as other standard synthetic organic chemistry techniques. As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" encompasses non-toxic base and acid addition salts of the compound to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases known in the art, including, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, acid tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid and the like. Compounds that are acidic by nature are capable of salts with various pharmaceutically acceptable bases. The bases that can be used to prepare Pharmaceutically acceptable base addition salts of such acidic compounds are those which form non-toxic base addition salts, ie, salts containing pharmacologically acceptable cations such as, but not limited to, alkali metal or alkaline earth metal salts and salts of calcium, magnesium, sodium or potassium in particular. Suitable organic bases include, but are not limited to, N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine. As used in this, and unless otherwise specified, the term "solvate" means a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is hydrate. As used herein and unless otherwise indicated, the term "pro-drug" means a derivative of a compound that can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of immunomodulatory compounds of the invention comprising biohydrolyzable portions such as amides biohydrolyzables, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides and biohydrolyzable phosphate analogues. Other examples of pro-drugs include derivatives of immunomodulatory compounds of the invention comprising portions -NO, -N02, -ONO or -ON02. Pro-drugs can normally be prepared using well-known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985). As used herein and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureido", "biohydrolyzable phosphate" mean an amide, an ester, a carbamate, a carbonate, a ureide or a phosphate, respectively of a compound that either: 1) does not interfere with the biological activity of the compound, but may confer advantageous properties on that compound in vivo, such as incorporation, the duration of action, or the start of action; or 2) is biologically inactive, but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (Such as acetoxilmetilo, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloiloxietilésteres), lactonilésteres (such as phthalidyl and tioftalidilésteres), lower alcoxiaciloxialquilésteres (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxicarboniloxietilésteres), alcoxialquilésteres, choline esters and alkyl acylamino (such as acetamidometilésteres). Examples of biohydrolyzable amides include, but are not limited to, lower alkylamides, α-amino acid amides, alkoxyacylamides and alkylaminoalkylcarbonylamides. Examples of hydrolysable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines and polyetheramines. As used herein, and unless otherwise specified, the term "stereoisomer" encompasses all the enantiomerically / stereomerically pure and enantiomerically / stereomerically enriched compounds of this invention. As used herein, and unless otherwise indicated, the term "stereomerically pure" or "enantiomerically pure" means that a compound comprises a stereoisomer and is substantially free of its anti-stereoisomer or enantiomer. For example, a The compound is stereomeric or enantiomerically pure when the compound contains 80%, 90% or 95% or more of a stereoisomer and 20%, 10% or 5% less of the anti-stereoisomer. In certain cases, a compound of the invention is considered optically active or stereomeric / enantiomerically pure (i.e., substantially the R-form or substantially the S-form) with respect to a chiral center when the compound is about 80% ee (enantiomeric excess) or greater, preferably equal to, or greater than 90% ee with respect to a particular chiral center, and more preferably 95% ee with respect to a particular chiral center. As used herein, and unless otherwise indicated, the term "stereomerically enriched" or "enantiomerically enriched" encompasses racemic mixtures as well as other mixtures of the stereoisomers of the compounds of this invention (eg, R / S = 30/70, 35/65, 40/60, 45/55, 55/45, 60/40, 65/35 and 70/30). Various immunomodulatory compounds of the invention contain one or more chiral centers, and may exist as racemic mixtures of enantiomers or mixtures of diastereomers. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures that comprise equal or unequal amounts of enenatomers of immunomodulatory compounds can be used in methods and compositions of the invention. These isomers can be synthesized or analyzed using standard techniques such as chiral columns or chiral solution agents. See, for example, Jacques, J., et al. , Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S.H., et al. , Tetrahedron 33: 2725 (1977); Eliel, E. L., Stereochemistry of Coal Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN, 1972). It should be noted that if there is a discrepancy between a structure described and a name given to that structure, the structure described will give more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated by, for example, solid lines or dashed lines, the structure or a portion of the structure is to be construed as encompassing all stereoisomers thereof. 4. 2 SECONDS ACTIVE AGENTS A second active agent can be used in the methods and compositions of the invention together with an immunomodulatory compound. It is believed that certain combinations work synergistically in the treatment of diseases or disorders related to asbestos. An immunomodulatory compound may also work to alleviate adverse effects associated with certain second active agents, and some second active agents may be used to alleviate adverse effects associated with an immunomodulatory compound. One or more second active agents can be used in the methods and compositions of the invention together with an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. Second active agents may be large molecules (eg, proteins) or small molecules (eg, synthetic inorganic, organometallic or organic molecules). Examples of active agents of large molecules are biological molecules, such as proteins of natural origin or made artificially. Particular proteins include, but are not limited to: cytokines such as GM-CSF, interleukins such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12 e IL-18; and interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-la and interferon gamma-Ib. In one embodiment of the invention, the large molecule active agent reduces, eliminates or prevents an effect adverse event associated with the administration of an immunomodulatory compound. Depending on the disease or disorder being treated, adverse effects may include, but are not limited to, numbness, drowsiness, nausea, vomiting, gastrointestinal upset, diarrhea, and vasculitis. Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of an immunomodulatory compound. Like some large molecules, many are believed to be capable of providing a synergistic effect when administered with (eg, before, after or at the same time) an immunomodulatory compound. Examples of second small molecule active agents include, but are not limited to anti-cancer agents, antibiotics, anti-inflammatory agents and steroids. Examples of anti-cancer agents include, but are not limited to: acivicin; aclarubicin; benzoyl hydrochloride; Acronine; adozelesina; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlina; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; sodium brequinar; biririmine; busulfan; cactinomycin; calusterona; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; Corylemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; Dacarbazine; Dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; Doxorubicin hydrochloride; droloxifene; Droloxifene citrate; drornostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromato; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; sodium estramustine phosphate; etanidazole; etoposide; etoposide phosphate; etoprin; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; Fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; sodium fostriecin; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosin; iproplatin; Irinotecan; Irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansina; mechlorethamine hydrochloride; Megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; sodium methotrexate; metoprine; meturedepa; mitinomide; mitocarcin; mitochromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; Peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; pentamethane; porfimer of sodium; porphyromycin; Prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine; simtrazene; sodium esparfosate; Esparsomycin; Spirogermanium hydrochloride; spiromustine; Spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalan; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; Teroxirone; testolactone; tiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamine; Toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidin sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zipiplatine; zinostatin; and zorubicin hydrochloride. Other anti-cancer drugs include, but are not limit to: 20-epi-l, 25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acilfulveno; adecipenol; adozelesina; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrografol; inhibitors of angiogenesis; antagonist D; antagonist G, antarelix; morphogenetic protein 1 anti-dorsolization; antiandrogen, prosthetic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; afidicolin glycinate; modulators of the apoptosis gene; apoptosis regulators; Apurinic acid; ara- CDP-DL-PTBA; arginine deaminase; asulacrine; atamestana; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathirosine; Baccatin III derivatives; balanol batimastat; BCR / ABL antagonists; benzoclorins; benzoylstaurosporine; beta lactam derivatives; beta-aletine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylpermine; bisnafida; bistratene A; bizelesin; breflato; biririmine; budotitan; butionine sulfoximine; calcipotriol; calfostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; inhibitor derived from cartilage; carzelesin; inhibitors of casein kinase (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; colismicin TO; colismicin B; combretastatin A4; combretastatin analogue; conagenina; crambescidin 816; crisnatol; cryptophycin 8; Cryptophycin A derivatives; curacin A; cyclopentantraquinones; Cycloplatam; cipemycin; cytarabine ocphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnospermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmicin SA; ebselen; ecomustine; edelfosin; Edrecolomab; eflornithine; elemena; emitefur; epirubicin; epristerida; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; Finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine, - ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulina; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifen; idramantone; ilmofosin; ilomastat; imatinib (for example, Gleevec®), imiquimod; immunostimulatory peptides; inhibitor of growth factor-1 receptor similar to insulin; interferon agonists; interferons; interleukins; iobenguan; iododoxorubicin; ipomeanol; 4-; iroplact; irsogladine; isobengazol; isohomohalicondrine B; itasetron; jasplaquinolide; kahalaluro F; lamelarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; Leukemia inhibition factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin, - levamisole; liarosol; linear polyamine analog; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lyophilin; lytic peptides; Maytansine; Handstatin A; marimastat; masoprocol; maspina; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; they went meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; fibroblast growth factor of mitotoxin-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotropin; cell wall sk of A + monophosphoryl lipid mycobacterium; mopidamol; mustard anticancer agent; micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavina; nafterpina; nartograstim; nedaplatin; memorubicin; neridronic acid; nilutamide; nisamycin; Nitric oxide modulators; nitroxide antioxidant; nitrulin; oblimersen (Genasense®); 06-benzylguanine; octreotide; okicenona; oligonucleotides; onapristone; ondansetron; ondansetron; oracine; oral cytokine inducer; ormaplatin; osaterone; Oxaliplatin; oxaunomycin; paclitaxel; Paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrizoxin; pamidronic acid; panaxytriol; panomiphene; parabactin; pazeliptina; pegaspargase; peldesina; sodium pentosan polysulfate; pentostatin; pentrozole; perflubron; perfosfamide; perilic alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetina A; placetina B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer of sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; immunomodulator based on protein A; inhibitor of protein kinase C; inhibitors of protein kinase C, microalgal; inhibitors of the protein tyrosine phosphatase; inhibitors of nucleoside purine phosphorylase; purpurins; pyrazoloacridine; conjugate of hemoglobin-polyoxyethylene pyridoxylates; raf antagonists; raltitrexed; ramosetron; ras rasnesyl transferase pin inhibitors; ras inhibitors; ras-GAP inhibitor; Demethylated reteliptine; rhenium etidronate Re 186; rhizoxin; ribozymes; Retinamide RII, roitukine; romurtida; roquinimex; Rubiginone Bl; ruboxyl; safingol; saintopine; SarCNU; sarcofitol A; sargramostim; Sdi imitators 1; semustine; inhibitor 1 derived from senescence; sense oligonucleotides; inhibitors of signal transduction; sizofiran; Sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; Somatomedin binding pin; sonermin; Esparfosic acid; Spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stihadid; stromelysin inhibitors; Sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista suramin; suainsonin; talimustine; tamoxifen methiodide; tauromustine; tazane; sodium tecogalan; tegafur; telurapyrilio; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; Taliblastine; thiocoraline; thrombopoietin; thrombopoietin mimic; timalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulation hormone; ethyl etiopurpurine tin; tirapazamine; titanocene bichloride; topsentin; toremifene; Translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; Tyrphostins; UBC inhibitors; ubenimex; growth inhibitory factor derived from the urogenital sinus; Urokinase receptor antagonists; vapreotide; Variolin B; velaresol; veramina; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zipiplatine; zilascorb; and zinostatin estimalmer. Second specific active agents include, but are not limited to anthracycline, platinum, alkylating agent, oblimersen (Genasense®), gemcitabine, cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, methotrexate, taxotere, irinotecan, topotecan, temozolomide , capecitabine, cisplatin, thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mepacrine, thiotepa, tetracycline and mitomycin C. 4. 3 METHODS OF TREATMENT AND HANDLING The methods of this invention encompass methods for treating, preventing and / or managing various types of diseases and disorders related to asbestos. As used in the present, unless otherwise specified, the term "treating" refers to the administration of an immunomodulatory compound or other additional active agent after the onset of the symptoms of asbestos-related diseases or disorders, while "preventing" is refers to administration before the onset of symptoms, particularly to patients at risk for mesothelioma or other asbestos-related disorders. The term "prevent" includes inhibiting or avoiding a symptom of the particular disease or disorder. Symptoms of diseases or disorders related to asbestos include, but are not limited to, dyspnea, diaphragm obstruction, radiolucent sheet-like covering of the pleura, pleural effusion, pleural thickening, decreased breast size, chest ailment, chest pain, easy fatigability, fever, sweating and weight loss. Examples of patients at risk of diseases or disorders related to asbestos include, but are not limited to those who have been exposed to asbestos in the workplace and their family members who have been exposed to asbestos embedded in work clothes. Patients who have a family history of diseases or disorders related to asbestos are also preferred candidates for preventive regimens. As used herein and unless it is in other words, the term "management of asbestos-related diseases or disorders" includes preventing the recurrence of diseases or disorders in a patient who has suffered from the diseases or disorders, and / or the prolongation of time that a patient who has suffered from those remains in remission. Methods encompassed by this invention comprise administering an immunomodulatory compound, or a salt, solvate, hydrate, stereoisomer, clathrate, or prodrug acceptable salt thereof to a patient (eg a human) suffering, or may suffer from diseases or disorders related to asbestos. Without being limited by theory, it is believed that the compounds of the invention can be administered prophylactically to prevent persons who have been previously exposed to asbestos from developing diseases or disorders related to asbestos. This prophylactic method can avoid, in the first place, actually developing diseases or disorders related to asbestos. Therefore, the invention encompasses a method for preventing diseases or asbestosrelated in people disorders who are at risk of diseases or asbestosrelated, comprising administering an effective amount of an immunomodulatory compound, or a salt, solvate, hydrate disorders, stereoisomer, pharmacologically acceptable prodrug or clathrate thereof, to those in need thereof. Without being limited by theory, it is also believed that the compounds of the invention can inhibit the spread of asbestos-related diseases or disorders after diagnosis, because the compounds can affect the production of cytokines (eg, TNF-α, IL-). 1/3 and IL12). The invention encompasses methods of treating, preventing and managing diseases or asbestosrelated in patients with various stages and specific types of diseases, including disorders, but not limited to, malignant mesothelioma, asbestosis, malignant pleural effusion, benign pleural effusion, pleural plaque , pleural calcification, diffuse pleural thickening, rounded atelectasis and bronchogenic carcinoma. If it also covers methods to treat patients who have been previously treated for diseases or disorders related to asbestos, but were not sensitive enough or were not sensitive, as well as those who have not been previously treated for diseases or disorders. Because patients have heterogeneous clinical manifestations and variable clinical outcomes, the treatment given to a patient may vary, depending on their prognosis. The specialist doctor will be able to easily determine without experimentation undue specific secondary agents and types of physical therapy that can be effectively used to treat a particular patient. In one embodiment of the invention, an immunomodulatory compound is administered orally and in daily, single or divided doses, in an amount of from about 0.10 mg to about 1,000 mg per day, from about 1 mg to about 1,000 mg per day, from about 1 mg to about 600 mg per day, from about 1 mg to about 250 mg per day, from about 5 mg to about 150 mg per day, or from about 10 mg to about 50 mg per day. In a particular embodiment, 4- (amino) -2- (2,6-dioxo (3-piperidyl)) -isoindolin-1,3-dione (Actimid ™) is administered in an amount from about 0.1 to about 1 mg per day, or alternatively from about 0.1 to about 5 mg every alternate day. In a preferred embodiment, 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione (Revimid ™) is administered in an amount from about 1 to about 25 mg per day or a higher dose, usually from about 1.5 to 2.5 times the daily dose every alternate day. In a particular embodiment, a method for preventing asbestos-related diseases comprises administering 3- (4-amino-1-oxo-l, 3-dihydro-isoindol-2-yl) - piperidin-2, 6-dione in an amount of about 1, 2.5, 5 or 10 mg per day as two divided doses in people who have recognized that they have been exposed to asbestos. In a particular embodiment of the prophylactic regimen, 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione is administered in an amount of about 5 mg at day. In the management of the patient, therapy should be started at a low dose, perhaps about 0.1 mg to about 10 mg, and if necessary increased to about 1 mg to about 1,000 mg per day either as a single dose or divided dose, depending on the overall response of the patient. 4.3.1 Combination Therapy with a Second Active Agent Specific methods of the invention comprise administering an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in combination with a second active agent. Examples of second active agents are described herein (see for example, section 4.2). The administration of an immunomodulatory compound and the second active agents to a patient can occur at the same time or sequentially by the same or different routes of administration. The adequacy of a particular route of administration used for a particular active agent it will depend on the active agent itself (for example, if it can be administered orally without decomposition before entering the bloodstream) and the disease being treated. A preferred route of administration of an immunomodulatory compound is oral. Preferred routes of administration for the second active agents of the invention are known to those of ordinary skill in the art, for example, in Physician's Desk Reference, 2003. The specific amount of the second active agent will depend on the specific agent used, the type, severity and stage of the diseases or disorders that are treated or handled, and the amount or amounts of immunomodulatory compounds and any additional optional active agents administered at the same time to the patient. In one embodiment, the second active agent is anthracycline, platinum, alkylating agent, oblimersen (Genasense®), cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, taxotere, irinotecan, capecitabine, cisplatin, thiotepa , fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil) ®), paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mecaprin, thiotepa, tetracycline and gemcitabine. In a specific embodiment, an immunomodulatory compound is administered in combination with vinorelbine to patients with malignant mesothelioma or mesothelioma syndrome of malignant pleural effusion. In another embodiment, an immunomodulatory compound is administered in combination with cyclophosphamide / adriamycin / cisplatin, cisplatin / methotrexate / vinblastine, cisplatin / gemcitabine, cisplatin / adriamycin / mitomycin C, bleomycin / intrapleural hyaluronidase, cisplatin / adriamycin, cisplatin / vinblastine / mitomycin C , gemcitabine / irinotecan, carboplatin / taxotere or carboplatin / pacilitaxel. 4. 3.2 Use with Conventional Therapy Standard methods of chemotherapy, radiation therapy, photodynamic therapy and surgery are used to treat or manage mesothelioma. Kaiser LR. , Semin Thorac Cardiovasc Surg. Oct; 9 (4): 383-90, 1997. Intracavirus methods using target cytokines and gene therapy have been examined in mesothelioma patients using recombinant adenovirus intratumoral (rAd) gene transfer containing the thymidine kinase gene of the herpes simplex virus (HSVtk) in the pleural space of patients. Jd. and Sterman DH, Hematol Oncol Clin North Am. Jun; 12 (3): 553-68, 1998. Certain embodiments of this invention encompass methods for treating or managing diseases or disorders related to asbestos, which comprise administering an effective amount of an immunomodulatory compound in conjunction with conventional therapy including (e.g. , before, during or after), but not limited to chemotherapy, surgery, photodynamic therapy, radiation therapy, gene therapy, immunotherapy or other therapy based on drugs currently used to treat or manage diseases or disorders. The combined use of an immunomodulatory compound and conventional therapy can provide a single treatment regimen that is unexpectedly effective in certain patients. As discussed elsewhere herein, the invention encompasses a method for reducing, treating and / or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, chemotherapy, photodynamic therapy, surgery, radiation therapy, gene therapy. and immunotherapy. An immunomodulatory compound and other active agent can be administered to a patient before, during or after the occurrence of the adverse effect associated with conventional therapy. Examples of adverse effects associated with chemotherapy and radiation therapy which can be treated or prevented by this method include, but are not limited to: gastrointestinal toxicity such as, but not limited to, diarrhea and flatulence of early and late formation; nausea; threw up; anorexy; leukopenia; anemia; neutropenia; asthenia; abdominal cramps; fever; pain; loss of body weight; dehydration; alopecia; dyspnoea; insomnia; dizziness, mucositis, dry mouth and renal failure. In one embodiment, an immunomodulatory compound is administered in an amount of from about 0.10 mg to about 1,000 mg per day, from about 1 mg to about 1,000 mg per day, from about 1 mg to about 500 mg per day, from about 1 mg to about 250 mg per day, from about 5 mg to about 150 mg per day, or from about 10 mg to about 50 mg per day orally and daily alone or in combination with a second active agent described herein (see for example, section 4.2) before, during or after the use of conventional therapy. In a specific modality of this method, an immunomodulatory compound and doxetaxol are administered to mesothelioma patients who have been previously treated with radiation therapy. In one modality of this method, a compound Immunomodulator is administered to patients with diseases or disorders related to asbestos in combination with trimodality therapy. Trimodality therapy involves a combination of three standard strategies of surgery, chemotherapy and radiation therapy. In one modality of this method, extrapleural pneumonectomy is followed by a combination of chemotherapy using an immunomodulatory compound and radiation therapy. In another embodiment of the trimodality treatment, an immunomodulatory compound is administered in combination with different chemotherapeutic regimens including a combination of cyclophosphamide / adriamycin / cisplatin, carboplatin / paclitaxel or cisplatin / methotrexate / vinblastine. 4. 3.3 Cycle therapy In certain embodiments, an immunomodulatory compound is administered cyclically to a patient. Cycle therapy involves the administration of an immunomodulatory compound over a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycle therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improve the effectiveness of the treatment. Consequently, in a specific modality of the invention, an immunomodulatory compound is administered daily in a single dose or divided into a cycle of four to six weeks with a rest period of about one week or two weeks. Typically, the number of cycles during which the combinatorial treatment is administered to a patient will be from about one to about 24 cycles, more usually from about two to about 16 cycles, and even more usually from about four to about six cycles. The invention also allows the frequency, number and duration of the dosing cycles to be increased. Thus, a specific embodiment of the invention encompasses the administration of an immunomodulatory compound for more cycles that are typical when administered alone. In another specific embodiment of the invention, an immunomodulatory compound is administered during a large number of cycles that would normally cause dose limiting toxicity in a patient who is not being given a second active agent. In one embodiment, an immunomodulatory compound is administered daily and continuously for three to four weeks in a dose of from about 0.1 to about 150 mg / d followed by an interval of one or two weeks in a cycle of four to six weeks. In another embodiment of the invention, a compound immunomodulator and a second active agent are administered orally, with the administration of an immunomodulatory compound that occurs 30 to 60 minutes before a second active agent, during a cycle of four to six weeks. In another embodiment, an immunomodulatory compound is administered with cisplatin in an amount of 100 mg / m2 on day 1 and gemcitabine in an amount of 1000 mg / m2 intravenously on days 1, 8 and day 15 of a cycle of 28 days for 6 cycles. 4. 4 PHARMACEUTICAL COMPOSITIONS AND UNIQUE UNIT DOSE FORMS Pharmaceutical compositions can be used in the preparation of single, single unit dosage forms. The pharmaceutical compositions and dosage forms of the invention comprise immunomodulatory compounds, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The pharmaceutical compositions and dosage forms of the invention may further comprise one or more excipients. The pharmaceutical compositions and dosage forms of the invention may also comprise one or more additional active ingredients. Consequently, the Pharmaceutical compositions and dosage forms of the invention comprise the active agents described herein (for example, immunomodulatory compounds, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent) . Examples of optional additional active agents are described herein (see for example, section 4.2). The unique unit dosage forms of the invention are suitable for oral, mucosal administration (eg, nasal, sublingual, vaginal, buccal or rectal) or parenteral (eg, subcutaneous, intravenous, bolus injection, intramuscular or intraarterial), transdermal or transcutaneous to a patient. Examples of dosage forms include, but are not limited to: tablets; pills; capsules, such as soft elastic gelatin capsules; wafers; trociscos; pills; dispersions; suppositories; powder; aerosols (for example, sprays or nasal inhalers); gels, liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or liquid water-in-oil emulsions), solutions and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (for example, solids crystalline and amorphous) which 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 normally vary depending on their use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active agents that it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active agents comprising an oral dosage form used to treat the same disease. These and other forms wherein the specific dosage forms encompassed by this invention will vary from one another will be readily apparent to those skilled in the art. See for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990). Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. If a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form it depends on a variety of factors well known in the art including, but not limited to, the manner in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients comprising primary or secondary amines are particularly susceptible to such accelerated decomposition. Accordingly, this invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose other than mono- or di-saccharides. As used herein, the term "lactose free" means that the amount of lactose present, if any, is insufficient to substantially increase the rate of degradation of an active ingredient. The lactose-free compositions of the invention may comprise excipients that are well known in the art and are listed, for example, in the American Pharmacopoeia (USP) 25-NF20 (2002). In general, the lactose-free compositions comprise active ingredients, a binder / filler, and a lubricant in pharmaceutically acceptable amounts. Preferred free lactose dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate. This invention also encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (eg, 5%) is widely accepted in pharmaceutical techniques as a means to simulate long-term storage in order to determine characteristics such as shelf-life of formulations stability over time. . See for example, Jens T., Carstensen, Drug Stabili ty: Principies & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. Thus, the effect of water in a formulation can be of greater significance since moisture and / or steam are commonly encountered during manufacturing, handling, packing, storage, shipping and the use of formulations. The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using low or anhydrous moisture containing ingredients and low humidity or low vapor conditions. The compositions Pharmaceuticals and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if substantial contact with moisture and / or vapor during manufacture, packing and / or storage is wait. An anhydrous pharmaceutical composition should be prepared and stored so that its anhydrous nature is maintained. Accordingly, the anhydrous compositions are preferably packaged using known materials to avoid exposure to water so that they can be included in suitable forms equipment. Examples of suitable packaging include, but are not limited to, hermetically sealed aluminum foil, plastics, dose unit containers (e.g., jars), blister packs and strip packaging. The invention further encompasses pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers", include, but are not limited to antioxidants such as ascorbic acid, pH buffers or saline buffers. As the amounts and types of excipients, the specific amounts and types of active ingredients in dosage form may differ depending on such factors as, but not limited to the route by which it will be administered to patients. However, typical dosage forms of the invention comprise an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in an amount of from about 1 to about 1,000 mg. Typical dosage forms comprise an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in an amount of 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 particular embodiment, a preferred dosage form comprises 4- (amino) -2- (2,6-dioxo (3-piperidyl)) -isoindoline-1,3-dione (Actimid ™) in an amount of about 1, 2.5, 5, 10, 25 or 50 mg. In a specific embodiment, a preferred dosage form comprises 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidine-2,6-dione (Revimid ™) in an amount of about 1, 2.5, 5, 10, 25 or 50 mg. Typical dosage forms comprise a second active agent in an amount of from about 1 to about 3,500 mg, from about 5 to about 2,500 mg, from about 10 to about 500 mg, or from about 25 to about 250 mg. Of course, the specific amount of the second active agent will depend on the specific agent used, the type of disease or disorder that is treated or managed, and the amount or amounts of immunomodulatory compounds and any optional additional active agents administered to the patient at the same time. 4. 4.1 Oral Dosage Forms The pharmaceutical compositions of the invention which are suitable for oral administration may be presented as discrete dosage forms, such as, but not limited to, tablets (eg, chewable tablets), pills, capsules and liquids (e.g. , flavored syrups). Such dosage forms contain predetermined amounts of active agents, and can be prepared by pharmacy methods well known to those skilled in the art. See generally, Remington'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 an intimate mixture with at least one excipient according to conventional pharmaceutical combination techniques. The excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, agents flavorings, preservatives and coloring agents. Examples of suitable excipients for use of solid oral dosage forms (e.g., powders, tablets, capsules and lozenges) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents. . Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the pharmacy methods. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then forming the product in the desired presentation if necessary. For example, a tablet can be prepared by compression or molding. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powders or granules, optionally mixed with an excipient. The molded tablets can be made by molding in a suitable machine a mixture of the wetted powdered compound with an inert liquid diluent.

Examples of excipients that can be used in the oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pre-gelatinized starch, hydroxypropylmethylcellulose (eg, Nos. 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viseose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ™ and Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talcum, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch and mixtures thereof. The binder or filler in the pharmaceutical compositions of the invention is normally presented from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. Disintegrants are used in compositions of the invention that provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant can disintegrate in storage, while those that contain too little can not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of the disintegrant used varies based on the type of the formulation, and is readily discernible by those skilled in the ordinary art. The normal pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of the disintegrant, preferably from about 1 to about 5 weight percent of the disintegrant. Disintegrants that may be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, sodium cross-smelose, crospovidone, potassium polacrilin, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algin, other celluloses, gums and mixtures thereof. Lubricants that may be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate , ethyl oleate, ethyl laureate, agar and mixtures thereof. Additional lubricants include, for example, a siloid silica gel (AEROSIL200, manufactured by W.R. Grace Co., of Baltimore, MD), a coagulated aerosol. of synthetic silicon (marketed by Degussa Co. of Plano, TX), CAB-O-SIL (a pyrogenic silica dioxide product sold by Cabot Co., of Boston, MA) and mixtures thereof. If used in all, the lubricants are normally used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms within which they are incorporated. A preferred solid oral dosage form of the invention comprises immunomodulatory compounds, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin. 4. 4.2 Forms of Delayed Release Dosage Active agents of the invention can be administered by controlled release means or by delivery arrangement which are well known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, example, hydroxypropylmethylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses unique unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel capsules, and lozenges that are adapted for controlled release. All controlled-release pharmaceutical products have a common goal to improve drug therapy over what was achieved by their uncontrolled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance that is used to cure or control the condition in a minimum amount of time. Advantages of controlled release formulations include the extended activity of the drug, a reduced frequency of dose, and increased adherence of the patient. In addition, formulations of Controlled release can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thus can affect the occurrence of side effects (eg, adverse). Most controlled release formulations are designed to initially release a quantity of drug (active ingredient) that immediately produces the desired therapeutic effect, and gradually and continuously release other amounts of drug that maintain this level of therapeutic or prophylactic effect for a period of time. extensive of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug that is metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various conditions including, but not limited to pH, temperature, enzymes, water or other physiological or compound conditions. 4. 4.3 Parenteral Dosage Forms Parenteral dosage forms can be administered to patients by several routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular and intra-arterial. Because that its administration normally deviates the patient's natural defenses against contaminants, the parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection and emulsions. Suitable carriers that can be used to provide the parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for USP Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection and Lactated Ringer's Injection; miscible vehicles in water 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 of the active ingredients described in present can also be incorporated in the parenteral dosage forms of the invention. For example, cyclodextrin and its derivatives can be used to increase the solubility of immunomodulatory compounds and their derivatives. See, for example, U.S. Patent No. 5,134,127, which is incorporated herein by reference. 4. 4.4 Topical and Mucosal Dosage Forms The topical and mucosal dosage forms of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions or other forms known to one skilled in the art. See for example, Remington's Pharmaceutical Sciences, 16fcl1 and 18th eds., Mack Publishing, Easton PA (1980 & 1990); e Jntroduction to Pharmaceutical Dosage Forms, 4th ed. , Read & Febiger, Philadelphia (1985). Suitable dosage forms for treating mucosal tissue within the oral cavity can be formulated as mouth rinses or as oral gels. Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical art, and depend on the particular tissue to which a given pharmaceutical composition or dosage form is will apply With that in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butan-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures thereof. to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants may also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See for example, Remington's 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 active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds, such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilic or lipophilic nature of one or more active ingredients so that delivery is improved. In this aspect, the stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or a surfactant, and as an agent that improves delivery or improves penetration. Different Salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition. 4. EQUIPMENT Normally, the active ingredients of the invention are not preferably administered to a patient at the same time or by the same route of administration. This invention therefore encompasses equipment which, when used by the practically physician, can simplify the administration of appropriate amounts of the active ingredients to a patient. A typical apparatus of the invention comprises a dosage form of immunomodulatory compounds, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, pro-drug or clathrate thereof. The equipment encompassed by this invention may further comprise additional active agents or a combination thereof. Examples of additional active agents include, but are not limited to anti-cancer agents, antibiotics, anti-inflammatory agents, steroids, immunomodulatory agents, cytokines, immunosuppressive agents or other therapeutics discussed herein (see for example, section 4.2). The equipment of the invention may further comprise devices that are used to administer theactive ingredients. Examples of such devices include, but are not limited to syringes, perfusion bags, patches and inhalers. The kits of the invention may further comprise pharmaceutically acceptable carriers that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the equipment may comprise a sealed container of a suitable vehicle wherein the active ingredient may be dissolved to form a sterile, particle-free solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: Water for USP Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection; Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection and Lactated Ringer's Injection; miscible vehicles in water 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.

. EXAMPLES The following studies are intended to further illustrate the invention without limiting its scope. . 1 PHARMACOLOGY STUDIES One of the biological effects normally exerted by immunomodulatory compounds is the reduction of TNF-a synthesis. Specific immunomodulatory compounds improve the degradation of TNF-a mRNA. TNF-a may play a pathological role in asbestos-related diseases. In a specific embodiment, inhibitions of TNF-a production after stimulation of LPS from human PBMC and human whole blood by 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) ) -piperidine-2,6-dione, 4- (amino) -2- (2,6-dioxo- (3-piperidyl)) -isoindole-1,3-dione or thalidomide were investigated in vi tro. The IC50 of 4- (amino) -2- (2,6-dioxo- (3-piperidyl)) -isoindolin-1,3-dione to inhibit the production of TNF-a after stimulation of PBMC LPS and Human whole blood were ~ 24 nM (6.55 ng / ml) and ~ 25 nM (6.83 ng / ml), respectively. The IC50 of 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione to inhibit the production of TNF-a after stimulation of PBMC LPS and Whole human blood were ~ 100 nM (25.9 ng / ml) and ~ 480 nM (103.6 ng / ml), respectively. Thalidomide, in contrast, had an IC50 of -194 μM (50.1 μg / ml) to inhibit TNF-a production after stimulation of PBMC LPS. In vitro studies suggest a profile of pharmacological activity for 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione or 4- (amino) -2- (2,6-dioxo- (3-piperidyl)) -isoindolin-1,3-dione is similar to, but 50 to 2,000 times more potent than thalidomide. In addition, it has been shown that 3- (4-amino-1-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione or 4- (amino) -2- (2 , 6-dioxo- (3-piperidyl)) -isoindolin-1,3-dione is approximately 50 to 100 times more potent than thalidomide in stimulating the proliferation of cells after primary induction by the activation of the T cell receptor (TCR). The compounds are also about 50 to 100 times more potent than thalidomide in increasing the production of IL2 and IFN-α. after TCR activation of PBMC (IL2) or T cells (IFN-?). In addition, the compounds exhibit dose-dependent inhibition of LPS-stimulated production of the pro-inflammatory cytokines TNF-α, IL1 / 3 and IL6 by PMBC while increasing the production of the anti-inflammatory cytokine IL10. . 2 CLINICAL STUDIES IN PATIENTS WITH MESOTHELIOMA Clinical trials with the administration of an immunomodulatory compound in an amount from about 1 mg to about 1,000 mg, from approximately 1 mg to approximately 500 mg, or from about 1 mg to about 250 mg per day are conducted in patients with asbestosis, malignant mesothelioma or mesothelioma syndrome of malignant pleural effusion. In a specific embodiment, patients receive approximately 1 mg to approximately 150 mg / day of 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione. alone or in combination with vinorelbine. Patients who experience clinical benefits are allowed to continue treatment. Other clinical studies are performed using 3- (4-amino-l-oxo-1,3-dihydro-isoindol-2-yl) -piperidin-2,6-dione in patients with non-amputated or recidivist mesothelioma who have not responded to conventional therapy. In one embodiment, 3- (4-amino-1-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione is administered in an amount of about 1 mg to about 150 mg / day to the patients. Treatment with 10 mg as a continuous oral daily dose is well tolerated. Studies in patients with mesothelioma or asbestosis treated with an immunomodulatory compound suggest that the drug has a therapeutic benefit in this disease. The embodiments of the invention described herein are only a sample of the scope of the invention. The entire scope of the invention is better understood with reference to the appended claims.

Claims (24)

1. CLAIMS 1. A method for treating, preventing or managing a disease or disorder related to asbestos, which comprises administering to a patient in need of such treatment, prevention or management of a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
2. 2. The method of claim 1, wherein the disease or disorder is mesothelioma, asbestosis, pleural effusion, pleural plaque, pleural calcification, diffuse pleural thickening, rounded atelectasis or bronchogenic carcinoma.
3. 3. The method of claim 1, further comprising administering to a patient a therapeutically or prophylactically effective amount of a second active agent.
4. 4. The method of claim 3, wherein the second active agent is an anti-cancer agent, an antibiotic, an anti-inflammatory agent, a steroid, an immunomodulatory agent, a cytokine, an immunosuppressive agent, or a combination thereof. same.
5. The method of claim 4, wherein the second active agent is anthracycline, platinum, alkylating agent, interferon, oblimersen, cisplatin, cyclophosphamide, irinotecan, topotecan, temozolomide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, methotrexate, taxotere, capecitabine, cisplatin, thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, GM-CSF, IL-2, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin, paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa, tetracycline or gemcitabine.
6. 6. A method for treating, preventing or managing a disease or disorder related to asbestos, which comprises administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a salt, pharmaceutically acceptable solvate or stereoisomer thereof, before, during or after chemotherapy, photodynamic therapy, surgery, radiation therapy, gene therapy, or immunotherapy.
7. The method of claim 6, wherein the disease or disorder is mesothelioma, asbestosis, pleural effusion, pleural plaque, pleural calcification, diffuse pleural thickening, rounded atelectasis or bronchogenic carcinoma.
8. 8. The method of claim 6, further comprising administering to a patient a therapeutic or prophylactically effective of a second active agent.
9. The method of claim 8, wherein the second active agent is an anti-cancer agent, an antibiotic, an anti-inflammatory agent, a steroid, an immunomodulatory agent, a cytokine, an immunosuppressive agent or a combination thereof .
10. The method of claim 9, wherein the second active agent is anthracycline, platinum, alkylating agent, interferon, oblimersen, cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, irinotecan, topotecan, temozolomide, methotrexate, taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, trioxide, arsenic, vincristine, doxorubicin, paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa, tetracycline or gemcitabine.
11. The method of claim 1, wherein the stereoisomer of the immunomodulatory compound is enantiomerically pure.
12. The method of claim 1, wherein the immunomodulatory compound is 4- (amino) -2- (2,6-dioxo (3-piperidyl)) -isoindole-1,3-dione.
13. 13. The method of claim 12, wherein the immunomodulatory compound is enantiomerically pure.
14. The method of claim 1, wherein the immunomodulatory compound is 3- (4-amino-1-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione.
15. 15. The method of claim 14, wherein the immunomodulatory compound is enantiomerically pure.
16. 16. The method of claim 1, wherein the immunomodulatory compound is of the formula (I): wherein one of X and Y is C = 0, the other of X and Y is C = 0 or CH2, and R2 is hydrogen or lower alkyl.
17. 17. The method of claim 16, wherein the immunomodulatory compound is enantiomerically pure.
18. 18. The method of claim 1, wherein the immunomodulatory compound is of the formula (II): (II) where: one of X and Y is C = 0 and the other is CH2 or C = 0; R1 is H, (C? _C8) alkyl, (C3-C7) cycloalkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, benzyl, aryl, (C0-C4) alkyl -heterocycloalkyl (C? -C6), (C0-C4) alkyl-heteroaryl of (C2-C5), C (0) R3, C (S) R3, C (0) 0R4, (C? -C8) alkyl- N (R6) 2, (C? -C8) -OR5 alkyl, (C? -C8) alkyl -C (0) OR5, C (0) NHR3, C (S) NHR3, C (0) NR3R3 ' , C (S) NR3R3 'or (C_-C8) alkyl-O (CO) R5; R 2 is H, F, benzyl, (C 1 -C 8) alkyl, (C 2 -C 8) alkenyl or (C 2 -C 8) alkynyl; R3 and R3 'are independently alkyl of (C? -C8), cycloalkyl of (C3-C7), alkenyl of (C2-C8), alkynyl of (C2-C8), benzyl, aryl, (C0-C4) alkyl -heterocycloalkyl of (C? -C6), (C0-C4) alkyl-heteroaryl of (.C2-C5), (C0-C8) alkyl ) -N (R6) 2, alkyl of (C? -8) -OR5, alkyl of (Ca-Cs) -C (0) OR5, alkyl of (C_-C8) -O (CO) R5 or C (0) ) 0R5; R4 is (C_-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C? -C4) -OR5 alkyl, benzyl, aryl, (C0-C4) alkyl -heterocycloalkyl of (C? -C6) or (C0-C4) alkyl-heteroaryl of (C2-C5); R5 is (C? -C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, benzyl, aryl or (C2-C5) heteroaryl; - each case of R6 is independently H, alkyl (C? -C8), (C2-C8) alkenyl, (C2-C8) alkynyl, benzyl, aryl, (C2-C5) heteroaryl or (C0-C8) alkyl-C (O) 0-RD or the Rd groups can be joined to form a heterocycloalkyl group; n is 0 or 1; and - * represents a chiral carbon center.
19. 19. The method of claim 18, wherein the immunomodulatory compound is enantiomerically pure.
20. The method of claim 1, wherein the immunomodulatory compound is a cyano or carboxyl derivative of a substituted styrene, l-oxo-2- (2,6-dioxo-3-fluoropiperidin-3-yl) isoindoline, 1, 3-dioxo-2- (2, β-dioxo-3-fluoropiperidin-3-yl) isoindoline or tetra- substituted 2- (2,6-dioxopiperidin-3-yl) -1-oxoisoindoline.
21. 21. The method of claim 20, wherein the immunomodulatory compound is enantiomerically pure.
22. 22. A pharmaceutical composition comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a second active agent capable of alleviating or reducing a symptom of a disease or disorder related to asbestos.
23. 23. The pharmaceutical composition of claim 22, wherein the second active agent is an anti-cancer agent, an antibiotic, an anti-inflammatory agent, a steroid, a cytokine, an immunomodulatory agent, an immunosuppressive agent or a combination of them. The pharmaceutical composition of claim 22, wherein the second active agent is anthracycline, platinum, alkylating agent, interferon, oblimersen, cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, methotrexate, taxotere, capecitabine, cisplatin , thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, irinotecan, topotecan, temozolomide , vincristine, doxorubicin, paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa, tetracycline or gemcitabine.