HK1112912A - 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

Compositions comprising immunomodulatory compounds for the treatment and management of asbestos-related diseases and disorders and methods of use thereof

1. Field of the invention

The present invention relates to methods of treating, preventing and managing asbestos-related diseases or disorders, which comprise administering an immunomodulatory compound, either alone or in combination with known therapies. The invention also relates to pharmaceutical compositions and dosage regimens. In particular, the invention encompasses the use of immunomodulatory compounds in combination with surgery or radiation therapy and/or other standard therapies for the treatment of diseases associated with asbestos poisoning.

2. Background of the invention

2.1 asbestos-related diseases or disorders

Worldwide, millions of people come into contact with asbestos in the manufacture and use of mineral refining or asbestos products. Aberle, sensiars in Roentgenology, 24 (2): 118, 1991. If the various pathological consequences of asbestos develop with long-term latency, then asbestos-related diseases will become major occupational and environmental diseases over time. Benign asbestos-related diseases and disorders include asbestosis, pleural effusion, pleural plaque, diffuse pleural thickening, and round atelectasis. Staples, Radiologic Clinics of North America, 30 (6): 1191, 1992. Malignant asbestos-related diseases include malignant pleural effusion, pleural or peritoneal mesothelioma, and bronchogenic carcinoma. Merck Index, 1999 (17 th edition), 645 and 651.

Asbestosis (pulmonary interstitial fibrosis) is defined as diffuse pulmonary fibrosis caused by the inhalation of asbestos fibers. Staples, Radiologic Clinics of North America, 30 (6): 1195, 1992. It is a major cause of occupational-related lung injury. Merck Index, 1999 (17 th edition), 622. Asbestosis is characterized by a latent period of 15-20 years, and disease can develop even after contact has ceased, but it rarely occurs in the absence of pleural plaque. Peach, Clinical Radiology, 55: 425, 2000. Fibrosis first occurs in and around the respiratory bronchioles, mainly in the sub-pleural part of the lower lobes of the lungs, and then progresses towards the center. Staples, Radiologic Clinics of North America, 30 (6): 1195, 1992. Asbestos stasis can cause progressive dyspnea to occur silently in addition to dry cough. In smokers with asbestosis, the incidence of lung cancer increases and a dose-response relationship is observed. MerckIndex, 1999 (17 th edition), 623.

Another asbestos-related disorder is pleural effusion. Pleural effusion is often an early symptom of asbestos-related diseases. Staples, Radiologic Clinics of North America, 30 (6): 1192, 1992. People exposed to asbestos can develop exudative pleural effusion after 5-20 years of exposure. Merck Index, 1999 (17 th edition), 645; staples, Radiologic Clinicsof North America, 30 (6): 1192, 1992; and c.peach, Clinical Radiology, 55: 427, 2000. Exudate may develop after a short contact, but more often after a moderate contact of 10-15 years. The clinical symptoms of benign asbestos-related pleural effusion vary from asymptomatic patients to patients with acute pleurisy chest pain and fever (supra, 426). The mechanism of formation is not clear, but it is hypothesized that fibers migrate from the lung into the pleura and this acts as an inflammatory response. In most people, exudate is cleared after 3-4 months, but may also persist for years or recur (ibid). As exudate decreases, many people develop diffuse pleural thickening (supra).

Pleural plaque is a common symptom of asbestos exposure, which usually occurs after 20-30 years of incubation. Staples, Radiologic Clinics of North America, 30 (6): 1191, 1992; and c.peach, Clinical Radiology, 55: 423, 2000. Histologically, pleural plaques are composed of bundles of acellular collagen forming a basket-net pattern that make up almost exclusively the parietal pleura. Staples, Radiologic Clinics of North America, 30 (6): 1191, 1992. The exact pathogenesis of pleural plaque is uncertain and is believed to be caused by the mechanical action of asbestos fibers penetrating the visceral pleura. Peach, Clinical Radiology, 55: 425, 2000. However, it is currently believed that fibers are transported to the parietal pleura through lymphatic channels and cause inflammatory reactions there (ibid). Pleural plaques grow slowly over time, even after cessation of contact, but they are not considered pre-malignant (supra). Subsequent calcification, often after 30-40 years of contact (see above) (424); and c.a. complexes, radioactive Clinics of northern america, 30 (6): 1191, 1992. Although the severity of pleural disease is significantly associated with the severity of asbestosis, pleural plaques tend to form alone and do not show any other symptoms of the asbestosis-associated disease. Peach, Clinical Radiology, 55: 425, 2000.

Another common symptom of asbestos exposure is diffuse pleural thickening. Staples, Radiologic Clinics of North America, 30 (6): 1193, 1992. Typically, its latency is about 15 years. Diffuse pleural thickening has lower specificity for asbestos exposure relative to pleural plaque, as thickening is also observed in TB pleuritis, pleural hemorrhage and empyema. Peach, Clinical Radiology, 55: 427, 2000. The most common symptom is dyspnea. The pathogenesis of this is still unclear, but it is thought to be caused by inflammation and fibrosis of visceral pleural lymph and is considered to be the extension of pulmonary fibrosis (supra). The development of diffuse pleural thickening has a similar temporal relationship to plaque formation. Thickening is often accompanied by asbestos stasis, a correlation of up to 10% being reported (supra).

Another asbestos exposure related disease is atelectasis, meaning atelectasis adjacent to pleural thickening, characterized by bronchial and vascular aspiration. Wallace, diagnostic cytopathic, 8 (6): 617, 1992; peach, Clinical Radiology, 55: 429, 2000; and c.a. complexes, radioactive Clinics of North America, 30 (6): 1193, 1992. It is also known as folded lung, pulmonary pseudotumor, atelectasis or Blesovsky syndrome (supra). It is postulated that the presence of exudate leads to passive atelectasis, with concomitant lung folding leading to adjacent pleural intussusception (supra). This process creates a restriction that prevents the lungs from re-expanding after the exudate is reduced and results in a round atelectasis (supra). An alternative explanation is that irritation of the pleura results in local inflammation and fibrosis, reducing the volume and wrinkling of the underlying lung (supra). The uvula is the most common location of injury, then the middle lobe, then the lower lobe, although the injury may be multiple and bilateral (supra).

Mesothelioma is a malignant pleural or peritoneal tumor, often associated with occupational exposure to asbestos. Merck Index, 1999 (17 th edition), 645. The clinical latency to asbestos exposure to the development of mesothelioma is typically 15-40 years (supra, 623); and c.peach, Clinical Radiology, 55: 427, 2000. Thus, despite the decrease in asbestos production, the number of mesothelioma patients continues to increase. JMW van Haarst et al, British Journal of Cancer, 86: 342, 2002. Common symptoms are chest pain, dyspnea, cough, weight loss, weakness and increased sputum. MerckIndex, 1999 (17 th edition), 645. The tumor progressively envelopes the lung, invades the chest wall, and forms pleural effusion in about 75% of patients (supra). It has a poor prognosis and also a poor response to radiosurgery, chemotherapy, or radiotherapy (supra).

The causal relationship between bronchopulmonary carcinoma and asbestos exposure has been widely recognized. Merck index, 1999 (17 th edition), 651; and d.r. aberle, sensiars in Roentgenology, 24 (2): 124, 1991. It appears to be dose-responsive at the level of occupational exposure (supra). Among asbestos workers, lung cancer is at a relative risk that is many times that of smokers, and asbestos-related interstitial pulmonary disease is often associated therewith (supra). Lung cancer has also been reported in people exposed to asbestos without interstitial lung disease (ibid).

2.2 conventional treatment

The main strategy for the treatment of asbestos-related diseases or disorders is prevention, abolishing the use of asbestos worldwide and replacing it with safe synthetic products. No effective treatment of asbestos stasis is known. Mesothelioma is extremely difficult to treat and there is currently no standard therapy for treating it. Kaiser lr., Semin Thorac Cardiovasc surg.10 months, 9 (4): 383-90, 1997. Chemotherapy, radiation therapy, and surgical approaches have been used, and although triple combination therapy combining the three therapies may improve survival in selected patients, it does not improve overall survival (ibid).

The two major surgical interventions for the treatment of mesothelioma are pleurectomy and extrapleural pneumonectomy (EPP). Pleurectomy is usually a palliative procedure to relieve chest wall pain and prevent recurrence of pleural effusions by peeling the visceral and parietal pleura. Turton, British Journal of Hospital Medicine, 23 (3): 249, 1980. EPP is an integrated resection of parietal and mediastinal pleura, lung, hemidiaphragm, ipsilateral pericardium, used to remove all conditions. Sugarberdj, Ann surg., 224 (3): 288-94, 1996. EPP is applicable to stage I tumors that do not involve mediastinal lymph nodes. EPP is a technically demanding procedure requiring significant morbidity. Surgical complications of pleurectomy and EPP include pneumonia, bronchopleural leakage, bronchial leaks, empyema, chylothorax, respiratory insufficiency, myocardial infarction, congestive heart failure, hemorrhage, torsion of the heart and intestine, subcutaneous emphysema, incomplete removal of tumors, and vocal cord paralysis (supra).

Radiation therapy is often palliative or as an adjunct to surgery. Turton, British journal of Hospital Medicine, 23 (3): 249, 1980. Brachytherapy, i.e., the intrapleural implantation of radioisotopes, can deliver high doses of radiation locally into the pleural space and is used to prevent recurrence of pleural effusions (supra). Postoperative radiation therapy can prevent recurrence at the chest wall incision site. Complications of radiation therapy include nausea and vomiting, radiation hepatitis, esophagitis, myelitis, myocarditis, and pneumonia resulting from deterioration of lung function.

Photodynamic therapy is an adjuvant therapy for treating patients with surgically treated pleural malignancies. P.baas, br.j.cancer, 76 (6): 819-26, 1997. Photoactivated photosensitizing drugs are infused into the pleura and excited with light of a certain wavelength to generate oxygen free radicals, which necrotize the tumor (ibid).

The response to chemotherapy is disappointing because it is difficult to obtain a relatively good chemotherapeutic effect. Intrapleural infusion of antibiotics such as mepacrine, thiotepa and tetracycline has been reported to be sometimes successful. Turton, British Journal of Hospital Medicine 23 (3): 247, 1980. Infusion of various cytotoxic drugs, including nitrogen mustards, into the pleural space has been attempted (supra). Current drugs used to treat mesothelioma include GM-CSF, doxorubicin, gemcitabine, cisplatin, vinblastine, doxorubicin, bleomycin, hyaluronidase, methotrexate and mitomycin. JMW vanHaarst et al, British Journal of Cancer, 86: 342-345, 2002. However, few patients get complete remission. Chemotherapy produces less than 20% of the response and has not shown improved survival in patients with mesothelioma (supra). Thus, there remains a need for a safe and effective method of treating and controlling mesothelioma and other asbestos-exposure related diseases.

2.3 immunomodulatory Compounds

A group of compounds that are effective in inhibiting TNF-. alpha.production by LPS-stimulated PBMCs has been investigated. L.g.corral et al, ann.rheum.dis.58: (supplement I) 1107-. These compounds are referred to as ImiDs^TM(Celgene Corp.) or immunomodulating agents, which showed not only a strong inhibitory effect on TNF- α but also a significant inhibition of LPS-induced monocyte IL1 β and IL12 production. LPS-induced IL6 was also inhibited, albeit only partially, by immunomodulatory compounds. These compounds are potent mimetics of LPS-induced IL10 (supra).

3. Summary of the invention

The invention encompasses methods of treating, preventing and managing an asbestos-related disease or disorder, 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.

Another embodiment of the invention encompasses the use of one or more immunomodulatory compounds in combination with another therapeutic agent commonly used to treat or prevent asbestos-related diseases or disorders, such as, but not limited to, anti-cancer agents, antibiotics, anti-inflammatory agents, cytokines, steroids, immunomodulatory agents, immunosuppressive agents, and other well-known therapeutic agents.

Another embodiment of the invention encompasses the use of one or more immunomodulatory compounds in combination with conventional therapies commonly used to treat, prevent or manage asbestos-related diseases or disorders, such as, but not limited to, chemotherapy, surgery, radiation therapy and photodynamic therapy.

The invention also encompasses pharmaceutical compositions, single unit dosage forms, and kits comprising one or more immunomodulatory compounds, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and one or more other active agents that are useful in the treatment, prevention, and/or management of asbestos-related diseases or disorders.

4. Detailed description of the invention

A first embodiment of the invention encompasses methods of treating, preventing or managing an asbestos-related disease or disorder, 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.

In the present invention, the terms "asbestos-related diseases, disorders or syndromes", "asbestos-exposure-related diseases or disorders" and "asbestos poisoning-related diseases or disorders" refer to diseases, disorders, syndromes or abnormalities associated with or involving asbestos exposure or asbestos poisoning. These terms include benign and malignant diseases or disorders, including but not limited to mesothelioma, asbestosis, malignant pleural effusion, benign effusion, pleural plaque, pleural calcification, diffuse pleural thickening, round atelectasis, fibrotic mass, and lung cancer. In certain embodiments, these terms do not include lung cancer. In certain embodiments, the asbestos-related disease, disorder, or syndrome does not include malignant mesothelioma or malignant pleural effusion mesothelioma syndrome.

Another embodiment of the invention encompasses pharmaceutical compositions suitable for use in the treatment, prevention, or management of an asbestos-related disease or disorder, which compositions comprise an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier.

The invention also encompasses single unit dosage forms suitable for use in the treatment, prevention, or management of an asbestos-related disease or disorder, which dosage forms comprise an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier.

Another embodiment of the invention encompasses a kit suitable for treating, preventing or managing an asbestos-related disease or disorder, the kit comprising: a pharmaceutical composition comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention also includes kits comprising a single unit dosage form.

Without being limited by theory, it is believed that immunomodulatory compounds may act in a complementary or synergistic manner with certain second active agents in the treatment, prevention, or management of asbestos-related diseases or disorders. Accordingly, one embodiment of the invention encompasses methods of treating, preventing and/or managing an asbestos-related disease or disorder, 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, and a therapeutically or prophylactically effective amount of a second active agent.

Examples of second active agents include, but are not limited to, common therapeutic agents for treating or preventing mesothelioma, such as anti-cancer agents, antibiotics, anti-inflammatory agents, steroids, cytokines, immunomodulators, immunosuppressants, and other therapeutic agents that can ameliorate or alleviate asbestos-related diseases or disorders, such as those described in the Physician's Desk Reference 2003.

It is believed that immunomodulatory compounds may reduce or eliminate adverse effects associated with administration of conventional therapeutic agents used to treat asbestos-related diseases or disorders, thereby allowing for administration of greater amounts of such agents to patients and/or improving patient compliance. Accordingly, another embodiment of the invention encompasses methods of reversing, alleviating, or avoiding an adverse effect associated with administration of a second active agent in a patient having an asbestos-related disease or disorder, which comprises 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.

The invention also encompasses pharmaceutical compositions, single unit dosage forms, and kits comprising an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent.

As described elsewhere herein, symptoms of asbestos-related diseases or disorders may be treated with chemotherapy, surgery, radiation therapy, photodynamic therapy, immunotherapy, and/or gene therapy. Without being bound by any theory, it is believed that the use of these conventional therapies in combination with immunomodulatory compounds provides a uniquely effective treatment for asbestos-related diseases or disorders. Accordingly, the invention includes methods of treating, preventing and/or managing an asbestos-related disease or disorder, which comprise administering to a patient (e.g., a human) an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before, during or after chemotherapy, surgery, radiation therapy, photodynamic therapy, immunotherapy, gene therapy and/or other non-drug based conventional therapies.

4.1 immunomodulatory compounds

The compounds of the present invention may be commercially available or prepared according to the methods described in the patents or patent applications disclosed in this specification. In addition, optically pure compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral columns, as well as other standard organic chemical synthesis techniques. The compounds for use in the present invention may include immunomodulatory compounds, which may be racemic, stereomerically enriched or stereomerically pure, or pharmaceutically acceptable salts, solvates, stereoisomers, inclusions and prodrugs thereof.

Preferred compounds for use in the present invention are small organic molecules having a molecular weight of less than 1,000g/mol and are not proteins, oligopeptides, oligonucleotides, oligosaccharides or other macromolecules.

As used herein, unless otherwise indicated, the terms "immunomodulatory compounds" and "ImiDs" are used^TM"(Celgene Corp.) includes small organic molecules that significantly inhibit TNF- α, LPS-induced monocyte IL1 β and IL12 and partially inhibit IL6 production. Specific immunomodulatory compounds are described below.

TNF- α is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF- α causes a diverse range of signaling events within the cell. TNF- α may play a pathological role in cancer. Without being limited by theory, one biological effect of the immunomodulatory compounds of the invention is to decrease synthesis of TNF- α. Immunomodulatory compounds of the invention can enhance the degradation of TNF- α mRNA.

Furthermore, without being limited by theory, immunomodulatory compounds used in the invention may also be potent co-stimulators of T cells and can significantly increase cell proliferation in a dose-dependent manner. Immunomodulatory compounds of the invention have greater co-stimulatory effects on the CD8+ T cell subpopulation as compared to the CD4+ T cell subpopulation. In addition, the compounds of the present invention preferably have anti-inflammatory properties and are effective in co-stimulating T cells. Furthermore, without being limited by theory, immunomodulatory compounds used in the invention may act directly by activating cytokines and directly on natural killer ("NK") cells and enhance the ability of NK cells to produce beneficial cytokines, such as, but not limited to, IFN- γ.

Specific examples of immunomodulatory compounds include, but are not limited to: cyano and carboxyl derivatives of substituted styrenes, such as those disclosed in U.S. Pat. No. 5,929,117; 1-oxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline and 1, 3-dioxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline, such as those described in U.S. Pat. nos. 5,874,448 and 5,955,476; tetrasubstituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolines, which are 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 disclosed in U.S. 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 indoline ring (e.g., 4- (4-amino-1, 3-dioxoisoindolin-2-yl) -4-carbamoylbutyric acid), described in U.S. Pat. No. 6,380,239; isoindolin-1-one and isoindoline-1, 3-dione substituted at the 2-position with a 2, 6-dioxo-3-hydroxypiperidin-5-yl group (e.g., 2- (2, 6-dioxo-3-hydroxy-5-fluoropiperidin-5-yl) -4-aminoisoindolin-1-one), which is described in U.S. Pat. No. 6,458,810; a class of non-polypeptide cyclic amides disclosed in U.S. Pat. nos. 5,698,579 and 5,877,200; amino thalidomide and analogs, hydrolysates, metabolites, derivatives and precursors of amino thalidomide, as well as substituted 2- (2, 6-dioxopiperidin-3-yl) phthalimides and substituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoles, such as those described in U.S. Pat. Nos. 6,281,230 and 6,316,471; and isoindole-imide compounds such as those described in U.S. patent application No. 09/972,487 (filed 5/10/2001), U.S. patent application No. 10/032,286 (filed 21/11/2001), and international application No. PCT/US01/50401 (international publication No. WO 02/059106). Each of the patents and patent applications listed herein is incorporated by reference in its entirety. 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 substituted with amino in the benzo ring, as described in U.S. Pat. No. 5,635,517, which is incorporated herein by reference. These compounds have structure I:

wherein one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂，R²Is hydrogen or lower alkyl, especially methyl. Specific immunomodulatory compounds include, but are not limited to:

1-oxo-2- (2, 6-dioxopiperidin-3-yl) -4-aminoisoindoline;

1-oxo-2- (2, 6-dioxopiperidin-3-yl) -5-aminoisoindoline;

1-oxo-2- (2, 6-dioxopiperidin-3-yl) -6-aminoisoindoline;

1-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 U.S. 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. Representative compounds have the formula:

wherein:

one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂；

(i)R¹、R²、R³And R⁴Each independently of the other, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, or (ii) R¹、R²、R³And R⁴One is-NHR⁵And R is¹、R²、R³And R⁴The remainder of (A) is hydrogen;

R⁵is hydrogen or contains 1 to 8 carbonsAn alkyl group of atoms;

R⁶is hydrogen, alkyl containing 1 to 8 carbon atoms, benzyl or halogen;

provided that if X and Y are C ═ O and (i) R¹、R²、R³And R⁴Are both fluorine or (ii) R¹、R²、R³Or R⁴One is amino, then R⁶Is not hydrogen.

Representative of this class of compounds have the formula:

wherein R is¹Is hydrogen or methyl. In a separate embodiment, the invention encompasses the use of enantiomerically pure forms of these compounds (e.g., the optically pure (R) or (S) enantiomer).

Other specific immunomodulatory compounds of the invention belong to the class of isoindole-imides and are disclosed in U.S. patent application publication Nos. 2003/0096841 and 2003/0045552 and International patent application No. PCT/US01/50401 (International publication No. WO02/059106), each of which is incorporated herein by reference. Representative compounds have formula II:

and pharmaceutically acceptable salts, hydrates, solvates, inclusions, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:

one of X and Y is C ═ O, and the other is CH₂Or C ═ O;

R¹is H, (C)₁-C₈) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl, C (O) R³、C(S)R³、C(O)OR⁴、(C₁-C₈) alkyl-N (R)⁶)₂、(C₁-C₈) alkyl-OR⁵、(C₁-C₈) alkyl-C (O) OR⁵、C(O)NHR³、C(S)NHR³、C(O)NR³R³′、C(S)NR³R³' or (C)₁-C₈) alkyl-O (CO) R⁵；

R²Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) An alkynyl group;

R³and R³' independently is (C)₁-C₈) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₈) Heteroaryl, (C)₀-C₈) alkyl-N (R)⁶)₂、(C₁-C₈) alkyl-OR⁵、(C₁-C₈) alkyl-C (O) OR⁵、(C₁-C₈) alkyl-O (CO) R⁵OR C (O) OR⁵；

R⁴Is (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, (C)₁-C₄) alkyl-OR⁵Benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl or (C)₀-C₄) Alkyl radical- (C)₂-C₅) A heteroaryl group;

R⁵is (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl or (C)₂-C₈) A heteroaryl group;

R⁶independently at each occurrence, H, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₂-C₅) Heteroaryl or (C)₀-C₈) alkyl-C (O) O-R⁵Or R is⁶Groups may be joined together to form a heterocycloalkyl group;

n is 0 or 1; and

^*represents a chiral carbon center.

In specific compounds of formula II, R is when n is 0¹Is (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl, C (O) R³、C(O)OR⁴、(C₁-C₈) alkyl-N (R)⁶)₂、(C₁-C₈) alkyl-OR⁵、(C₁-C₈) alkyl-C (O) OR⁵、C(S)NHR³Or (C)₁-C₈) alkyl-O (CO) R⁵；

R²Is H or (C)₁-C₈) An alkyl group; and

R³is (C)₁-C₈) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzylRadical, aryl radical, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl, (C)_s-C₈) alkyl-N (R)⁶)₂；(C₀-C₈) alkyl-NH-C (O) O-R⁵；(C₁-C₈) alkyl-OR⁵、(C₁-C₈) alkyl-C (O) OR⁵、(C₁-C₈) alkyl-O (CO) R⁵OR C (O) OR⁵(ii) a And other variations having the same definition.

In other specific compounds of formula II, R²Is H or (C)₁-C₄) An alkyl group.

In other specific compounds of formula II, R¹Is (C)₁-C₈) Alkyl or benzyl.

In other specific compounds of formula II, R¹Is H, (C)₁-C₈) Alkyl, benzyl, CH₂OCH₃、CH₂CH₂OCH₃Or is or

In other embodiments of the compounds of formula II, R¹Is that

Or

Wherein Q is O or S, R⁷Each occurrence is independently H, (C)₁-C₈) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkene(s)Base, (C)₂-C₈) Alkynyl, benzyl, aryl, halogen, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl, (C)₀-C₈) alkyl-N (R)⁶)₂、(C₁-C₈) alkyl-OR⁵、(C₁-C₈) alkyl-C (O) OR⁵、(C₁-C₈) alkyl-O (CO) R⁵OR C (O) OR⁵Or adjacent R⁷May together form an alkyl or aryl bicyclic ring.

In other specific compounds of formula II, R¹Is C (O) R³。

In other specific compounds of formula II, R³Is (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl, (C)₁-C₈) Alkyl, aryl or (C)₀-C₄) alkyl-OR⁵。

In other specific compounds of formula II, heteroaryl is pyridyl, furyl, or thienyl.

In other specific compounds of formula II, R¹Is C (O) OR⁴。

In other specific compounds of formula II, H of C (O) NHC (O) may be replaced by (C)₁-C₄) Alkyl, aryl or benzyl.

Other examples of such compounds include, but are not limited to: [2- (2, 6-dioxo-piperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-ylmethyl ] -amide; (2- (2, 6-dioxo-piperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-ylmethyl) -carbamic acid tert-butyl ester; 4- (aminomethyl) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione; n- (2- (2, 6-dioxo-piperidin-3-yl) -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-ylmethyl) -acetamide; n- { (2- (2, 6-dioxo (3-piperidinyl) -1, 3-dioxoisoindolin-4-yl) methyl) 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- { 1-oxo-4- (benzylamino) isoindolin-2-yl } piperidine-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-furanyl carboxamide; methyl { N- (2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl) carbamoyl } acetate; 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; n- { [2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl ] methyl } (butylamino) carboxamide; n- { [2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl ] methyl } (octylamino) carboxamide; and N- { [2- (2, 6-dioxo (3-piperidyl)) -1, 3-dioxoisoindolin-4-yl ] methyl } (benzylamino) carboxamide.

Other specific immunomodulatory compounds of the invention belong to the isoindole-imides and are disclosed in U.S. patent application No. 2002/0045643, international publication No. WO 98/54170, and U.S. patent No. 6,395,754, which are incorporated herein by reference. Representative compounds have formula III:

and pharmaceutically acceptable salts, hydrates, solvates, inclusions, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:

one of X and Y is C ═ O, and the other is CH₂Or C ═ O;

r is H or CH₂OCOR′；

(i)R¹、R²、R³Or R⁴Each independently of the other, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, or (ii) R¹、R²、R³Or R⁴One of which is nitro or-NHR⁵And R is¹、R²、R³And R⁴The remainder of (A) is hydrogen;

R⁵is hydrogen or alkyl having 1 to 8 carbon atoms;

R⁶is hydrogen, alkyl having 1 to 8 carbon atoms, benzo, chloro or fluoro;

r' is R⁷-CHR¹⁰-N(R⁸R⁹)；

R⁷Is m-or p-phenylene or- (C)_nH_2n) -, where n is 0 to 4;

R⁸and R⁹Independently of one another, hydrogen or alkyl having 1 to 8 carbon atoms, or R⁸And R⁹Together being tetramethylene, pentamethylene, hexamethylene or-CH₂CH₂X₁CH₂CH₂-, wherein X₁is-O-, -S-or-NH-;

R¹⁰is hydrogen, alkyl of 8 carbon atoms or phenyl; and

^*represents a chiral carbon center.

Other representative compounds have the formula:

wherein:

one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂；

(i)R¹、R²、R³Or R⁴Each independently of the other, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, or (ii) R¹、R²、R³Or R⁴One is-NHR⁵And R is¹、R²、R³And R⁴The remainder of (A) is hydrogen;

R⁵is hydrogen or alkyl having 1 to 8 carbon atoms;

R⁶is hydrogen, alkyl having 1 to 8 carbon atoms, benzo, chloro or fluoro;

R⁷is m-or p-phenylene or- (C)_nH_2n) -, where n is 0 to 4;

R⁸and R⁹Independently of one another, hydrogen or alkyl having 1 to 8 carbon atoms, or R⁸And R⁹Together being tetramethylene, pentamethylene, hexamethylene or-CH₂CH₂X¹CH₂CH₂-, wherein X¹is-O-, -S-or-NH-;

R¹⁰is hydrogen, alkyl of 8 carbon atoms or phenyl.

Other representative compounds have the formula:

wherein the content of the first and second substances,

one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂；

R¹、R²、R³And R⁴Each independently of the other, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, or (ii) R¹、R²、R³And R⁴One is nitro or protected amino, and R¹、R²、R³And R⁴The remainder of (A) is hydrogen; and

R⁶is hydrogen, alkyl having 1 to 8 carbon atoms, benzo, chloro or fluoro;

other representative compounds have the formula:

wherein:

one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂；

(i)R¹、R²、R³Or R⁴Each independently of the other, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, or (ii) R¹、R²、R³Or R⁴One is-NHR⁵And R is¹、R²、R³And R⁴The remainder of (A) is hydrogen;

R⁵is hydrogen, alkyl having 1 to 8 carbon atoms or CO-R⁷-CH(R¹⁰)NR⁸R⁹Wherein R is⁷、R⁸、R⁹And R¹⁰Each as defined above; and

R⁶is alkyl containing 1-8 carbon atoms, benzo, chloro or fluoro;

specific examples of the compounds have the following formula:

wherein:

one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂；

R⁶Is hydrogen, alkyl having 1 to 8 carbon atoms, benzyl, chlorine or fluorine;

R⁷is m-or p-phenylene or- (C)_nH_2n) -, where n is 0 to 4;

R⁸and R⁹Independently of one another, hydrogen or alkyl having 1 to 8 carbon atoms, or R⁸And R⁹Together being tetramethylene, pentamethylene, hexamethylene or-CH₂CH₂X¹CH₂CH₂-, wherein X¹is-O-, -S-or-NH-; and

R¹⁰is hydrogen, alkyl of 1 to 8 carbon atoms or phenyl.

The most preferred immunomodulatory compounds of the invention are 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione and 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione. Such compounds can be obtained by standard synthetic methods (see, e.g., U.S. patent No. 5,635,517, which is incorporated herein by reference). This compound is available from Celgene corporation (warrenn, NJ). 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione has the following chemical structure:

the compound 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione has the following chemical structure:

in another embodiment, specific immunomodulatory compounds of the invention include polymorphic forms of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione, such as forms A, B, C, D, E, F, G and H disclosed in U.S. provisional application No. 60/499,723, filed 9/4/2003, which is incorporated herein by reference. For example, form a of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a non-solvated crystalline, which can be obtained from a non-aqueous solvent system. The X-ray powder diffraction pattern of form a comprises distinct peaks at about 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 2 Θ, with a differential scanning calorimetry maximum melting temperature of about 270 ℃. Form a is weakly or non-hygroscopic and is the thermodynamically most stable anhydrous polymorph of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione to date.

Form B of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a hemihydrate crystalline, which can be obtained from a variety of solvent systems, including but not limited to hexane, toluene, and water. The X-ray powder diffraction pattern for form B contained distinct peaks at about 16, 18, 22, and 27 degrees 2 theta, with the DSC curve showing endotherms at about 146 and 268 ℃, and dehydration and melting as confirmed by hot-stage microscopy experiments. Interconversion studies have shown that form B converts to form E in aqueous solvent systems and to other forms in acetone and other anhydrous systems.

Form C of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a semi-solvated crystalline, which can be obtained from a solvent such as, but not limited to, acetone. Form C has an X-ray powder diffraction pattern comprising distinct peaks at about 15.5 and 25 degrees 2-theta and a differential scanning calorimetry maximum melting temperature of about 269 ℃. Form C is not hygroscopic below about 85% RH, but can be converted to form B at high relative humidity.

Form D of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a crystalline solvated polymorph prepared from a mixture of acetonitrile and water. Form D has an X-ray powder diffraction pattern comprising distinct peaks at about 27 and 28 degrees 2 Θ and a differential scanning calorimetry maximum melting temperature of about 270 ℃. Form D is weakly or non-hygroscopic, but generally converts to form B when under pressure at high relative humidity.

Form E of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a dihydrate crystal, which can be obtained by slurrying 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in water, and slowly evaporating 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione in a solvent system of acetone: water of about 9: 1. Form E has an X-ray powder diffraction pattern comprising distinct peaks at about 20, 24.5, and 29 degrees 2 Θ and a differential scanning calorimetry maximum melting temperature of about 269 ℃. Form E can be converted to form C in an acetone solvent system and form G in a THF solvent system. Form E is the most stable form in aqueous solvent systems. The anti-dissolution experiment for form E showed that form E was converted to form B when heated at about 125 ℃ for about 5 minutes. Form B converts to form F upon heating at 175 ℃ for about 5 minutes.

Form F of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a non-solvated crystalline material, which can be obtained by dehydrating form E. The X-ray powder diffraction pattern for form F contains significant peaks at about 19, 19.5, and 25 degrees 2 Θ, with a differential scanning calorimetry maximum melting temperature of about 269 ℃.

Form G of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a non-solvated crystalline material that can be obtained from a slurry of forms B and E in a solvent such as, but not limited to, Tetrahydrofuran (THF). The X-ray powder diffraction pattern of form G contains significant peaks at about 21, 23, and 24.5 degrees 2 Θ, with a differential scanning calorimetry maximum melting temperature of about 267 ℃.

Form H of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is a partially hydrated crystalline material, which can be obtained by exposing form E to 0% relative humidity. The X-ray powder diffraction pattern of form H contains significant peaks at about 15, 26, and 31 degrees 2 Θ, with a differential scanning calorimetry maximum melting temperature of about 269 ℃.

Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline and 1, 3-dioxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline, such as those described in U.S. Pat. Nos. 5,874,448 and 5,955,476, which are incorporated herein by reference. Representative compounds have the formula:

wherein Y is oxygen or H₂And are and

R¹、R²、R³and R⁴Each independently hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or amino.

Other specific immunomodulatory compounds of the invention include, but are not limited to: tetrasubstituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolines, which are described in U.S. Pat. No. 5,798,368, which is incorporated herein by reference. Representative compounds have the formula:

wherein R is¹、R²、R³And R⁴Each independently a halogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 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, which are disclosed in U.S. Pat. No. 6,403,613, which is incorporated herein by reference. Representative compounds have the formula:

wherein

Y is oxygen or H₂，

R¹And R²One of which is halogen, alkyl, alkoxy, alkylamino, dialkylamino, cyano or carbamoyl, R¹And R²Wherein the other is independently hydrogen, halogen, alkyl, alkoxy, alkylamino, dialkylamino, cyano or carbamoyl, and

R³is hydrogen, alkyl or benzyl.

Specific examples of such compounds have the formula:

wherein R is¹And R²One of halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, dialkylamino (wherein each alkyl has 1 to 4 carbon atoms), cyano or carbamoyl,

R¹and R²One is independently hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylamino (wherein the alkyl has 1 to 4 carbon atoms), dialkylamino (wherein each alkyl has 1 to 4 carbon atoms), cyano or carbamoyl, and

R³is hydrogen, alkyl having 1 to 4 carbon atoms or benzyl. Specific examples include, but are not limited to, 1-oxo-2 (2, 6-dioxopiperidin-3-yl) -4-methylisoindoline.

Other representative compounds have the formula:

wherein R is¹And R²One of halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, dialkylamino (wherein each alkyl has 1 to 4 carbon atoms), cyano or carbamoyl,

R¹and R²One is independently hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylamino (wherein the alkyl has 1 to 4 carbon atoms), dialkylamino (wherein each alkyl has 1 to 4 carbon atoms), cyano or carbamoyl, and

R³is hydrogen, alkyl having 1 to 4 carbon atoms or benzyl.

Specific compounds include, but are not limited to, 1-oxo-2- (2, 6-dioxopiperidin-3-yl) -4-methylisoindoline and its enantiomer, the disclosure of which is in U.S. 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 U.S. patent No. 6,380,239 and co-pending U.S. application No. 10/900,270 filed on 7/28 of 2004, which are incorporated herein by reference. Representative compounds have the formula:

wherein, is represented as C^*Form a chiral centre (when n is different from 0 and R¹And R²When not identical); x¹And X²One of which is amino, nitro, alkyl having 1 to 6 carbon atoms or NH-Z, and X¹Or X²The other is hydrogen; r¹And R²Each independently is hydroxy or NH-Z; r³Is hydrogen, alkyl containing 1 to 6 carbon atoms, halogen or haloalkyl; z is hydrogen, aryl, alkyl containing 1 to 6 carbon atoms, formyl or acyl containing 1 to 6 carbon atoms; and n has a value of 0, 1 or 2; provided that if X is¹Is amino and n is 1 or 2, then R¹And R²Are not hydroxyl; and salts thereof.

Other representative compounds have the formula:

wherein when n is not 0 and R¹And R²When not identical, is represented as C^*The carbon atom of (a) constitutes a chiral center; x¹And X²One of which is amino, nitro, alkyl having 1 to 6 carbon atoms or NH-Z, and X¹Or X²The other is hydrogen; r¹And R²Each independently is hydroxy or NH-Z; r³Is alkyl containing 1-6 carbon atoms, halogen or hydrogen; z is hydrogen, aryl or alkyl or acyl containing 1 to 6 carbon atoms; and n has a value of 0, 1 or 2.

Specific examples include, but are not limited to, 2- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -4-carbamoyl-butyric acid and 4- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -4-carbamoyl-butyric acid, respectively, having the following structures, and pharmaceutically acceptable salts, solvates, prodrugs, and stereoisomers thereof:

and

representative other compounds have the formula:

wherein, is represented as C^*Form a chiral centre (when n is different from 0 and R¹And R²When not identical); x¹And X²One of which is amino, nitro, alkyl of 1 to 6 carbon atoms or NH-Z, X¹Or X²Is hydrogen; r¹And R²Each independently is hydroxy or NH-Z; r³Is alkyl of 1 to 6 carbon atoms, halogen or hydrogen; z is hydrogen, aryl or alkyl or acyl of 1-6 carbon atoms; and n has a value of 0, 1 or 2; and salts thereof.

Specific examples include, but are not limited to, 4-carbamoyl-4- {4- [ (furan-2-yl-methyl) -amino ] -1, 3-dioxo-1, 3-dihydro-isoindol-2-yl } -butyric acid, 4-carbamoyl-2- {4- [ (furan-2-yl-methyl) -amino ] -1, 3-dioxo-1, 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 having the following structure, and 2- {4- [ (furan-2-yl-methyl) -amino ] -1, 3-dioxo-1, 3-dihydro-isoindol-2-yl } -glutaric acid, and pharmaceutically acceptable salts, solvates, prodrugs, and stereoisomers thereof:

and

other specific examples of the compound have the following formula:

wherein, X¹And X²One is nitro or NH-Z, and X¹Or X²The other of (a) is hydrogen;

R¹and R²Each independently is hydroxy or NH-Z;

R³is alkyl containing 1-6 carbon atoms, halogen or hydrogen;

z is hydrogen, phenyl, acyl containing 1 to 6 carbon atoms or alkyl containing 1 to 6 carbon atoms; and

n has a value of 0, 1 or 2;

provided that if X is¹And X²One is nitro and n is 1 or 2, then R¹And R²Is not a hydroxyl group; and

if-COR¹And- (CH)₂)_nCOR²Is different, then is represented as C^*The carbon atom(s) constituting the chiral center. Other representative compounds have the formula:

wherein, X¹And X²One is an alkyl group containing 1 to 6 carbon atoms;

R¹and R²Each independently is hydroxy or NH-Z;

R³is alkyl containing 1-6 carbon atoms, halogen or hydrogen;

z is hydrogen, phenyl, acyl containing 1 to 6 carbon atoms or alkyl containing 1 to 6 carbon atoms; and

has a value of 0, 1 or 2; and

if-COR¹And- (CH)₂)_nCOR²Is different, then is represented as C^*The carbon atom(s) constituting the chiral center.

Other specific immunomodulatory compounds of the invention include, but are not limited to: isoindolin-1-ones and isoindolin-1, 3-diones substituted at the 2-position with a 2, 6-dioxo-3-hydroxypiperidin-5-yl group, which are described in U.S. Pat. No. 6,458,810, which is incorporated herein by reference. Representative compounds have the formula:

wherein:

by using^*The carbon atoms represented constitute the chiral center;

x is-C (O) -or-CH₂-；

R¹Is alkyl having 1 to 8 carbon atoms or-NHR³；

R²Is hydrogen, alkyl having 1 to 8 carbon atoms or halogen; and

R³is hydrogen;

alkyl having 1 to 8 carbon atoms, unsubstituted or substituted with alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms;

cycloalkyl groups containing 3 to 18 carbon atoms;

phenyl, unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms;

benzyl, unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms, or-COR⁴Wherein

R⁴Is hydrogen;

alkyl having 1 to 8 carbon atoms, unsubstituted or substituted with alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms;

cycloalkyl groups containing 3 to 18 carbon atoms;

phenyl, unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms; or

Benzyl, unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms, halogen, amino or alkylamino having 1 to 4 carbon atoms.

The compounds of the present invention may be commercially available or prepared according to the methods described in the patents or patent applications disclosed in this specification. In addition, optically pure compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral columns, as well as other standard organic chemical synthesis techniques.

The term "pharmaceutically acceptable salts" as used herein, unless otherwise indicated, includes non-toxic acid and base addition salts of the compounds to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases known in the art, including, for example, hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, acetic, tartaric, lactic, succinic, citric, malic, maleic, sorbic, aconitic, salicylic, phthalic, embolic (embonic acid), heptanoic, and the like.

Naturally occurring acidic compounds are capable of forming salts with various pharmaceutically acceptable bases. The bases which can be used for the preparation of pharmaceutically acceptable base addition salts of such acidic compounds are those which form non-toxic base addition salts, that is, salts containing pharmacologically acceptable cations, such as, but not limited to, alkali metal or alkaline earth metal salts, especially calcium, magnesium, sodium, potassium salts. Suitable organic bases include, but are not limited to, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine.

The term "solvate" as used herein, unless otherwise specified, refers to a compound of the invention or a salt thereof, and also includes stoichiometric or non-stoichiometric amounts of solvents bound by non-covalent intermolecular forces. If the solvent is water, then the solvate is a hydrate.

As used herein, and unless otherwise indicated, the term "prodrug" refers to a derivative of a compound that hydrolyzes, oxidizes, or otherwise reacts 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 moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other examples of prodrugs include those containing-NO, -NO₂-ONO or-ONO₂Derivatives of some of the immunomodulatory compounds of the invention. Prodrugs can generally be prepared by well-known methods, such as those described in Burger's Medicinal Chemistry and drug discovery, 172-178, 949-982 (edited E.Wolff, 5 th edition 1995) and Design of Prodrugs (H.Bundgaand, Elselvier, New York 1985)。

As used herein, unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" refer to an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound having the following properties: 1) does not interfere with the biological activity of the compound, but may confer advantageous properties to the compound in vivo, such as absorption, duration of action or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (e.g., phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (e.g., methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylaminoalkyl esters (e.g., acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

The term "stereoisomer" as used herein, unless otherwise indicated, includes all enantiomerically/stereomerically pure and enantiomerically/stereomerically enriched compounds of the present invention.

As used herein, unless otherwise indicated, the term "stereomerically pure" or "enantiomerically pure" means that a compound includes one stereoisomer and is substantially free of the opposite stereoisomer or enantiomer of the compound. For example, a compound is stereoisomerically or enantiomerically pure when it contains 80%, 90%, or 95% or more of one stereoisomer and 20%, 10%, or 5% or less of the opposite stereoisomer. In certain instances, when a compound of the invention is about 80% ee (enantiomeric excess) or greater, preferably equal to or greater than 90% ee, more preferably 95% ee relative to a particular chiral center, then the compound is considered optically active or stereoisomerically/enantiomerically pure (i.e., substantially R-form or substantially S-form) relative to the chiral center.

As used herein, unless otherwise indicated, the term "stereomerically enriched" or "enantiomerically enriched" includes racemic as well as other mixtures of stereoisomers of the compounds of the invention (e.g., 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 or diastereomeric mixtures of enantiomers. The invention includes the use of stereomerically pure forms of such compounds as well as the use of mixtures of those forms. For example, mixtures containing equal or unequal amounts of enantiomers of particular immunomodulatory compounds of the invention may be used in methods and compositions of the invention. These isomers can be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example: jacques, j. et al, entiinoers, Racemates and solutions (Wiley-Interscience, New York, 1981); wilen, s.h. et al, Tetrahedron 33: 2725 (1977); eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of solving Agents and Optical solutions, p.268 (eds. E.L.Eliel, Univ.of Notre Dame Press, Notre Dame, IN, 1972).

It should be noted that if there is a difference between the structure shown and the name of the structure, the structure shown should be the subject of the difference. Furthermore, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be understood as encompassing all stereoisomers of it.

4.2 second active Agents

A second active ingredient or active agent may be used in the methods and compositions of the invention with an immunomodulatory compound. It is believed that certain combinations can act in a synergistic manner in the treatment of asbestos-related diseases or disorders. Immunomodulatory compounds can also be used to reduce side effects associated with certain second active agents, and certain second active agents can be used to reduce side effects associated with immunomodulatory compounds.

In the methods and compositions of the present invention, one or more second active agents can be used with an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The second active agent can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic moiety).

Examples of macromolecular active agents are biological molecules, such as naturally or artificially prepared proteins. Specific proteins include, but are not limited to: cytokines such as GM-CSF; interleukins, such as IL-2 (including recombinant IL-II ("rIL 2") and canarypox (canarypox) IL-2), IL-10, IL-12 and IL-18; interferons such as interferon alpha-2 a, interferon alpha-2 b, interferon alpha-n 1, interferon alpha-n 3, interferon beta-Ia and interferon gamma-Ib.

In one embodiment of the invention, the macromolecular active agent reduces, eliminates or prevents side effects associated with administration of an immunomodulatory compound. Depending on the disease or condition to be treated, side effects include, but are not limited to, drowsiness, lethargy, nausea, vomiting, gastrointestinal discomfort, diarrhea, and vasculitis.

The second active agent in the form of a small molecule may also be used to alleviate side effects associated with administration of the immunomodulatory compound. However, as with some macromolecules, many such second active agents are believed to produce a synergistic effect when administered with (e.g., before, after, or simultaneously with) an immunomodulatory compound. The second active agent in small divided form includes but is 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; (ii) aristozole hydrochloride; (ii) abelmoscine; (ii) Alexanox; aldesleukin; altretamine; an apramycin; amenthraquinone acetate; amsacrine; anastrozole; an atramycin; asparaginase enzyme; a triptyline; azacitidine; azatepa; (ii) azomycin; batimastat; benzotepa; bicalutamide; bisantrene hydrochloride; bisnefaede dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; briprimine; busulfan; actinomycin C; (ii) carpoterone; a carbimide; a carbapenem; carboplatin; carmustine; a doxorubicin hydrochloride; folding to get new; cediogo; celecoxib (COX-2 inhibitor); chlorambucil; a sirolimus; cisplatin; cladribine; krestist mesylate; cyclophosphamide; cytarabine; dacarbazine; actinomycin D; daunorubicin hydrochloride; decitabine; (ii) dexomaplatin; tizanoguanine; dizyguanine mesylate; diazaquinone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drotandrosterone propionate; azomycin; edatrexae; eflornithine hydrochloride; elsamitrucin; enloplatin; an enpu urethane; epinastine; epirubicin hydrochloride; (ii) ebuzole; isosbacin hydrochloride; estramustine; sodium phosphate estramustine; etanidazole; etoposide; etoposide phosphate; chlorphenethyl pyrimethanil; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; (iii) flucitabine; a phosphorus quinolone; fostrexasin sodium; gemcitabine; gemcitabine hydrochloride; a hydroxyurea; idarubicin hydrochloride; ifosfamide; ilofovir dipivoxil; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprorelin acetate; liazole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; (ii) maxolone; maytansine; mechlorethamine hydrochloride; megestrol acetate; (ii) estrene acetate; melphalan; (ii) a melanoril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meltupipide; mitodomide; mitocarcin; mitorubin; mitoxantrone; mitosin; mitomycin; mitospirane culturing; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; a noggin; oxaliplatin; oshuzuren; paclitaxel; a pemetrexed; a calicheamicin; nemadectin; pelamicin sulfate; cultivating phosphoramide; pipobroman; piposulfan; piroxantrone hydrochloride; (ii) a plicamycin; pramipexole; sodium porfimer; porphyrins; deltemustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazole furan rhzomorph; (ii) lybodenosine; safrog; safrog hydrochloride; semustine; octreozine; sodium phosphonoaspartate (Sparfosate sodium); a sparamycin; germanospiramine hydrochloride; spiromustine; spiroplatinum; streptonigrin; a streptozocin; a sulfochlorophenylurea; a talithromycin; sodium tegaserod (tecogalan Sodium); docetaxel; tegafur; tiloxanthraquinone hydrochloride; temoporfin; (ii) teniposide; a tiroxiron; cheese in the testis; (ii) a thiopurine; thioguanine; thiotepa; a thiazolfuzoline; tirapazamine; toremifene citrate; triton acetate; triciribine phosphate; trimetrexate; tritrosa glucuronide; triptorelin; tobramzole hydrochloride; uramustine; uretipi; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinblastine epoxy sulfate; vinorelbine tartrate; vinblastine sulfate; vinzolidine sulfate; (ii) vorozole; zeniplatin; 1, neat setastine; zorubicin hydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-1, 25 dihydroxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; an acylfulvene; adecyenol; (ii) Alexanox; aldesleukin; ALL-TK antagonist; altretamine; estramustine; (ii) amidox; amifostine; (ii) aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; an angiogenesis inhibitor; an antagonist D; an antagonist G; anrlex; anti-dorsal morphogenetic protein-1; anti-androgens, prostate cancer; an antiestrogen; anti-neoplastic ketones; an antisense oligonucleotide; alfedimycin glycinate; an apoptosis gene modulator; a modulator of apoptosis; none glance sideways at(ii) a nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestan; amoxicillin; axinatatin 1; axinatatin 2; axinatatin 3; azasetron; azalomycin; n-thymine; baccatin III derivatives; balanol; batimastat; a BCR/ABL antagonist; chromanol; benzoyl echinocandin star; beta lactam derivatives; beta-alethine; beta-clamycin B; betulinic acid; a bFGF inhibitor; bicalutamide; a bisantrene group; dinitropropinyl spermine; (ii) bisnefarde; bistetralene A; bizelesin; brefflate; briprimine; titanium is distributed; butyl alumine; calcipotriol; calphos protein C; a camptothecin derivative; capecitabine; carboxamide-amino-triazole; carboxamide triazoles; CaRest M3; CARN 700; an inhibitor derived from cartilage; folding to get new; casein kinase Inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; (ii) chlorolins; a chloroquinoxaline sulfonamide drug; (ii) cicaprost; a cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colimycinB; combretastatin a 4; combretastatin analogs; a concanagen; crambescidin 816; clinatot; cyclopeptide 8 from nostoc; a cyclopeptide a derivative from nostoc; curve A; cyclopentaquinone; cycloplatam; cypemycin; cytarabine ocfosfate; a cytolytic factor; a cytostatin; daclizumab; decitabine; dehydromembrane ecteinascidin B; deslorelin; dexamethasone; (ii) dexifosfamide; dexrazoxane; (ii) verapamil; diazaquinone; dynastine B; didox; diethyl norspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; a dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; etokomustine; edifulin; epidolumab; eflornithine; elemene; ethirimuron fluoride; epirubicin; epristeride; an estramustine analogue; an estrogen agonist; an estrogen antagonist; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flutemastine; a flashterone; fludarabine; fluoroxolone hydrochlorideErythromycin; fowler; fulvestrant; fostrexed; fotemustine; gadolinium deuteroporphyrin; gallium nitrate; galocitabine; ganirelix; a gelatinase inhibitor; gemcitabine; a glutathione inhibitor; hepsulfam; heregulin; hexamethylene bisamide; hypericin; ibandronic acid; idarubicin; idoxifene; iloperidone; ilofovir dipivoxil; ilomastat; imatinib (e.g. Gleevec)^®) (ii) a Imiquimod; immunostimulatory peptides; an insulin-like growth factor-1 receptor inhibitor; an interferon agonist; an interferon; an interleukin; iodobenzylguanidine; iododoxorubicin; yam, 4-; iprop; isradine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N-triacetic acid; lanreotide; leinamycin; leguminous kiosks; mushroom polysaccharide sulfate; leptin statin; letrozole; leukemia inhibitory factor; leukocyte interferon-alpha; leuprorelin + estrogen + progesterone; leuprorelin; levamisole; liazole; a linear polyamine analog; a lipophilic glycopeptide; a lipophilic platinum compound; lissoclinamide 7; lobaplatin; earthworm phosphatide; lometrexol; lonidamine; losoxanthraquinone; loxoribine; lurtotecan; lutetium porphyrinates; lysofylline; dissolving the peptide; maytansine; manostatin A; marimastat; (ii) maxolone; maspin; inhibitors of gene lytic factors; a matrix metalloproteinase inhibitor; (ii) a melanoril; malbaruron; 1, meperiline; methioninase; metoclopramide; an inhibitor of MIF; mifepristone; miltefosine; a Millisetil; mitoguazone; dibromodulcitol; mitomycin analogs; mitonaphthylamine; mitotoxin fibroblast growth factor-saporin (saporin); mitoxantrone; mofagotine; moraxest; erbitux, human chorionic gonadotropin; monophosphoryl grease A + lactobacillus cell wall sk; mopidanol; a nitrogen mustard anti-cancer agent; indian ocean sponge B; a mycobacterial cell wall extract; myriaporone; n-acetyldinaline; an N-substituted benzamidine; nafarelin; nagestip; naloxone + tebuconazole; napavin; naphterpin; a nartostim; nedaplatin; nemorubicin; neridronic acid; a linonactam; nisamycin; a nitrogen oxide modifier; a nitroxide antioxidant; nitrulyn; oblimersen(Genasense^®)；O⁶-benzylguanine; octreotide; okicenone; an oligonucleotide; onapristone; ondansetron; ondansetron; oracin; an oral cytokine inducer; oxaliplatin; an oxateclone; oxaliplatin; oxanonomycin; paclitaxel; a paclitaxel analog; a paclitaxel derivative; a palau amine; palmitoyl rhizomycin; pamidronic acid; panaxatriol; panomifen; para-bacteriocin (paramactin); pazeliptin; a pemetrexed; pedasine (peldesine); pentosan polysulfate sodium; pentostatin; (ii) pentazole; perfluorobromoalkane; cultivating phosphoramide; sinapyl alcohol; phenazinomomycin; phenyl acetate; a phosphatase inhibitor; a streptolysin; pilocarpine hydrochloride; pirarubicin; pirtroxine; placentinA; placetin B; inhibitors of plasminogen activation; synthesizing platinum; a platinum compound; synthesizing platinum-triamine; sodium porfimer; a podomycin; prednisone; propyldi-acridone; prostaglandin J2; a proteolytic degradation inhibitor; a protein a-based immunomodulator; inhibitors of protein kinase C; inhibitors of protein kinase C; microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoloacridine; a glycoxethyl hemoglobin polyethylene oxide conjugate; a raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; (ii) a ras inhibitor; ras-GAP inhibitors; demethylated reteplatin; sodium etidronate rhenium Re 186; rhizomycin; a ribozyme; RII retinoamide; rohitukine; romurtide; loquimex; rubiginone B1; ruboxyl; safrog; saintopin; SarCNU; sarcophylol A; sargrastim; sdi 1 mimetics; semustine; aging-derived inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; a texaphyrin; sobuconazole; sodium boron carbonate; sodium phenyl acetate; solverol; a growth regulator binding protein; sonaming; a spa acid; spicamycin D; spiromustine; spleenetin; natural substance spongin 1; squalamine; stiiamide; a matrix lytic enzyme inhibitor; sulfinosine; a superactive vasoactive intestinal peptide antagonist; (ii) surfasta; suramin; adding indolizinetriol; tamustine; tamoxifen methyl iodide; taulomustine; tazarotene; sodium tegafur; tegafur; telluropyrylium; telomeraseAn inhibitor; temoporfin; (ii) teniposide; tetrachlorodecane oxide; tetrazomine; (ii) a thioablistatin; thiocoraline; thrombopoietin; a thrombopoietin mimetic; thymalfasin (Thymalfasin); a thymopoietin receptor agonist; thymotreonam; thyroid stimulating hormone; tin (ll) ethyl porphyrin; tirapazamine; titanocene dioxide; topstein; toremifene; a translation inhibitor; tretinoin; triacetyl uridine; (iii) triciribine; trimetrexate; triptorelin; tropisetron; toleromide; tyrosine kinase inhibitors; tyrphostins; an UBC inhibitor; ubenimex; urogenital sinus growth inhibitory factor; a urokinase receptor antagonist; vapreotide; variolin B; vilareol; ver amine; verdins; verteporfin; vinorelbine; vinxaline; vitaxin; (ii) vorozole; zanoteron; zeniplatin; benzal vitamin C; and neat stastatin ester.

Specific second active agents include, but are not limited to: anthracyclines, platinum, alkylating agents, oblimersen (Genasense)^®) Gemcitabine, cisplatin (cispininum), cyclophosphamide, temodar, carboplatin, procarbazine, carmustine, tamoxifen, methotrexate, docetaxel, irinotecan, topotecan, temozolomide, capecitabine, cisplatin (cisclinin), thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronate, palmitronate, biaxin, busulfan, prednisone, bisphosphate, arsenic trioxide, vincristine, doxorubicin (Doxil)^®) Paclitaxel, ganciclovir, doxorubicin, bleomycin, hyaluronidase, mepacrilin, thiotepa, tetracycline and mitomycin C.

4.3 methods of treatment and control

The methods of the present invention include methods of treating, preventing and/or managing various types of asbestos-related diseases or disorders. As used herein, unless otherwise indicated, the term "treatment" refers to the administration of an immunomodulatory compound or other additional active agent after the onset of symptoms of an asbestos-related disease or disorder, while "prevention" refers to the administration prior to the onset of symptoms, particularly symptoms in a patient at risk of developing mesothelioma or other asbestos-related disorder. The term "preventing" includes inhibiting or avoiding a symptom of a particular disease or disorder. Symptoms of asbestos-related diseases or disorders include, but are not limited to, dyspnea, diaphragm deletion, radiolucent sheet-like encapsulation of the pleura, pleural effusion, pleural thickening, decreased chest size, chest discomfort, chest pain, susceptibility to fatigue, fever, sweating, and weight loss. Patients at risk for asbestos-related diseases or disorders include, but are not limited to: people exposed to asbestos at construction sites, and family members exposed to asbestos embedded in worker clothing. Patients with a family history of asbestos-related diseases or disorders are preferred candidates for a prophylactic regimen.

As used herein, unless otherwise indicated, the term "managing an asbestos-related disease or disorder" includes preventing the recurrence of the disease or disorder in a patient having suffered from the disease or disorder, and/or prolonging the time that a patient having suffered from the disease or disorder remains in remission.

The methods of the invention comprise administering an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) having, or at risk of having, an asbestos-related disease or disorder.

Without being limited by theory, it is believed that the compounds of the present invention can be administered prophylactically to prevent the development of asbestos-related diseases or disorders in persons who have previously been exposed to asbestos. This method of prevention may actually prevent the development of an asbestos-related disease or disorder at the first location. Accordingly, the invention includes a method of preventing an asbestos-related disease or disorder in a human subject likely to have the asbestos-related disease or disorder, the method comprising administering to a human subject in need thereof an effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Without being limited by theory, it is believed that the compounds of the present invention are capable of inhibiting the expansion of asbestos-related diseases or disorders after diagnosis because such compounds are capable of affecting cytokine production (e.g., TNF- α, IL-1 β, and IL 12).

The present invention includes methods of treating, preventing and managing asbestos-related diseases or disorders in patients with various stages and specific types of diseases, including, but not limited to, malignant mesothelioma, asbestosis, malignant pleural effusion, benign pleural effusion, pleural plaque, pleural calcification, diffuse pleural thickening, round atelectasis, and bronchogenic carcinoma. The invention also includes methods of treating patients who have previously been treated for an asbestos-related disease or condition but who have not responded adequately or who have not been treated accordingly, as well as patients who have not previously been treated for the disease or condition. Because patients may have different clinical manifestations and different clinical outcomes, the treatment given to a patient may vary depending on his/her prognosis. An ordinary clinician will be able to readily determine without undue experimentation the type of specific second agent that may be effective in treating the physical therapy of each patient.

In one embodiment, the immunomodulatory compound is administered orally in a single or divided dose in a daily dose of about 0.10mg to about 1,000mg per day, 1mg to about 1,000mg per day, about 1mg to about 500mg per day, about 1mg to about 250mg per day, about 5mg to about 150mg per day, or about 10mg to about 50mg per day. In a particular embodiment, 4- (amino) -2- (2, 6 dioxo (3-piperidyl)) -isoindoline-1, 3-dione (Actimid)^TM) About 0.1 to 1 mg/day, or about 0.1 to 5mg every other day. In a preferred embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid)^TM) About 1-25 mg/day or greater, typically about 1.5-2.5 times the daily dose every other day.

In particular embodiments, the method of preventing an asbestos-related disease comprises administering about 1, 2.5, 5, or 10mg of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione per day to a population believed to be exposed to asbestos. In an embodiment of a particular prophylactic regimen, the amount of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione administered daily is about 5 mg.

In controlling the patient, treatment should be initiated at a lower dose, approximately from about 0.1mg to 10mg, and if necessary increased to about 1mg to 1,000mg per day depending on the patient's systemic response, administered as a single divided dose.

4.3.1 combination therapy with a second active agent

Particular 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 disclosed herein (see, e.g., section 4.2).

Administration of the selective cytokine inhibitory drug and the second active agent can be simultaneous or sequential, by the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without breaking down before entering the blood stream) and the disease being treated. One preferred route of administration of the immunomodulatory compounds is oral. Preferred routes of administration for the second active agents or components of the invention are known to those skilled in the art, see, e.g., Physicians' Desk Reference, 2003.

The specific dosage of the second active agent will depend upon the specific active agent used, the type, severity and stage of the disease or condition being treated or controlled, and the amounts of immunomodulatory compound and any optional additional active agent administered in combination to the patient.

In one embodiment, the second active agent is an anthracycline, platinum, an alkylating agent, an oblimersen (Genasense)^®) Cisplatin (cissplatinum), cyclophosphamide, temodar, carboplatin, procarbazine, carmustine, tamoxifen, topotecan, methotrexate, docetaxel, irinotecan, capecitabine, cisplatin (cissplatin), thiotepa, fludarabine, carboplatin, and mixtures thereof,Liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphate, arsenic trioxide, vincristine, doxorubicin (Doxil)^®) Paclitaxel, ganciclovir, doxorubicin, bleomycin, hyaluronidase, mitomycin C, mepacrilin, thiotepa, tetracycline, and gemcitabine.

In particular embodiments, the immunomodulatory compound is administered in combination with vinorelbine to a patient suffering from malignant mesothelioma or malignant pleural effusion mesothelioma syndrome.

In another embodiment, the immunomodulatory compound is administered in combination with cyclophosphamide/doxorubicin/cisplatin, cisplatin/methotrexate/vinblastine, cisplatin/gemcitabine, cisplatin/doxorubicin/mitomycin C, bleomycin/intrapleural hyaluronidase, cisplatin/doxorubicin, cisplatin/vinblastine/mitomycin C, gemcitabine/irinotecan, carboplatin/docetaxel, or carboplatin/paclitaxel.

4.3.2 use with conventional therapy

Mesothelioma is treated or controlled using standard methods of chemotherapy, radiation therapy, photodynamic therapy, and surgery. Kaiser lr., emmin Thorac Cardiovasc surg.10 months; 9(4): 383-90, 1997. Intraluminal methods using targeted cytokines and gene therapy have been attempted for patients with mesothelioma, in which intratumoral genes are transferred into the pleural space of the patient using a recombinant adenovirus (rAd) containing the herpes simplex virus thymidine kinase (HSVtk) gene. The same as above, and StermanDH, Hematol Oncol Clin North am.6 months; 12(3): 553-68, 1998.

Certain embodiments of the invention encompass methods of treating and managing an asbestos-related disease or disorder, which comprise administering an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with conventional therapy (e.g., before, during, or after). Such conventional therapies include, but are not limited to: chemotherapy, surgery, photodynamic therapy, radiation therapy, gene therapy, immunotherapy, or non-drug therapies currently used to treat or control diseases or disorders. The use of immunomodulatory compounds in combination with conventional therapies provides a unique treatment regimen with unexpected effects in certain patients.

As described elsewhere herein, the invention includes methods of reducing, treating and/or preventing adverse or unwanted effects associated with conventional therapies, including but not limited to chemotherapy, photodynamic therapy, surgery, radiation therapy, gene therapy, and immunotherapy. The selective cytokine inhibitory drug and other active agents can be administered before, during, or after the occurrence of adverse effects associated with conventional therapies. Side effects associated with chemotherapy and radiation therapy that may be treated or prevented by the present methods include, but are not limited to: gastrointestinal toxicities such as, but not limited to, early or late established diarrhea and flatulence; nausea; vomiting; anorexia; leukopenia; anemia; neutropenia; debilitation; abdominal colic; fever is caused; pain; loss of body weight; dehydrating; alopecia; dyspnea; insomnia; dizziness, mucositis, xerostomia, and renal failure.

In one embodiment, an immunomodulatory compound is administered orally before, during, or after conventional therapy from about 0.10mg to about 1,000mg per day, from about 1mg to about 500mg per day, from about 1mg to about 250mg per day, from about 5mg to about 150mg per day, or from about 10mg to about 50mg per day, alone or in combination with a second active agent described herein (see, e.g., section 4.2). In a particular embodiment of the method, the immunomodulatory compound and doxetaxol are administered to a patient having mesothelioma prior to over-radiotherapy treatment.

In one embodiment of the method, the selective cytokine inhibitory drug is administered to a patient suffering from an asbestos-related disease or disorder in combination with triple therapy. Triple therapy involves a combination of three standard approaches, namely surgery, chemotherapy, and radiation therapy. In one embodiment of the method, the chemotherapy and radiation therapy with the immunomodulatory compound is used in combination after a pleuroperectomy. In another embodiment of the triple therapy, the immunomodulatory compound is administered in combination with a different chemotherapeutic regimen comprising a combination of cyclophosphamide/doxorubicin/cisplatin, carboplatin/paclitaxel, or cisplatin/methotrexate/vinblastine.

4.3.3 periodic treatment

In certain embodiments, the selective cytokine inhibitory drug is administered to the patient periodically. Periodic treatment involves administration of an immunomodulatory compound for a period of time, followed by a rest period for a period of time, and repeating the dosing sequence. Periodic treatment can reduce the development of resistance to one or more therapeutic agents, avoid or reduce the side effects of a treatment, and/or increase the efficacy of a treatment. Thus, in one embodiment of the invention, the selective cytokine inhibitory drugs are administered daily in individual or divided doses over a period of 4-6 weeks (with a rest period of about 1 or 2 weeks). Typically, the combination therapy is administered to the patient for a number of cycles ranging from about 1 to 24 cycles, more typically from about 2 to 16 cycles, and more typically from about 4 to 6 cycles. The invention also allows for increased frequency, number and extended dosing cycles. Thus, a particular embodiment of the invention encompasses administration of an immunomodulatory compound for more cycles than would normally be the case if administered alone. In another embodiment of the invention, the selective cytokine inhibitory drug is administered for more cycles that would normally cause dose-limiting toxicity in a patient to whom the second active agent is not administered.

In one embodiment, the selective cytokine inhibitory drug is administered daily in an amount of about 0.1-150 mg/day for 3 or 4 weeks, followed by a rest for one or two weeks, over a period of 4 or 6 weeks.

In another embodiment of the invention, the immunomodulatory compound and the second active agent are administered orally over a period of 4-6 weeks, wherein the immunomodulatory compound is administered 30-60 minutes prior to administration of the second active agent.

In another embodiment, the immunomodulatory compound is administered at 100mg/m with cisplatin on day 1 for a 28-day cycle²Is measured intravenouslyAdministration at 1000mg/m with gemcitabine on days 1, 8 and 15²The amount of (a) is administered intravenously for a total of 6 cycles.

4.4 pharmaceutical compositions and Single Unit dosage forms

The pharmaceutical compositions may be used to prepare individual single unit dosage forms. Pharmaceutical compositions and dosage forms of the invention comprise an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The pharmaceutical compositions and dosage forms of the present invention may also comprise one or more excipients.

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

The single unit dosage forms of the invention are suitable for administration to a patient orally, mucosally (e.g., nasally, sublingually, vaginally, buccally or rectally), or parenterally (e.g., subcutaneously, intravenously, by bolus injection, intramuscularly or intraarterially), transdermally or transdermally. Examples of dosage forms include, but are not limited to: a tablet; a caplet; capsules, such as elastic soft gelatin capsules; a cachet; keeping in mouth; a lozenge; a dispersant; suppositories; a powder agent; aerosols (e.g., nasal sprays or inhalants); gelling agent; liquid dosage forms suitable for oral or transmucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

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

Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those of ordinary skill in the pharmaceutical arts, and non-limiting examples of suitable excipients are provided in the present specification. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to a patient. For example, oral dosage forms (e.g., tablets) may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient may depend on the particular active ingredient in the dosage form. For example, some excipients (e.g., lactose), or when exposed to water, may accelerate the decomposition of some active ingredients. Active ingredients containing primary or secondary amines are particularly sensitive to this accelerated decomposition. Thus, the invention includes pharmaceutical compositions and dosage forms that contain little, if any, lactose or other mono-or disaccharides. In the present invention, the term "lactose-free" is used to indicate that the amount of lactose, if any, is insufficient to substantially accelerate the rate of degradation of the active ingredient.

Lactose-free compositions of the invention may contain excipients well known in the art, such as those listed in, for example, the United States Pharmacopeia (USP)25-NF20 (2002). Typically, lactose-free compositions contain pharmaceutically compatible and pharmaceutically acceptable amounts of active agent, binder/filler and lubricant. Preferably, the lactose-free dosage form contains the active agent, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing the active agent, as water may promote the degradation of certain compounds. As water promotes the degradation of certain compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine properties of the formulation over time, such as shelf life or stability. See, e.g., jenst. carstensen, "drug stability: principles and practices (Drug Stability: Principles & Practice), second edition, Marcel Dekker, NY, NY, 1995, pages 379-80. In fact, water and heat will accelerate the decomposition of some compounds. Thus, the effect of water on the formulation is very significant, as moisture and/or humidity is often encountered during manufacture, handling, packaging, storage, shipment, and use of the formulation.

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

Anhydrous pharmaceutical compositions should be prepared and stored in a manner that maintains their anhydrous nature. Accordingly, anhydrous compositions are preferably packaged with materials known to prevent exposure to water, so that they can be packaged in suitable formulation boxes. Examples of suitable packaging include, but are not limited to, sealed films, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

The invention also includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of decomposition of the active ingredient. Such compounds are referred to herein as "stabilizers" and include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers.

As with the amount and type of excipient, the type and amount of a particular active ingredient in a dosage form may vary depending upon a variety of factors including, but not limited to, the route of administration. However, a typical dosage form of the invention contains from about 1 to about 10,00mg of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, thereof,Hydrates, stereoisomers, clathrates or prodrugs. Typical dosage forms contain about 0.1, 1, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150, or 200mg of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. In specific embodiments, preferred dosage forms contain about 1, 2.5, 5, 10, 25, or 50mg of 4- (amino) -2- (2, 6-dioxo (3-piperidyl)) -isoindoline-1, 3-dione (Actimid)^TM). In certain embodiments, preferred dosage forms contain about 1, 2.5, 5, 10, 25, or 50mg of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione (Revimid)^TM). Typical dosage forms contain from about 1 to about 3,500mg, from about 5mg to about 2,500mg, from about 10mg to about 500mg, or from about 25mg to about 250mg of the second active agent. The specific amount of the second active agent will, of course, depend upon the specific active agent used, the type of macular degeneration being treated or controlled, and the amount of immunomodulatory compound and any optional additional active agents concurrently administered to the patient.

4.4.1 oral dosage forms

Pharmaceutical compositions of the invention suitable for oral administration may be formulated in discrete dosage forms such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of active agent and may be prepared by pharmaceutical methods well known to those of ordinary skill in the art. See generally, Remington's pharmaceutical sciences, 18th edition, Mack Publishing, Easton PA (1990).

Typical oral dosage forms are prepared by intimately mixing the active agent with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients may 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, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) 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 using solid excipients represent the most advantageous oral unit dosage form. If desired, the tablets may be coated by standard aqueous or non-hydrated techniques. Such dosage forms may be prepared by any pharmaceutical method. Pharmaceutical compositions and dosage forms are generally prepared by: the active agent is intimately mixed with a liquid carrier, a well-dispersed solid carrier, or both, and the product is then shaped as desired.

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

Examples of excipients that may be used in the oral dosage forms of the present 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 (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

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

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

Disintegrants are used in the compositions of the invention to provide tablets that disintegrate upon exposure to an aqueous environment. Tablets containing too much disintegrant may disintegrate in storage, while tablets containing too little may not disintegrate at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that does not significantly alter the release of the active agent, either too much or too little, should be used to form the solid oral dosage form of the present invention. The amount of disintegrant used varies with the type of formulation and is readily determined by one skilled in the art. Typical pharmaceutical compositions contain from about 0.5% to about 15% by weight of disintegrant, preferably from about 1% to about 5% by weight of disintegrant.

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

Lubricants useful in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Other lubricants include, for example, syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), solidified aerosol of synthetic silica (sold by Degussa Co. of Plano, TX), CAB-O-SIL (a sintered silica product sold by Cabot Co. of Boston, MA), and mixtures thereof. Lubricants, if used at all, are generally used in amounts less than about 1% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

Preferred solid oral dosage forms comprise an immunomodulatory compound, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide, and gelatin.

4.4.2 Slow Release dosage forms

The active agents of the present invention may be administered by controlled release devices or delivery devices known to those skilled in the art. Examples include, but are not limited to, those described in the following patents: U.S. Pat. nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 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 may be used to provide sustained or controlled release of one or more active agents by using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, isotonic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to produce desired release profiles in varying proportions. Suitable controlled release formulations include those described herein, which are well known to those skilled in the art and are readily selected for use with the active agents of the present invention. Thus, the present invention encompasses single unit dosage forms suitable for controlled release and for oral administration, including but not limited to tablets, capsules, gelcaps, and caplets.

All controlled release drug products share the following common objectives: the curative effect of the medicine is improved to exceed the curative effect of the non-released product. Ideally, the use of optimally designed controlled release formulations in medical treatment is characterized by: the disease is cured or controlled in the shortest time with the least amount of medicine. Advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency and improved patient compliance. In addition, controlled release formulations may be used to affect the time at which the effect begins or other characteristics, such as blood levels of the drug, and thereby affect the incidence of side effects (e.g., adverse side effects).

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

4.4.3 parenteral dosage forms

Parenteral dosage forms can be administered to a patient by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial routes. Since their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, dry products that can be dissolved or suspended in a pharmaceutically acceptable carrier for injection, injectable suspensions, 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: USP water for injection; aqueous carriers such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate

Compounds that increase the solubility of one or more of the active agents disclosed herein may also be incorporated into the parenteral dosage forms of the invention. For example, cyclodextrins and derivatives thereof can be used to increase the solubility of immunomodulatory compounds and derivatives thereof. See, for example, U.S. Pat. No. 5,134,127, which is incorporated herein by reference.

4.4.4 topical and transmucosal dosage forms

Topical and transmucosal administration forms of the present invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, or other forms known to those skilled in the art. See, e.g., Remington's Pharmaceutical sites, 16 th and 18th editions, Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical DosageForms, 4 th edition, Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissue in the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materials that may be used in the preparation of the topical and transmucosal dosage forms of the present invention are well known to those skilled in the art of pharmacy and depend on the particular tissue to which a given pharmaceutical composition or dosage form is to be administered. In fact, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1, 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form a non-toxic and pharmaceutically acceptable solution, emulsion, or gel. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms, if desired. Examples of such other ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th and 18th edition, Mack Publishing, Easton PA (1980 & 1990).

The pH of the pharmaceutical composition or dosage form may also be adjusted to enhance delivery of one or more active agents. Similarly, the polarity of the solvent vehicle, its ionic strength, or tonicity can be adjusted to enhance delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active agents to enhance delivery. In this regard, stearates can be used as lipid carriers, emulsifiers or surface active agents, as well as delivery or penetration enhancers for the formulation. Different salts, hydrates or solvates of the active agent may also be used to adjust the properties of the resulting composition.

4.4.5 kits

It is generally preferred that the active agents of the invention are not administered at the same time or by the same route of administration. Thus, the present invention includes kits that, when used by medical personnel, can simplify the administration of an appropriate amount of an active agent to a patient.

Typical kits of the invention comprise a dosage form consisting of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof. The kits of the invention may also comprise one or more additional active agents or combinations thereof. Examples of such other active agents include, but are not limited to: anti-cancer agents, antibiotics, anti-inflammatory agents, steroids, immunomodulators, cytokines, immunosuppressants, and other therapeutic agents described herein (see, e.g., section 4.2).

The kit of the invention may also comprise a device for administering the active agent. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

The kits of the invention may also comprise a pharmaceutically acceptable carrier that can be used to administer one or more active agents. For example, if the active agent is in solid form and must be formulated for parenteral administration, the kit may comprise a sealed container containing a suitable carrier in which the active agent can be dissolved to form a sterile, particle-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: USP water for injection; aqueous carriers such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-hydrated vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

5. Examples of the embodiments

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

5.1 pharmacological test

One biological effect of immunomodulatory compounds is to decrease synthesis of TNF- α. Certain immunomodulatory compounds promote the degradation of TNF- α mRNA. TNF-alpha has a pathological role in asbestos-related diseases.

In a specific embodiment, the inhibition of TNF- α production by 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione, 4- (amino) -2- (2, 6-dioxo- (3-piperidyl)) -isoindoline-1, 3-dione, or thalidomide, upon LPS-stimulation in human PBMC and human whole blood is determined in vitro. IC for inhibition of TNF-alpha production by 4- (amino) -2- (2, 6-dioxo- (3-piperidyl)) -isoindoline-1, 3-dione on PBMC and human whole blood following LPS-stimulation₅₀Are-24 nM (6.55ng/mL) and-25 nM (6.83ng/mL), respectively. IC of 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione for inhibition of TNF-alpha production by PBMC and human whole blood after LPS-stimulation₅₀Are-100 nM (25.9ng/mL) and-480 nM (103.6ng/mL), respectively. IC of TNF-alpha production inhibition of PBMC after LPS-stimulation by thalidomide₅₀194 μ M (50.1 μ g/ml). In vitro experiments showed that 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione or 4- (amino) -2- (2, 6-dioxo- (3-piperidyl)) -isoindoline-1, 3-dione is 50-2,000 times more potent than thalidomide in pharmacological activity in vitro.

In addition, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione or 4- (amino) -2- (2, 6-dioxo- (3-piperidyl)) -isoindoline-1, 3-dione is about 50-100 times stronger than thalidomide in stimulating T-cell proliferation after initial induction by T-cell receptor (TCR) activation. The compound is also about 50-100 fold more potent than thalidomide in increasing IL-2 and IFN- γ production following TCR activation of PBMC (IL-2) or T cells (IFN- γ). In addition, the compounds show dose-dependent inhibition of LPS-stimulated production of the pro-inflammatory cytokines TNF- α, IL1 β and IL6 by PBMCs, while they increase the production of the anti-inflammatory cytokine IL 10.

5.2 clinical trials in mesothelioma patients

The immunomodulatory compound is administered to a patient suffering from asbestosis, malignant mesothelioma, or malignant pleural effusion mesothelioma syndrome at a dose of about 1mg to 1,000mg, about 1mg to 500mg, or about 1mg to 250mg per day. In a particular embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered alone or in combination with vinorelbine in an amount of 1 mg/day to 150 mg/day. Clinically effective patients allow treatment to continue.

Other clinical trials were conducted with 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione for patients with unresectable or recurrent mesothelioma who did not respond to conventional therapy. In one embodiment, 3- (4-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione is administered to the patient in an amount of about 1mg to 150mg per day. Treatment with a continuous oral daily dose of 10mg is well tolerated. Tests with immunomodulatory compounds for treating patients with mesothelioma or asbestosis have shown that the drugs have therapeutic effect on this disease.

The embodiments of the invention described herein are only examples of the scope of the invention. The full scope of the invention can be better understood with reference to the appended claims.

Claims (24)

1. A method of treating, preventing or managing an asbestos-related disease or disorder, 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 pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The method of claim 1, wherein the disease or disorder is mesothelioma, asbestosis, pleural effusion, pleural plaque, pleural calcification, diffuse pleural thickening, round atelectasis, or bronchogenic carcinoma.

3. The method of claim 1, further comprising administering to the patient a therapeutically or prophylactically effective amount of a second active agent.

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 immunomodulator, a cytokine, an immunosuppressant, or a combination thereof.

5. The method of claim 4, wherein the second active agent is anthracycline, platinum, alkylating agent, interferon, oblimersen, cisplatin (cissplatinum), cyclophosphamide, irinotecan, topotecan, temozolomide, temodar, carboplatin, procarbazine, carmustine, tamoxifen, methotrexate, docetaxel, capecitabine, cisplatin (cilastatin), thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel, vinblastine, GM-CSF, IL-2, dacarbazine, vinorelbine, zoledronate, palmitrone, biaxin, busulfan, prednisone, bisphosphate, arsenic trioxide, vincristine, doxorubicin, taxol, ganciclovir, bleomycin, hyaluronidase, mitomycin C, pamphleomycin, tiaclin, tetracycline, or gemcitabine.

6. A method of treating, preventing or managing an asbestos-related disease or disorder, 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 pharmaceutically acceptable salt, 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, round atelectasis, or bronchogenic carcinoma.

8. The method of claim 6, further comprising administering to the patient a therapeutically or prophylactically effective amount 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 immunomodulator, a cytokine, an immunosuppressant, or a combination thereof.

10. The method of claim 9, wherein the second active agent is anthracycline, platinum, alkylating agent, interferon, oblimersen, cisplatin (cissplatinum), cyclophosphamide, temodar, carboplatin, procarbazine, carmustine, tamoxifen, irinotecan, topotecan, temozolomide, methotrexate, docetaxel, irinotecan, capecitabine, cisplatin (cissplatin), thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitrone, biaxin, busulfan, prednisone, bisphosphate, arsenic trioxide, vincristine, doxorubicin, paclitaxel, ganciclovir, doxorubicin, bleomycin, hyaluronidase, mitomycin C, clin, tiazelin, tetracycline, tetracyclin, or gemcitabine.

11. The method of claim 1, wherein a 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)) -isoindoline-1, 3-dione.

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-1, 3-dihydro-isoindol-2-yl) -piperidine-2, 6-dione.

15. The method of claim 14, wherein the immunomodulatory compound is enantiomerically pure.

16. The method of claim 1, wherein the immunomodulatory compound is a compound of formula (I):

wherein one of X and Y is C ═ O, and the other of X and Y is C ═ O or CH₂，R²Is hydrogen or lower alkyl.

17. The method of claim 16, wherein the immunomodulatory compound is enantiomerically pure.

18. The method of claim 1, wherein the immunomodulatory compound is a compound of formula (II):

wherein:

one of X and Y is C ═ O, and the other is CH₂Or C ═ O;

R¹is H, (C)₁-C₈) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₅) Heteroaryl, C (O) R³、C(S)R³、C(O)OR⁴、(C₁-C₈) alkyl-N (R)⁶)₂、(C₁-C₈) alkyl-OR⁵、(C₁-C₈) alkyl-C (O) OR⁵、C(O)NHR³、C(S)NHR³、C(O)NR³R³′、C(S)NR³R³' or (C)₁-C₈) alkyl-O (CO) R⁵；

R²Is H, F, benzyl, (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl or (C)₂-C₈) An alkynyl group;

R³and R³' independently is (C)₁-C₈) Alkyl, (C)₃-C₇) Cycloalkyl group, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl group, (C)₀-C₄) Alkyl radical- (C)₂-C₈) Heteroaryl, (C)₀-C₈) alkyl-N (R)⁶)₂、(C₁-C₈) alkyl-OR⁵、(C₁-C₈) alkyl-C (O) OR⁵、(C₁-C₈) alkyl-O (CO) R⁵OR C (O) OR⁵；

R⁴Is (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, (C)₁-C₄) alkyl-OR⁵Benzyl, aryl, (C)₀-C₄) Alkyl radical- (C)₁-C₆) Heterocycloalkyl or (C)₀-C₄) Alkyl radical- (C)₂-C₅) A heteroaryl group;

R⁵is (C)₁-C₈) Alkyl, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl or (C)₂-C₈) A heteroaryl group;

R⁶each occurrence independently isH、(C₁-C₈) Alkyl, (C)₂-C₈) Alkenyl, (C)₂-C₈) Alkynyl, benzyl, aryl, (C)₂-C₅) Heteroaryl or (C)₀-C₈) alkyl-C (O) O-R⁵Or R is⁶Groups may be joined together to form a heterocycloalkyl group;

n is 0 or 1; and

^*represents a chiral carbon center.

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 carboxy derivative of substituted styrene, 1-oxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline, 1, 3-dioxo-2- (2, 6-dioxo-3-fluoropiperidin-3-yl) isoindoline, or tetrasubstituted 2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindoline.

21. The method of claim 20, wherein the immunomodulatory compound is enantiomerically pure.

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 an asbestos-related disease or disorder.

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 immunomodulator, an immunosuppressant, or a combination thereof.

24. The pharmaceutical composition of claim 22, wherein the second active agent is anthracycline, platinum, alkylating agent, interferon, oblimersen, cisplatin (cissplatinum), cyclophosphamide, temodar, carboplatin, procarbazine, carmustine, tamoxifen, methotrexate, docetaxel, capecitabine, cisplatin (cissplatin), thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphate, arsenic trioxide, irinotecan, topotecan, temozolomide, vincristine, doxorubicin, taxol, ganciclovir, doxorubicin, hyaluronidase, mitomycin C, mackeramicin C, meclizine, thiaclopramide, tetracycline or gemcitabine.