MXPA06004999A

MXPA06004999A - Methods of using and compositions comprising pde4 modulators for the treatment and management of asbestos-related diseases and disorders

Info

Publication number: MXPA06004999A
Application number: MXPA/A/2006/004999A
Authority: MX
Inventors: B Zeldis Jerome
Original assignee: Celgene Corporation; B Zeldis Jerome
Priority date: 2003-11-06
Filing date: 2006-05-04
Publication date: 2006-10-17

Abstract

Methods of treating, preventing and managing an asbestos-related disease or disorder are disclosed. Specific embodiments encompass the administration of a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent and/or chemotherapy, surgery, or radiation therapy. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in the methods of the invention are also disclosed.

Description

METHODS OF UTILIZATION AND COMPOSITIONS THAT INCLUDE PDE4 MODULATORS FOR THE TREATMENT AND MANAGEMENT OF DISEASES AND DISORDERS RELATED TO ASBESTOS 1. FIELD OF THE INVENTION This invention relates to methods for treating, preventing and managing an asbestos-related disease or disorder, which comprise the administration of a PDE4 modulator alone or in combination with known therapeutics. The invention also relates to pharmaceutical compositions and dosage regimens. In particular, the invention encompasses the use of a PDE4 modulator in conjunction with surgery or radiation therapy and / or other standard therapies for diseases associated with asbestos poisoning. 2. BACKGROUND OF THE INVENTION 2.1 DISEASES OR TRANSTORNES RELATED TO ASBESTOS Several million individuals around the world were exposed to asbestos in the exploitation of minerals or the manufacture and use of asbestos products. D.R. Aberle, Seminars in Roentgenology, 24 (2): 118, 1991. Given the extensive latency time for the development of many pathological consequences of asbestos, asbestos-related diseases will probably dominate the field of occupational and environmental diseases for some time. The diseases and disorders related to benign asbestos include asbestosis, pleural effusion, pleural plaques, diffuse pleural thickening and rounded atelectasis. AC Staples, Radiologic Clinics of North America, 30 (6): 1191, 1992. Diseases related to malignant asbestos include malignant pleural effusion, pleural or peritoneal mesothelioma and bronchogenic carcinoma. Merck Index, 1999 (17th ed.), 645 and 651. Asbestosis (interstitial fibrosis) is defined as diffuse pulmonary fibrosis due to the inhalation of asbestos fibers. AC Staples, Radiologic Clinics of North America, 30 (6): 1195, 1992. This is one of the major causes of professionally related lung damage. Merck Index, 1999 (last ed.), 622. Asbestosis characteristically occurs after a latent period of 15-20 years, with progression of the disease even after the exposure has ended, but rarely occurs in the absence of pleural plaques . C. Peacock, Clinical Radiology, 55: 425, 2000. Fibrosis first develops in and around the respiratory bronchioles, predominating in the subpleural portions of the lung in the lower lobes, and then progresses centrally. AC Staples, Radiologic Clinics of North America, 30 (6): 1195, 1992. Asbestosis can cause an insidious onset of progressive dyspnea in addition to dry cough.

The incidence of lung cancer increases in smokers with asbestosis, and a dose response relationship has been observed. Merck Index, 1999 (17th ed.), 623. Another disorder related to asbestos is the pleural effusion. Pleural effusions are often the earliest manifestation of an asbestos-related disease. AC Staples, Radiologic Clinics of North America, 30 (6): 1192, 1992. Persons exposed to asbestos may develop an exudative pleural effusion five to 20 years after exposure. Merck Index, 1999 (17th ed.), 645; C. A. Staples, Radiologic Clinics of North America, 30 (6): 1192, 1992; and C. Peacock, Clinical Radiology, 55: 427, 2000. The effusion may follow a short exposure, but more often follows an intermediate exposure of approximately 10 to 15 years. The clinical picture in the pleural effusion related to benign asbestos varies from asymptomatic patients to patients with an acute episode of pleuritic chest pain and pyrexia. Id., 426. The mechanism is unknown, but it is assumed that the fibers migrate from the lungs to the pleura and induce an inflammatory response. In most people, spills clear up after three to four months, but they can persist or recur for several years. Id. When the effusion clears, many develop diffuse pleural thickening. Id. Pleural plaques are a common manifestation of exposure to asbestos, usually occurring after a latent period of approximately 20-30 years. C. A. Staples, Radiologic Clinics of North America, 30 (6): 1191, 1992; and C. Peacock, Clinical Radiology, 55: 423, 2000. Histologically, pleural plaques consist of bundles of acellular collagen that form a radiating ligament pattern, which involves almost exclusively the parietal pleura. AC Staples, Radiologic Clinics of North America, 30 (6): 1191, 1992. The precise pathogenesis of pleural plaques remains undetermined, although some have assumed that they are caused by the mechanical effect of asbestos fibers that perforate the visceral pleura. C. Peacock, Clinical Radiology, 55: 425, 2000. Currently, however, it is believed that the fibers are transported to the parietal pleura through lymphatic channels, where they stimulate an inflammatory response. Jd. Plaques grow slowly over time, even after cessation of exposure, but they are not considered pre-malignant. Id. Calcification occurs later, frequently 30-40 years after exposure. Id., 424; and C.A. Staples, Radiologic Clinics of North America 30 (6): 1191, 1992. Although there is a significant correlation between the severity of pleural disease and that of asbestosis, pleural plaques tend to occur in isolation without any other manifestations of diseases related to asbestos C.

Peacock, Clinical Radiology, 55: 425, 2000. Another common manifestation of exposure to asbestos is diffuse pleural thickening. AC Staples, Radiologic Clinics of North America, 30 (6): 1193, 1992. Usually, the latent period is approximately 15 years. Diffuse pleural thickening is less specific for asbestos exposure than the presence of pleural plaques, since thickening can also be observed after TB pleuritis, hemothorax, and empyema. C. Peacock, Clinical Radiology, 55: 427, 2000. The most common symptom is dyspnea. The pathogenesis is not clear, but it is thought to be due to inflammation and fibrosis of visceral lymphatics, and it has been considered an extension of parenchymal fibrosis. Jd. The development of diffuse pleural thickening has a similar time course as plaque formation. Thickening is a concomitant finding common to asbestosis, with a reported reported incidence of 10%. Jd. Another disease associated with asbestos exposure is rounded atelectasis, which refers to atelectatic lung adjacent to pleural thickening with collapsed features of bronchi and blood vessels. T. Wallace, Diagnostic Cytopathology, 8 (6): 617, 1992; C. Peacock, Clinical Radiology, 55: 429, 2000; and C.A. Staples, Radiologic Clinics of North America, 30 (6): 1193, 1992. It is also known as refolded lung, pseudotumor pulmonar, pleuroma or Blesovsky syndrome. Jd. The presence of the effusion has been postulated to cause passive atelectasis, with narrowing of the lung resulting in the intussusception of the adjacent pleura. Jd. This process causes captivity, which prevents the re-expansion of the lung in the resolution of the effusion and which causes rounded atelectasis. Jd. An alternative explanation is that an assault on the pleura leads to localized inflammation and fibrosis, which results in volume loss and subsidence of the underlying lung. Jd. The lingula is the most common site, followed by the middle and then the lower lobes, although the lesions can be multiple and bilateral. Jd. Mesothelioma is a malignant pleural or peritoneal neoplasm which is usually associated with occupational exposure to asbestos. Merck Index, 1999 (17th ed.) 645. The clinical latency period between asbestos exposure and the development of mesiotelio a is normally 15-40 years. Jd., 623; and C. Peacock, Clinical Radiology, 55: 427, 2000. As a result, the number of patients with mesothelioma has continued to rise despite the decreased production of asbestos. JM van Haarst et al. , Bri tish Journal of Cancer, 86: 342, 2002. Common symptoms are chest pain, dyspnea, cough, weight loss, weakness and increased sputum production. Merck Index, 1999 (17th ed.), 645. The tumor gradually coats the lungs, invades the chest wall and produces pleural effusion in approximately 75% of patients. Jd. The prognosis is depressing, with slow response to radial surgery, chemotherapy or radiation therapy, Jd. The causal relationship between bronchogenic carcinoma and asbestos exposure is well accepted. Merck Index, 1999 (17th ed.), 651; and D.R. Aberle, Seminars in Roentgenology, 24 (2): 124, 1991. This shows a dose response at occupational exposure levels. Jd. The relative risk of lung cancer in asbestos workers increases multiplicatively with combined smoking, and interstitial disease related to asbestos is frequently associated with this. Jd. Lung cancer has also been reported in individuals without interstitial lung disease who are exposed to asbestos. Jd. 2. 2 CONVENTIONAL TREATMENTS The main strategy for dealing with asbestos-related diseases or disorders is prevention, with the worldwide elimination of the use of asbestos and the replacement of asbestos with safe synthetic products. No treatment for asbestosis is known to be effective. Mesothelioma is very difficult to treat, and no standard therapy for its treatment currently exists. Kaiser LR. , Semin Thorac Cardiovasc Surg. Oct . , 9 (4): 383-90, 1997. Methods of chemotherapy, radiation therapy and surgery have all been used with little improvement in overall survival, although trimodality therapy involving a combination of all three treatments has shown which improves survival in selected patients. Jd. The two main surgical interventions used to treat mesothelioma are pleurectomy and extrapleural pneumonectomy (PPE). Pleurectomy is usually a palliative procedure to relieve chest wall pain and prevent recurrent pleural effusions by dissolving the visceral and parietal pleural. C. Turton, Bri tish Journal of Hospi tal Medicine, 23 (3): 249, 1980. PPE is a group resection of the parietal and mediastinal pleura, the lung, the hemi-diaphragm and the ipsilateral pericardium to remove all diseases in general. Sugarbaker DJ. Ann Surg. , 224 (3): 288-94, 1996. EPP is indicated for stage I tumors without the involvement of mediastinal lymph nodes. PPE is a technically demanding surgery with significant morbidity. Complications of surgery for pleurectomy and PPE include pneumonia, bronchopleural fistulas, bronchial leaks, empyema, chylothorax, respiratory failure, myocardial infarction, congestive heart failure, hemorrhage, cardiac volvulus, subcutaneous emphysema, incomplete tumor removal, and paralysis of vocal chords. Jd. Radiation therapy is usually a palliative or a supplement for surgery. C. Turton, British Journal of Hospital Medicine, 23 (3): 249, 1980. Brachytherapy, intrapleural implantation of radioactive isotopes, delivers high-dose radiation locally to the pleural space and is used for recurrent pleural effusions. Jd. Post-operative radiation therapy can prevent recurrence within the incision sites of the chest wall. Radiation therapy complications include nausea and vomiting, radiation hepatitis, esophagitis, myelitis, myocarditis, and pneumonitis with impaired lung function. Photodynamic therapy is an adjuvant treatment in patients with surgically treated pleural malignancies. P. Baas, Br. J. Cancer. , 16 (6) -. 819-26, 1997. A light-activated photosensitive drug is instilled intrapleurally and stimulated with light of a certain wavelength that produces oxygen free radicals that cause tumor necrosis. Jd. The response to chemotherapy has been disappointing because it has been difficult to compare chemotherapies. Intrapleural instillations of antibiotics such as mepacrine, thiotepa and tetracycline have been reported to be sometimes successful. C. Turton, British Journal of Hospi tal Medicine 23 (3) -.247, 1980. Several cytotoxic drugs including mustine have been instilled into the pleural cavity. Jd. i Medications currently used during mesothelioma treatment include '5 GM-CSF, doxorubicin, gemcitabine, cisplatin, vinblastine, adriamycin, bleomycin, hyaluronidase, methotrexate and mitomycin. JMW van Haarst et al. , Bri tish Journal of Cancer, 86: 342-345, 2002. However, patients rarely get complete relief. Chemotherapy results in less 0 to 20% response and has not yet shown to improve survival in patients with mesothelioma. Jd. Therefore, there remains a need for safe and effective methods to treat and manage mesothelioma and other diseases associated with asbestos exposure. 5 2.3 PDE4 MODULATORS The compounds referred to as PDE4 modulators have been synthesized and tested. These compounds potentially inhibit the production of TNF-α, and exhibit modest inhibitory effects on IL13 and IL12 induced by LPS. L.G.

Corral, et al. , Ann. Rheum. Dis. 58: (Suppl I) 1107-1113 (1999) . The additional characterization of the modulators PDE4 shows that they are powerful PDE4 inhibitors. PDE4 is one of the largest phosphodiesterase isoenzymes found in human myeloid and lymphoid lineage cells. The enzyme plays a crucial part in the regulation of cellular activity by degrading the ubiquitous second cAMP messenger and maintaining it at low intracellular levels. Jd. The inhibition of PDE4 activity results in increased cAMP levels leading to the modulation of cytokines induced by LPS including the inhibition of TNF-α production in monocytes as well as in lymphocytes. 3. SUMMARY OF THE INVENTION This invention encompasses methods for treating, preventing and managing diseases or disorders related to asbestos, which comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of a PDE4 modulator, or a salt, solvate, hydrate, stereoisomer, clathrate or pharmaceutically acceptable prodrug thereof. Another embodiment of the invention encompasses the use of one or more PDE4 modulators in combination with other therapeutics normally used to treat or prevent diseases or disorders related to asbestos such as, but not limited to anti-cancer agents, antibiotics, anti-inflammatory agents, cytokines, steroids, immunomodulatory agents, immunosuppressive agents and other known therapeutics.

Yet another embodiment of the invention encompasses the use of one or more PDE4 modulators in combination with conventional therapies used to treat, prevent or manage diseases or disorders related to asbestos including, but not limited to, chemotherapy, surgery, radiation therapy and therapy. photodynamic The invention further encompasses pharmaceutical compositions, unique unit dosage forms and equipment suitable for use in the treatment, prevention and / or management of asbestos-related diseases or disorders, which comprise one or more PDE4 modulators, or a salt, pharmaceutically acceptable solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and one or more additional active agents.

DETAILED DESCRIPTION OF THE INVENTION A first embodiment of the invention encompasses methods for treating, preventing or managing diseases or disorders related to asbestos, which comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. As used herein, the terms "disease, disorder or syndrome related to asbestos", "disease or disorder associated with exposure to asbestos" and "disease or disorder associated with asbestos poisoning" means any disease, disorder, syndrome or abnormality associated with, or related to, exposure to asbestos or asbestos poisoning. The terms encompass benign and malignant diseases or disorders, and include, but are not limited to mesothelioma, asbestosis, malignant pleural effusion, benign exudative effusion, pleural plaques, pleural calcification, diffuse pleural thickening, rounded atelectasis, fibrotic masses and lung cancer. In a specific modality, the terms do not cover lung cancer. In a certain modality, the disease, disorder or syndrome related to asbestos does not include malignant mesothelioma or mesothelioma syndrome of malignant pleural effusion. Another embodiment of the invention encompasses a pharmaceutical composition - suitable for the treatment, prevention or management of diseases or disorders related to asbestos, comprising a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug of the same, and an optional carrier. Also encompassed by the invention are unique unit dose forms suitable for use to treat, prevent or manage diseases or disorders related to asbestos comprising a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug of the themselves, and an optional carrier. Another embodiment of the invention encompasses equipment suitable for use to treat, prevent or manage diseases or disorders related to asbestos comprising: a pharmaceutical composition comprising a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug of the same. The invention also encompasses kits comprising unique unit dosage forms. Without being limited by theory, it is believed that a PDE4 modulator can act in complementary or synergistic ways with certain second active agents in the treatment, prevention or management of diseases or disorders related to asbestos. Therefore, one embodiment of the invention encompasses a method for treating, preventing and / or managing an asbestos-related disease or disorder, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a PDE4 modulator. , 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, therapeutics used to treat or prevent mesothelioma such as anti-cancer agents, antibiotics, anti-inflammatory agents, stereoids, cytokines, immunomodulatory agents, immunosuppressive agents and other therapeutic drugs capable of mitigating or alleviating a symptom of asbestos-related diseases or disorders, which can be found, for example, in the Physician's Desk Reference, 2003. It is further believed that a PDE4 modulator can reduce or eliminate adverse effects associated with the administration of conventional therapeutic agents used to treat diseases or disorders related to asbestos, whereby the administration of larger amounts of those conventional agents to patients and / or the increasing compliance of the patient is allowed. Accordingly, another embodiment of the invention encompasses a method for reversing, reducing or avoiding an adverse effect associated with the administration of a second active agent in a patient suffering from an asbestos-related disease or disorder, which comprises administering to a patient with need therefor a therapeutically or prophylactically effective amount of a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The invention also encompasses pharmaceutical compositions, unique unit dosage forms and equipment comprising a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, and a second active agent. As discussed elsewhere in this, the symptoms of diseases or disorders related to asbestos can be treated with chemotherapy, surgery, radiation therapy, photodynamic therapy, immunotherapy and / or gene therapy. Without being limited by theory, it is believed that the combined use of such conventional therapies and a PDE4 modulator can provide an exceptionally effective treatment of asbestos-related diseases or disorders. Therefore, this invention encompasses a method for treating, preventing and / or managing diseases or disorders related to asbestos, which comprises administering to a patient (e.g., a human being) a PDE4 modulator or a salt, solvate, hydrate, stereoisomer, clathrate or pharmaceutically acceptable prodrug thereof, before, during or after chemotherapy, surgery, radiation therapy, photodynamic therapy, immunotherapy, gene therapy and / or other conventional drug-based therapies. 4. 1 PDE4 MODULATORS The compounds used in the invention include stereomerically pure and stereomerically enriched, racemic PDE4 modulators, stereomeric and enantiomerically pure compounds having selective cytokine inhibitory activities and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates and prodrugs thereof. As used herein and unless otherwise indicated, the term "PDE4 modulators" encompasses small molecule drugs, "for example, small organic molecules which are not peptides, proteins, nucleic acids, oligosaccharides or other macromolecules. Preferred compounds inhibit the production of TNF-α The compounds may also have a modest inhibitory effect on IL13 and IL12 induced by LPS More preferably, the compounds of the invention are potent PDE4 inhibitors Specific examples of PDE4 modulators include, but are not limited to, they are limited to cyclic imides, described in patents Nos. 5,605,914 and 5,463,063, cycloalkylamides and cycloalkyl nitriles of U.S. Patents Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281, arylamines (for example, one embodiment is N-benzoyl). -3-amino-3- (3 ', 4'-dimethoxyphenyl) -propanamide) of US Patents Nos. 5,801,195, 5,736,570, 6,046,221 and 6, 284,780, the ethers and imide / amide alcohols (for example, 3-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propan-1-ol) described in US Patent No. 5,703,098; succinimides and maleimides (for example methyl 3- (3 ', 4', 5 ', 6'-tetrahydrophthalimide) -3- (3", 4" -dimethoxyphenyl) propionate) described in US Pat. No. 5,658,940; the imido and amido substituted alkanohydroxamic acids described in US Pat. No. 6,214,857 and WO 99/06041; the substituted phenethylsulfones described in U.S. Patent Nos. 6,011,050 and 6,020,358; the fluoroalkoxy-substituted 1,3-dihydroisoindolyl compounds described in the Patent Application North American No. 10 / 748,085 filed on December 29, 2003; the substituted imides (for example, 2-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propane) described in US Pat. No. 6,429,221; the substituted 1, 3, 4-oxadiazoles (e.g., 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1,3-, 4-oxadiazol-2-ylethyl] -5-methylisoindoline-1, 3-dione) described in US Pat. No. 6,326,388, the cyano and carboxy derivatives of substituted styrenes (for example, 3,3-bis (3,4-dimethoxyphenyl) acrylonitrile) described in U.S. Patents Nos. 5,929,117, 6,130,226 , 6,262,101 and 6,479,554, isoindolin-1-one and isoindoline-1,3-dione substituted at position 2 with an a- (3,4-disubstituted phenyl) alkyl group and at position 4 and / or 5 with a nitrogen-containing group described in WO 01/34606 and US Patent No. 6,667,316, and the acyl-hydroxamic acids substituted with imido and amido (e.g., (3- (1,3-dioxoisoindolin-2-yl) -3- ( 3-ethoxy-4-methoxyphenyl) methylamino) propanoate described in WO 01/45702 and US Patent No. 6,699,899. Other PDE4 modulators include diphenylethylene compounds described in the patent application No. 10 / 934,974, filed September 3, 2004, as a CEP of US Patent Application No. 10 / 794,931, filed March 5, 2004, which claims priority to the North American provisional patent application No. 60 / 452,460, filed March 5, 2003. Other PDE4 modulators include isoindoline compounds described in US Patent Applications Nos. 10 / 900,332 and 10 / 900,270, both filed July 28, 2004. Other PDE4 modulators include substituted heterocyclic compounds described in US Provisional Patent Application No. 60 / 607,408, filed September 3, 2004. The totalities of each of the patents and patent applications identified herein are incorporated herein by reference. The additional PDE4 modulators belong to a family of synthesized chemical compounds of which typical embodiments include 3- (1, 3-dioxobenzo- [f] isoindol-2-yl) -3- (3-cyclopentyloxy-4-methoxyphenyl) propionamide and 3- (1,3-dioxo-4-azaisoindol-2-yl) -3- (3 , 4-dimethoxyphenyl) -propionamide. Other specific PDE4 modulators belong to a class of non-polypeptide cyclic amides described in U.S. Patent Nos. 5,698,579, 5,877,200, 6,075,041 and 6,200,987 and WO 95/01348, each of which is incorporated herein by reference. Representative cyclic amides include compounds of the formula: where n has a value of 1, 2 or 3; R5 is o-phenylene, substituted or unsubstituted with 1 to 4 substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms and halo; R7 is (i) phenyl or phenyl substituted with one or more substituents each independently selected from the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino , alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo, (ii) substituted or unsubstituted benzyl with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbotoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo, (iii) naphthyl and (iv) benzyloxy; R12 is -OH, alkoxy of 1 to 12 carbon atoms, or R8 is hydrogen or alkyl of 1 to 10 carbon atoms; and R9 is hydrogen, alkyl of 1 to 10 carbon atoms, -COR10 or -SO2R10, wherein R10 is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl. Specific compounds of this class include, but are not limited to: 3-phenyl-2- (l-oxoisoindolin-2-yl) propionic acid; 3-phenyl-2- (l-oxoisoindolin-2-yl) propionamide; 3-phenyl-3- (l-oxoisoindolin-2-yl) propionic acid; 3-phenyl-3- (1-oxoisoindolin-2-y1) propionamide; 3- (4-Methoxyphenyl) -3- (1-oxisoinindolin-yl) propionic acid; 3- (4-methoxyphenyl) -3- (1-oxisoindolin-yl) propionamide; 3- (3,4-Dimethoxyphenyl) -3- (l-oxisoindolin-2-yl) propionic acid; 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydroisoindol-2-yl) propionamide; 3- (3, 4-dimethoxyphenyl) -3- (1-oxisoindolin-2-yl) propionamide; 3- (3,4-Diethoxyphenyl) -3- (1-oxoisoindolin-1-yl) propionic acid; 3- (1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionate methyl; 3- (l-Oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionic acid; 3- (l-Oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid; 3- (l-Oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionic acid, 3- (l-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionamide; 3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionamide; 3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionate methyl; and methyl 3- (l-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionate.

Other representative cyclic amides include compounds of the formula: in which Z is: wherein: R1 is the divalent residue of (i) 3,4-pyridine, (ii) pyrrolidine, (iii) imidazole, (iv) naphthalene, (v) thiophene or (vi) a linear or branched alkane of 2 to 6 carbon atoms, substituted or unsubstituted with phenyl or phenyl substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy 1 to 10 carbon atoms or halo, wherein the divalent bonds of the residue are on the carbon atoms of the vicinal ring. R2 is -CO or -S02-; R3 is (i) phenyl substituted with 1 to 3 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms alkoxy of 1 to 10 carbon atoms, or halo, (ii) pyridyl, (iii) pyrrolyl, (iv) imidazolyl, (v) naphthyl, (vi) thienyl, (vii) quinolyl, (viii) furyl or (ix) indolyl; R 4 is alanyl, arginyl, glycyl, phenylglycyl, histidyl, leucyl, isoleucyl, lysyl, methionyl, prolyl, sarcosyl, seryl, homoseryl, threnyl, thironyl, tyrosyl, vayl, benzimidazol-2-yl, benzoxazol-2-yl, phenylsulfonyl, methylphenylsulfonyl or phenylcarbamoyl; and n has a value of 1, 2 or 3. Other representative cyclic amides include compounds of the formula: wherein R5 is (i) o-phenylene, substituted or unsubstituted with 1 to 4 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo, or (ii) the divalent residue of pyridine, pyrrolidine, idizol, naphthalene or thiophene, where the bonds divalents are in the carbon atoms of the neighborhood ring; Rs is -CO-, -CH2- or -S02-; R7 is (i) hydrogen if R6 is -S02-, (ii) linear, branched or cyclic alkyl of 1 to 12 carbon atoms, (iii) pyridyl, (iv) phenyl or phenyl substituted with one or more substituents, each independently selected from the other, from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo, (v) alkyl of 1 to 10 carbon atoms, (vi) substituted or unsubstituted benzyl with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl , acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo, (vii) naphthyl, (viii) benzyloxy, or (ix) imidazol-4-ylmethyl; R12 is -OH, alkoxy of 1 to 12 carbon atoms, or n has a value of 0, 1, 2 or 3; R8 'is hydrogen or alkyl of 1 to 10 carbon atoms; and R9 'is hydrogen, alkyl of 1 to 10 carbon atoms, -COR10 or -S02R10 wherein R10 is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl. Other representative imides include compounds of the formula: wherein R7 is (i) linear, branched or cyclic alkyl of 1 to 12 carbon atoms, (ii) pyridyl, (iii) phenyl or phenyl substituted with one or more substituents independently selected from the other from nitro, cyano, trifluoromethyl , carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, carboxy of 1 to 10 carbon atoms, or halo, (iv) benzyl substituted or unsubstituted with one to three substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 atoms carbon or halo, (v) naphthyl, (vi) benzyloxy or (vii) imidazol-4-ylmethyl; R12 is -OH, alkoxy of 1 to 12 carbon atoms, -0- CH2-pyridyl, -0-benzyl or where n has a value of 0, 1, 2 or 3; R8 is hydrogen or alkyl of 1 to 10 carbon atoms; and R9 'is hydrogen, alkyl of 1 to 10 carbon atoms, -CH2-pyridyl, benzyl, -COR10, or -S02R10 wherein R10 is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl. Other specific PDE4 modulators include the imido and amido substituted alkanohydroxamic acids described in WO 99/06041 and US Pat. No. 6,214,857, each of which is incorporated herein by reference. Examples of such compounds include, but are not limited to: wherein each of R1 and R2, when taken independently from each other, is hydrogen, lower alkyl, or R1 and R2, when taken together with the described carbon atoms to which each is attached, is o-phenylene, o-naphthylene or cyclohexen-1,2-diyl, substituted or unsubstituted with 1 to 4 substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy , carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo; R3 is phenyl substituted with one to four substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, cycloalkylidenemethyl of C-C6, alkylidenemethyl of C3-C? 0, indanyloxy and halo; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R4 'is hydrogen or alkyl of 1 to 6 carbon atoms; R5 is -CH2-, -CH2-CO-, -S02-, -S- or -NHCO-; and n has a value of 0, 1 or 2; and the acid addition salts of such compounds which contain a nitrogen atom capable of being protonated. Specific PDE4 modulators used in the invention include, but are not limited to: 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxoisoindolinyl) propionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-methoxy-3- (1-oxoisoindolinyl) propionamide; N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3-phthalimidopropionamide; N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide; N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (1-oxoisoindolinyl) propionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide; N-hydroxy-3- (3,4-dimethoxyphenyl) -3-phthalimidopropionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (3-nitrophthalimido) propionamide; N-hydroxy-3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolinyl) propionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (4-methyl-phthalimido) propionamide; 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide; 3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1,3-dioxo-2,3-dihydro-1H-benzo [f] isoindol-2-yl) propionamide; N-hydroxy-3-. { 3- (2-propoxy) -4-methoxyphenyl} -3-phthalimidopropionamide; 3- (3-ethoxy-4-methoxyphenyl) -3- (3,6-difluorophthalimido) -N-hydroxypropionamide; 3- (4-aminophthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide; 3- (3-Aminophthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide; N-hydroxy-3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolinyl) propionamide; 3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxoisoindolinyl) propionamide; and N-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propionamide. PDE4 modulators used in the invention include the substituted phenethylsulfones, substituted in the phenyl group with an oxoisoindin group. Examples of such compounds include, but are not limited to those described in US Patent No. 6,020,358, which is incorporated herein by reference, which includes the following: wherein the designated carbon atom * constitutes a center of chirality; Y is C = 0, CH2, S02 or CH2C = 0; each of R1, R2, R3, and R4 independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or -NR8R9; or any two of R1, R2, R3 and R4 on the adjacent carbon atoms, together with the described phenylene ring are naphthylidene; each of R5 and Rs, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano or cycloalkoxy of up to 18 carbon atoms; R7 is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR8'R9 '; each of R8 and R9 taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R8 and R9 is hydrogen and the other is -COR10 or -S02R10, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene or -CH2CH2X1CH2CH- wherein X1 is -0-, -S- or -NH-; and each of R8 'and R9' taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R8 'and R9' is hydrogen and the other is -COR10 'or -S02R10' or R8 'and R9' taken together are tetramethylene, pentamethylene, hexamethylene or -CH2CH2XCH2CH2- wherein X2 is -0-, -S- or -NH-. It will be appreciated that although for convenience, the above compounds are identified as phenethylsulfones, these include sulfonamides when R7 is NR8'R9 '.

Specific groups of such compounds are those in which Y is C = 0 or CH2. A further specific group of such compounds are those wherein each of R1, R2, R3 and R4 independently of the others, is hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy or -NR8R9, wherein each of R8 and R9 taken independently of the other is hydrogen or methyl or one of R8 and R9 is hydrogen and the other is -COCH3. Particular compounds are those in which one of R1, R2, R3 and R4 is -NH2 and the rest of R1, R2, R3 and R4 are hydrogen. Particular compounds are those in which one of R1, R2, R3 and R4 is -NHC0CH3 and the remainder of R1, R2, R3 and R4 are hydrogen. Particular compounds are those in which one of R1, R2, R3 and R4 is -N (CH3) 2 and the remainder of R1, R2, R3 and R4 are hydrogen. A further preferred group of such compounds are those wherein one of R1, R2, R3 and R4 are methyl and the remainder of R1, R2, R3 and R4 are hydrogen. Particular compounds are those in which one of R1, R2, R3 and R4 is fluoro and the remainder of R1, R2, R3 and R4 are hydrogen. Particular compounds are those where each of R? and R6, independently of the other, is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentyloxy or cyclohexoxy. Particular compounds are those in which R5 is methoxy and Rs is monocycloalkoxy, polycycloalkoxy and benzocycloalkoxy. Particular compounds are those in which R5 is methoxy and R6 is ethoxy. Particular compounds are those wherein R7 is hydroxy, methyl, ethyl, phenyl, benzyl, or NR8'R9 'wherein each of R8' and R9 'taken independently of the other is hydrogen or methyl. Particular compounds are those wherein R7 is methyl, ethyl, phenyl, benzyl or NR8'R9 'wherein each of R8' and R9 'taken independently of the other is hydrogen or methyl. Particular compounds are those in which R7 is methyl. Particular compounds are those wherein R7 is NR8'R9 'wherein each of R8' and R9 'taken independently of the other is hydrogen or methyl. Particular PDE4 modulators include compounds 1, 3-dihydro-isoindolyl substituted with fluoroalkoxy described in US Patent Application No. 10 / 748,085 filed December 29, 2003, which is incorporated herein by reference. Representative compounds of the formula are: wherein: Y is -C (O) -, -CH2, -CH2C (0) -, -C (O) CH2- or S02; Z is -H, -C (0) R3, - (C0-? Alkyl) -S02- (C? _4 alkyl), -C.sub.8 alkyl, -CH20H, CH2 (O) (C_ alkyl. _8) or -CN; Ri and R2 are each independently -CHF2, C? _8 alkyl, C3_8 cycloalkyl or (C? -? O alkyl) (C3_? Cycloalkyl?), And at least one of Ri and R2 is CHF2; R3 is -NRR5, -alkyl, -OH, -O-alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl; R4 and R5 are each independently -H, -alkyl Rs is -alkyl of C? _8, -amino (C__8alkyl), -phenyl, -benzyl or -aryl; Xi, X2, X3 and X are each independently -H, -halogen, -nitro, -NH2, -CF3, -alkyl of C _._., - (C0-4 alkyl) - (C3_6 cycloalkyl), ( C0_4 alkyl) -NR7R8, (C0_4 alkyl) -N (H) C (O) - (R8), - (C0_4 alkyl) -N (H) C (O) N (R7R8), - ( C0-4) -N (H) C (O) 0 (R7R8), - (C0-4 alkyl) -OR8, - (C04 alkyl) -imidazolyl, (C0_) alkyl-pyrrolyl, (C04 alkyl) ) -oxadiazolyl or (C _-_) -triazolyl alkyl, or two of Xi, X2, X3 and X4 can be joined together to form a cycloalkyl or heterocycloalkyl ring, (for example, X_ and X / X2 and X3i X3 and X4 iy X3 X2 and X4 or X_ and X4 can form a ring of 3, 4, 5, 6 or 7 members which can be aromatic, whereby a bicyclic system with the isoindolyl ring is formed); and R7 and R8 are each independently H, C? -9 alkyl, C3-6 cycloalkyl, (C? _6 alkyl) - (C3_6 cycloalkyl), (C_6 alkyl) -N (R7R8), (alkyl) of C ...) -OR8, phenyl, benzyl or aryl; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. PDE4 modulators include enantiomerically pure compounds described in U.S. Patent Application No. 10 / 392,195, filed March 19, 2003; International patent applications Nos. PCT / US03 / 08737 and PCT / US03 / 08738, filed on March 20, 2003; US provisional patent applications Nos. 60 / 438,450 and 60 / 438,448 to G. Muller et al. , both, which were presented on January 7, 2003; US Provisional Patent Application No. 60 / 452,460 for G. Muller et al. , filed on March 5, 2003; and U.S. Patent Application No. 10 / 715,184 filed on November 17, 2003, all of which are incorporated herein by reference. Preferred compounds include an enantiomer of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4-acetylaminoisoindoline-1,3-dione and an enantiomer of 3- (3,4-dimethoxy-phenyl) ) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide. The preferred PDE4 modulators used in the invention are 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide and. { 2- [1- (3-Ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3 -oxo-2,3-dihydro-l-y-isoindol-4-yl} -cyclopropanecarboxylic acid amide, which are available from Celgene Corp., Warren, NJ. 3- (3, 4-Dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide has the following chemical structure: Other specific PDE4 modulators include, but are not limited to, the cycloalkylamides and the cycloalkyl nitriles of U.S. Patent Nos. 5,728,844, 5,728,845, 5,968,945, 6,180,644 and 6,518,281 and WO 97/08143 and WO 97/23457, each of which is incorporated herein by reference. the present for reference. Representative compounds of the formula are: wherein: one of R1 and R2 is R3-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carboalkoxy (lower), acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo or R3-X-; R3 is monocycloalkyl, bicycloalkyl or benzocycloalkyl of up to 18 carbon atoms; X is a carbon-carbon bond, -CH2- or -O-; R5 is (i) o-phenylene, substituted or unsubstituted with 1 to 3 substituents each independently selected from nitro, cyano, halo, trifluoromethyl, carboalkoxy (lower), acetyl or carbamoyl, substituted or unsubstituted with lower alkyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower acylamino or lower alkoxy; (ii) a neighborly divalent residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent linkages are on the carbon atoms in the vicinal ring; (iii) a vicinally divalent cycloalkyl or cycloalkenyl of 4-10 carbon atoms, substituted or unsubstituted with 1 to 3 substituents, each independently selected from the group consisting of nitro, cyano, halo, trifluoromethyl, carboalkoxy (lower), acetyl , carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy or phenyl; (iv) vinylene di-substituted with lower alkyl; or (v) ethylene, unsubstituted, mono-substituted or di-substituted with lower alkyl, -R6 is -CO-, -CH2- or -CH2CO-; Y is -COZ, -C = N, -OR8, lower alkyl, or aryl, Z is -NH2, -OH, -NHR, -R9 or -OR9 R8 is hydrogen or lower alkyl; R9 is alkyl or lower benzyl; and, n has a value of 0, 1, 2 or 3. In another embodiment, one of R1 and R2 is R3-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carboalkoxy (lower), acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo or R3- X-; R3 is monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, X is -CH2-, or -0-; R5 is (i) the vicinally divalent residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the two bonds of the divalent residue are on the carbon atoms in the vicinal ring; (ii) a vicinally divalent cycloalkyl of 4-10 carbon atoms, substituted or unsubstituted with 1 to 3 substituents each independently selected from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl , acetyxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or phenyl; (iii) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; (iv) ethylene, substituted or unsubstituted with 1 to 2 substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, substituted carbamoyl and alkyl, from 1 to 3 carbon atoms, acetoxy , carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; R6 is -CO-, -CH2- or -CH2C0-; Y is -COX, -C = N, -OR8, alkyl of 1 to 5 carbon atoms or aryl; X is -NH2, -OH, -NHR, -R9, -OR9 or alkyl of 1 to 5 carbon atoms; R8 is hydrogen or lower alkyl; R9 is alkyl or benzyl; and n has a value of 0, 1, 2 or 3. In another embodiment, one of R1 and R2 is R3-X- and the other is hydrogen, nitro, cyano, trifluoromethyl, carboalkoxy (lower), acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy, halo, HF2CO, F3C0 or R3-X-; R3 is monocycloalkyl, bicycloalkyl, benzocycloalkyl of up to 18 carbon atoms, tetrahydropyran or tetrahydrofuran; X is a carbon-carbon bond, -CH2-, -0-, or -N =; R5 is (i) o-phenylene, substituted or unsubstituted with 1 to 3 substituents each independently selected from nitro, cyano, halo, trifluoromethyl, carboalkoxy (lower), acetyl or carbamoyl, substituted or unsubstituted with lower alkyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower acylamino, or lower alkoxy; (ii) a neighborly divalent residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent linkages are on the carbon atoms in the vicinal ring; (iii) a vicinally divalent cycloalkyl or cycloalkenyl of 4-10 carbon atoms, substituted or unsubstituted with 1 or more substituents each independently selected from the group consisting of nitro, cyano, halo, trifluoromethyl, carboalkoxy (lower), acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkylamino, lower alkyl, lower alkoxy or phenyl; (iv) vinylene disubstituted with lower alkyl; or (v) ethylene, unsubstituted or mono-substituted or di-substituted with lower alkyl; R6 is -CO-, -CH2- or -CH2CO-; Y is -COX, -C = N, -OR8, alkyl of 1 to 5 carbon atoms or aryl; X is -NH2, -OH, -NHR, -R9, -OR9 or alkyl of 1 to 5 carbon atoms; R8 is hydrogen or lower alkyl; R9 is alkyl or benzyl; and, n has a value of 0, 1, 2 or 3. Other compounds representative of the formula are: where: Y is -C = N or C0 (CH2) mCH3; m is 0, 1, 2 or 3; R5 is (i) o-phenylene, substituted or unsubstituted with 1 to 3 substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, substituted carbamoyl and alkyl of 1 to 3 carbon atoms; carbon, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; (ii) the divalent residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent linkages are on the carbon atoms in the vicinal ring; (iii) a divalent cycloalkyl of 4-10 carbon atoms, substituted or unsubstituted with one or more substituents, each independently selected from the other group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl , carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iv) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; or (v) ethylene, substituted or unsubstituted with 1 to 2 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, substituted carbamoyl and alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; R6 is -CO-, -CH2-, -CH2C0- or -S02-; R7 is (i) straight or branched alkyl of 1 to 12 carbon atoms; (ii) cyclic or bicyclic alkyl of 1 to 12 carbon atoms; (iii) pyridyl; (iv) phenyl substituted with one or more substituents, each independently selected from the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, linear alkyl, branched, cyclic or bicyclic of 1 to 10 carbon atoms, linear, branched, cyclic or bicyclic alkoxy of 1 to 10 carbon atoms, CH2R wherein R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms or halo; (v) benzyl substituted with one to three substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 atoms of carbon, alkoxy of 1 to 10 carbon atoms or halo; (vi) naphthyl; or (vii) benzyloxy; and n has a value of 0, 1, 2 or 3; In another modality, the PDE4 modulators, specific to the formula are: wherein: R5 is (i) the divalent residue of pyridine, pyrrolidine, imidazole, naphthalene or thiophene, wherein the divalent linkages are on the carbon atoms in the vicinal ring; (ii) a divalent cycloalkyl of 4-10 carbon atoms, substituted or unsubstituted with one or more substituents independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iii) di-substituted vinylene, substituted with nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; or (iv) ethylene, substituted or unsubstituted with 1 to 2 substituents each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with and alkyl of 1 to 3 carbon atoms, acetoxy , carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; R6 is -CO-, -CH2-, -CH2C0- or -S02-; R7 is (i) cyclic or bicyclic alkyl of 4 to 12 carbon atoms; (ii) pyridyl; (iii) phenyl substituted with one or more substituents, each independently selected from the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, linear alkyl, branched, cyclic or bicyclic of 1 to 10 carbon atoms, linear, branched, cyclic or bicyclic alkoxy of 1 to 10 carbon atoms, CH2R wherein R is a cyclic or bicyclic alkyl of 1 to 10 carbon atoms or halo; (iv) benzyl substituted with one to three substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 4 atoms of carbon, alkoxy of 1 to 10 carbon atoms or halo; (v) naphthyl; or (vi) benzyloxy; and Y is COX, -C = N, OR8, alkyl of 1 to 5 carbon atoms or aryl; X is -NH2, -OH, -NHR, -R9, -OR9 or alkyl of 1 to 5 carbon atoms; R8 is hydrogen or lower alkyl; R9 is alkyl or benzyl; and n has a value of 0, 1, 2 or 3. Other specific PDE4 modulators include, but are not limited to, the arylamides (e.g., one embodiment is N-benzoyl-3-amino-3- (3 ', 4' -dimethoxyphenyl) -propanamide) of US Pat. Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780, each of which is incorporated herein by reference. Representative compounds of the formula are: wherein: Ar is (i) unsubstituted, linear, branched or cyclic alkyl of 1 to 12 carbon atoms; (ii) linear, branched or cyclic substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; (iv) phenyl substituted with one or more substituents, each independently selected from the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino , alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; (v) heterocycle; or (vi) heterocycle substituted with one or more substituents, each independently selected from the other starting from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl from 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; R is -H, alkyl of 1 to 10 carbon atoms, CH 2 OH, CH 2 CH 2 OH or CH 2 C 0 Z wherein Z is alkoxy of 1 to 10 carbon atoms, benzyloxy or NHR 1 wherein R 1 is H or alkyl of 1 to 10 carbon atoms; and Y is i) a substituted or unsubstituted or substituted phenyl or heterocyclic ring, one or more substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy , hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo or ii) naphthyl. Specific examples of the compounds of the formula are: wherein: Ar is 3,4-disubstituted phenyl wherein each substituent is independently selected from the group from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo; Z is alkoxy of 1 to 10 carbon atoms, benzyloxy, amino or alkylamino of 1 to 10 carbon atoms, and Y is (i) a phenyl substituted or unsubstituted with one or more substituents, each independently selected from the other, from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo , or (ii) naphthyl. Other specific PDE4 modulators include, but are not limited to ethers and imide / amide alcohols (e.g., 3-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propan-1-ol) described in the U.S. Pat. No. 5,703,098, which is incorporated herein by reference. Representative compounds have the formula: wherein: R1 is (i) unsubstituted, linear, branched or cyclic alkyl of 1 to 12 carbon atoms; (ii) substituted, linear, branched or cyclic alkyl of 1 to 12 carbon atoms; (iii) phenyl; or (iv) phenyl substituted with one or more substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amine, acylamino , alkylamino, di (alkyl) amino, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, bicycloalkyl of 5 to 12 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 10 carbon atoms, bicycloalkoxy of 5 to 12 carbon atoms and halo; R 2 is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, pyridylmethyl or alkoxymethyl; R3 is (i) ethylene, (ii) vinylene, (iii) a branched alkylene of 3 to 10 carbon atoms, (iv) a branched alkenylene of 3 to 10 carbon atoms, (v) cycloalkylene of 4 to 9 carbon atoms. carbon substituted or unsubstituted with one or more substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl from 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms and halo; (vi) cycloalkenylene of 4 to 9 carbon atoms substituted or unsubstituted with one or more substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy , carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (vii) o-phenylene substituted or unsubstituted with one or more substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy , amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo; (viii) naphthyl, or (ix) pyridyl; R4 is -CX-, -CH2- or -CH2CX-; X is 0 or S; and n is O, 1, 2 or 3. Other specific PDE4 modulators include, but are not limited to, succinimides and maleimides (e.g., 3- (3 ', 4', 5 ', 6' -tetrahydrophthalimido) -3- (Methyl 3", 4" -dimethoxy-phenyl) propionate described in U.S. Patent No. 5,658,940, which is incorporated herein by reference. Representative compounds of the formula are: wherein: R1 is -CH2-, -CH2C0- or -CO-; R2 and R3 taken together are (i) ethylene substituted or unsubstituted with alkyl of 1 to 10 carbon atoms or phenyl, (ii) vinylene substituted with two substituents, each independently selected from the other, from the group consisting of alkyl of 1-10 carbon atoms and phenyl, or (iii) a divalent cycloalkyl of 5-10 carbon atoms, substituted or unsubstituted with one or more substituents, each independently selected from the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl substituted or unsubstituted with alkyl of 1-3 carbon atoms, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, norbornyl, phenyl or halo; R4 is (i) straight or branched unsubstituted alkyl of 4 to 8 carbon atoms, (ii) cycloalkyl or bicycloalkyl of 5-10 carbon atoms, substituted or unsubstituted with one or more substituents, each independently selected from the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, branched alkyl, linear or cyclic of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; (iii) phenyl substituted with one or more substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino , alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkyl or bicycloalkyl of 3 to 10 carbon atoms, cycloalkoxy or bicycloalkoxy of 3 to 10 carbon atoms, phenyl or halo, (iv) pyridine or pyrrolidine, substituted or unsubstituted with one or more substituents, each selected independently from the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl or halo; and, R5 is -COX, -CN, -CH2COX, alkyl of 1 to 5 carbon atoms, aryl, -CH2OR, -CH2 aryl or -CH2OH, wherein X is NH2, OH, NHR or OR6, wherein R is lower alkyl; and wherein R6 is alkyl or benzyl. Other specific PDE4 modulators include, but are not limited to, substituted imides (e.g., 2-phthalimido-3- (3 ', 4'-dimethoxyphenyl) propane) described in US Pat. No. 6,429,221, which is incorporated herein by reference. present for reference. The representative compounds have the formula: wherein: R1 is (i) linear, branched or cyclic alkyl of 1 to 12 carbon atoms, (ii) phenyl or phenyl substituted with one or more substituents, each independently selected from the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, linear or branched alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; (iii) benzyl or benzyl substituted with one or more substituents, each independently selected from the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl from 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; or (iv) -Y-Ph wherein Y is a linear, branched or cyclic alkyl of 1 to 12 carbon atoms and Ph is phenyl or phenyl substituted with one or more substituents, each independently selected from the other from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or halo; R2 is -H, a branched or unbranched alkyl of 1 to 10 carbon atoms, phenyl, pyridyl, heterocycle, -CH2-aryl or -CH2-heterocycle; R3 is i) ethylene, ii) vinylene, iii) a branched alkylene of 3 to 10 carbon atoms, iv) a branched alkenylene of 3 to 10 carbon atoms, v) substituted or unsubstituted cycloalkylene of 4 to 9 carbon atoms. with 1 to 2 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo, vi) cycloalkenylene of 4 to 9 carbon atoms substituted or unsubstituted with 1 to 2 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy , carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; or vii) o-phenylene substituted or unsubstituted with 1 to 2 substituents, each independently selected from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo; and, R 4 is -CX or -CH 2 -; X is O or S. Other specific PDE4 modulators include, but are not limited to, substituted 1, 3, 4-oxadiazoles (e.g., 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1, 3,4-oxadiazol-2-yl) ethyl] -5-methylisoindoline-1,3-dione) described in US Pat. No. 6,326,388, which is incorporated herein by reference. Representative compounds of the formula are: wherein: the designated carbon atom * constitutes a center of chirality; Y is C = 0, CH2, S02 or CH2C = 0; X is hydrogen or alkyl of 1 to 4 carbon atoms; each of R1, R2, R3 and R4 independently of the others, is hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, -CH2NR8R9 , - (CH2) 2NR8R9 or -NR8R9 or any of two of R1, R2, R3 and R4 on the adjacent carbon atoms, together with the benzene ring described are naphthylidene, quinoline, quinoxaline, benzimidazole, benzodioxole or 2-hydroxybenzimidazole; each of R5 and R6, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms, bicycloalkoxy of up to 18 carbon atoms. carbon, tricycloalkoxy of up to 18 carbon atoms or cycloalkylalkoxy of up to 18 carbon atoms; each of R8 and R9, taken independently of the other is hydrogen, linear or branched alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl or one of R8 and R9 is hydrogen and the other is -COR10 or -S02R10 or R8 and taken together are tetramethylene, pentamethylene, hexamethylene, -CH = NCH = CH ~ or -CH2CH2X1CH2CH2- wherein X1 is -O-, -S-, or -NH-. R10 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR1: LR12, CH2R14R15 or NR1: LR12 wherein R14 and R15, independently on the other, they are hydrogen, methyl, ethyl or propyl, and wherein R 11 and R 12, independently of one another, are hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl; and the acid addition salts of such compounds, which contain a nitrogen atom susceptible to protonation. Specific examples of the compounds of the formula are: wherein: the designated carbon atom * constitutes a center of chirality; Y is C = 0, CH2, S02 or CH2C = 0; X is hydrogen or alkyl of 1 to 4 carbon atoms; (i) each of R1, R2, R3 and R4, independently of the others, is hydrogen, halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, -CH2NR8R9, - (CH2) 2NR8R9, -NR8R9 or (ii) any of two of R1, R2, R3 and R4 on the adjacent carbon atoms, together with the described benzene ring to which they are attached are naphthylidene, quinoline , quinoxaline, benzimidazole, benzodioxole or 2-hydroxybenzimidazole; each of R5 and Rs, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano, benzocycloalkoxy, cycloalkix of up to 18 carbon atoms, bicycloalkoxy of up to 18 atoms of carbon, tricycloalkoxy of up to 18 carbon atoms, or cycloalkylalkoxy of up to 18 carbon atoms; (i) each of R8 and R9, independently of the other, is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl, pyridylmethyl, or (ii) one of R8 and R9 is hydrogen and the other is - COR10 or -S02R10, wherein R10 is hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl, pyridylmethyl, NR ^ R12 or CH2NR14R15, wherein R11 and R 12, independently of one another, are hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl and R 14 and R 15, independently of one another, are hydrogen, methyl, ethyl or propyl; or (iii) R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene, -CH = NCH = CH- or -CH2CH2X1CH2CH2- wherein X1 is -O-, -S- or -NH-. Other specific PDE4 modulators include, but are not limited to, cyano and carboxy derivatives of substituted styrenes (e.g., 3, 3-bis- (3,4-dimethoxyphenyl) acrylonitrile) described in U.S. Patent Nos. 5,929,117, 6,130,226, 6,262,101 and 6,479,554, each of which is incorporated herein by reference. Representative compounds of the formula are: wherein: (a) X is -O- or - (CnH2n) - wherein n has a value of 0, 1, 2 or 3, and R1 is alkyl of one to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms carbon, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH = and R 1 is alkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of up to 10 carbon atoms; R 2 is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidene, lower alkoxy or halo; R3 is (i) phenyl, substituted or unsubstituted with 1 or more substituents, each independently selected from nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with alkyl of 1 to 3 carbon atoms; carbon, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 carbon atoms, alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkoxy of up to 10 carbon atoms, cycloalkoxy of up to 10 carbon atoms, alkylidenemethyl of up to 10 carbon atoms, cycloalkylidenemethyl of up to 10 carbon atoms, phenyl or methylenedioxy; (ii) pyridine, substituted pyridine, pyrrolidine, idizol, naphthalene or thiophene; (iii) cycloalkyl of 4-10 carbon atoms, substituted or unsubstituted with 1 or more substituents, each independently selected from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy , carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, phenyl; each of R4 and R5 taken individually is hydrogen or R4 and R5 taken together are a carbon-carbon bond; Y is -COZ, -C = N, or lower alkyl of 1 to 5 carbon atoms; Z is -OH, -NRSR6, -R7 or -OR7; R6 is hydrogen or lower alkyl; and R7 is alkyl or benzyl. Specific examples of the compounds of the formula are: wherein: (a) X is -0- or - (CnH2r?) - wherein n has a value of 0, 1, 2 or 3 and R1 is alkyl of one to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms; carbon, polycycloalkyl of up to 10 carbon atoms or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH = and R 1 is alkylidene of up to 10 carbon atoms, monocycloalkylidene of up to 10 carbon atoms, or bicycloalkylidene of up to 10 carbon atoms; R 2 is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbcmethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkylidene, lower alkoxy or halo; R3 is pyrrolidine, imidazole or thiophene substituted or unsubstituted with 1 or more substituents, each independently selected from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or phenyl; each of R4 and R5 taken individually is hydrogen or R4 and R5 taken together are a carbon-carbon bond; Y is -COZ, -G = N or lower alkyl of 1 to 5 carbon atoms; Z is -OH, -NR6R6, -R7 or -OR7; R6 is hydrogen or lower alkyl; and R7 is alkyl or benzyl. Particularly preferred nitriles are compounds of the formula: wherein: (a) X is -O- or - (CnH2rx) ~ where n has a value of 0, 1, 2 or 3 and R1 is alkyl of up to 10 carbon atoms, monocycloalkyl of up to 10 carbon atoms, polycycloalkyl of up to 10 carbon atoms, or benzocyclic alkyl of up to 10 carbon atoms, or (b) X is -CH =, and R 1 is alkylidene of up to 10 carbon atoms or monocycloalkylidene of up to 10 carbon atoms; R2 is hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, lower alkyl, lower alkoxy or halo, - and R3 is (i) phenyl or naphthyl, substituted or unsubstituted with 1 or more substituents, each independently selected of nitro, cyano, halo, trifluoromethyl, carbethoxy, carboethoxy, carbopropoxy, acetyl, carbamoyl or carbamoyl substituted with alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 5 atoms of carbon, alkoxy or cycloalkoxy of 1 to 10 carbon atoms; or (ii) cycloalkyl of 4 to 10 carbon atoms, substituted or unsubstituted with one or more substituents each independently selected from the group consisting of nitro, cyano, halo, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy , carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or phenyl. Particularly preferred nitrile is of the formula: Other specific PDE4 modulators include, but are not limited to, isoindolin-1-one and isoindoline-1,3-dione substituted at position 2 with an a- (3,4-disubstituted phenyl) alkyl group at the 4-position and / or 5 with a nitrogen-containing group described in WO 01/34606 and US Patent No. 6,667,316, which is incorporated herein by reference. Representative compounds of the formula are: include pharmaceutically acceptable salts and stereoisomers thereof, wherein: one of X and X 'is = C = 0 or = S02, and the other of X and Xf is = C = 0, = CH2, = S02 or = CH2C = 0; n is 1- 2 or 3; Ri and R are each independently C 1 -C alkyl / C 1 -C 4 alkoxy, cyano, (C 3 -C 8 cycloalkyl) f C 3 -C 18 cycloalkoxy or C 3 -C 18 cycloalkyl-methoxy; R3 is S02-Y, COZ, CN or hydroxyalkyl of C_-C6, wherein: Y is C? -C5 alkyl, benzyl or phenyl; Z is -NR6R7, C6-C6 alkyl, benzyl or phenyl; R 6 is H. C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 5 alkanoyl, benzyl or phenyl, each of which may be optionally substituted with halo, amino or C 1 -C 4 alkylamino; R is H or C1-C4 alkyl; R4 and R5 are taken together to provide ~ NH-CH2-R8-, -NH-CO-R8- or -N = CH ~ R8-, wherein: R8 is CH2, O, NH, CH = CH, CH = N or N = CH; or one of R4 and R5 is H, and the other of R4 and R5 is imidazoyl, pyrrolyl, oxadiazolyl, triazolyl, or a structure of the formula (A), (A) wherein: z is 0 or 1; R9 is: H; C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 5 alkanoyl or C-Ce cycloalkanoyl, optionally substituted with halo, amino, C 1 -C 4 alkylamino or C 1 -C 4 dialkylamino; phenyl; benzyl; benzoyl; C2-C5 alkoxycarbonyl; C3-C5 alkoxyalkylcarbonyl; N-morpholinocarbonyl; carbamoyl; N-substituted carbamoyl, substituted with C 1 -C 4 alkyl; or methylsulfonyl; and Rio is H, C1-C4 alkyl, methylsulfonyl or C3-C5 alkoxyalkylcarbonyl, or Rg and Rio are taken together to provide -CH = CH-CH = CH-, -CH = CH-N = CH- or alkylidene of C? ~ C2, optionally substituted with amino, C 1 -C 4 alkylamino or C 1 -C 4 dialkylamino, or R 4 and R 5 are both structures of the formula (A). In one embodiment, z is not 0 when (i) R3 is -S02- Y - COZ, or -CN and (ii) one of R4 or R5 is hydrogen In another embodiment, R9 and R10, taken together, is -CH = CH-CH = CH , -CH '= CH- N = CH- or C 1 -C 2 alkylidene substituted by amino, C 1 -C 4 alkyl-amino or C 1 -C 4 dialkylamino In another embodiment, R 4 mode, R and R 5 are both structures of the formula (A) The specific compounds of the formula are: and the enantiomers thereof The specific compounds are of the formulas: Additional examples include, but are not limited to: 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-dinitroisoindoline-1,3-dione; 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-diaminoisoindoline-1,3-dione; 7- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-e] benzimidazole-6,8-dione; 7- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] hydro-3-pyrrolino [3,4-e] benzimidazole-2,6,6-trione; 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -3-pyrrolino [3,4-f] quinoxaline-1,3-dione; Cyclopropyl-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} carboxamide; 2-Chloro-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2-Amino-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2-N, N-Dimethylamino-N-. { 2- [- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} -2, 2, 2-trifluoroacetamide; N-. { 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -1,3-dioxoisoindolin-4-yl} methoxycarboxamide; 4- [1-Aza-2- (dimethylamino) vinyl] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -isoindoline-1,3-dione; 4- [l-Aza-2- (dimethylamino) prop-1-enyl] -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonyl-ethyl] isaindoline-1,3-dione; 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- (5-methyl-1,3, -oxadiazol-2-yl) isoindoline-1,3-dione; 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulphonylethyl] -4-pyrrolyl-isoindolin-1,3-dione; 4- (Aminomethyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -isoindolin-1,3-dione; 2- [1- (3-Ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4- (pyrrolylmethyl) isoindoline-1,3-dione; N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1- (3-Ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [IR- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [IR- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl) acetamide; N-. { 2- [SS- (3-Ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [ÍS- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; 4-Amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl isoindoline-1,3-dione; 4-Amino-2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -isoindoline-1,3-dione; 2- [1- (3-Ethoxy-4-methoxyphenyl) -3-oxo-butyl] -4-pyrrolyl-isoindoline-1,3-dione; 2-Chloro-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindol-4-yl} acetamide; 2- (Dimethylamino) -N- (2- [1- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl.} Acetamide; 4-Amino-2- [ IR- (3-ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -isoindoline-1,3-dione; 4-Amino-2- [1R- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -isoindolin-1 , 3-dione; 2- [IR- (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -4-pyrrolyl-isoindoline-1,3-dione; 2- (Dimethylamino) -N- { 2- [IR - (3-ethoxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl.} Acetamide; cyclopentyl-N-. {2- [1- (3-ethoxy-4-methoxyphenyl) ) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl}. Carboxamide; 3- (Dimethylamino) -N-. {2- 2- [1- (3-ethoxy-4-methoxyphenyl) - 2- (Methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl}. Propanamide; 2- (Dimethylamino) -N- { 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl.} propanamide; N-. {2- [(IR) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] ] -l, 3-dioxoisaindolin-4-yl.} -2- (dimethylamino) acetamide, N- { 2- [(SS) -1- (3-et oxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl) -2- (dimethylamino) acetamide; - 4-. { 3- [(Dimethylamino) methyl] pyrrolyl) -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindoline-1,3-dione; Cyclopropyl-N-. { 2- [(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl) carboxamide; 2- [1- (3, 4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -4-pyrrolylisoindoline-1,3-dione; N-. { 2- [1- (3, 4-dimethoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} -2- (dimethylamino) acetamide; Cyclopropyl-N-. { 2- [1- (3,4-dimetpxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindslin-4-yl) carboxamide; Cyclopropyl-N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxamide; 2- (Dimethylamino) -N-. { 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} acetamide; Cyclopropyl-N-. { 2- [(1S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxamide; Cyclopropyl-N-. { 2- [(IR) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -3-oxoisoindolin-4-yl} carboxamide; (3R) -3- [7- (Acetylamino) -l-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; (3R) -3- [7- (Cyclopropylcarbonylamino) -l-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; 3- . { 4- [2- (Dimethylamino) acetylamino] -1,3-dioxoisoindolin-2-yl} -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; (3R) -3- [7- (2-Chloroacetylamino) -l-oxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxy-phenyl) -N, N-dimethylpropanamide, - (3R) -3 -. { 4- [2- (dimethylamino) acetylamins] -1,3-dioxoisoindolin-2-yl] -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; 3- (1,3-Dioxo-pyrrolylisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) -N, N-dimethylpropanamide; 2- [1- (3-Ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4- (imidazolyl-methyl) isoindoline-1,3-dione; N- ( { 2- [1- (3-Ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide; 2-Chloro-N- (. {2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl} methyl) acetamide; 2- (Dimethylamino) -N- (. {2- 2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -1,3-dioxoisoindolin-4-yl}. Methyl) acetamide; 4- [Bis (methylsulfonyl) amino] -2- [1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] isoindoline-1,3-dione; 2- [1- (3-Ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethyl] -4- [(methylsulfonyl) amino] isaindoline-1,3-dione; N-. { -2- [1- (3-Ethoxy-4-methoxyphenyl) -3-hydroxypentyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1- (3-Ethoxy-4-methoxyphenyl) -3-oxopentyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2- [(IR) -1- (3-Ethoxy-4-methoxyphenyl) -3-hydroxybutyl] -4- (pyrrolylmethyl) isoindoline-1,3-dione; 2- [(IR) -1- (3-Ethoxy-4-methoxyphenyl) -3-oxobutyl] -4- (pyrrolylmethyl) isoindoline-1,3-dione; N-. { 2- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -3-hydroxybutyl] -1,3-dioxoisoindolin-4-yl} acetamide; N-. { 2- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -3-oxobutyl] -1,3-dioxoisoindolin-4-yl} acetamide; 2- [1- (3-Cyclopentyloxy-4-methoxyphenyl) -3 -oxo-butyl] -4-pyrrolyl-isoindolin-1,3-dione; 2- [1- (3, 4-Dimethoxyphenyl) -3-oxobutyl] -4- [bis (methylsulfonyl) amino] isoindoline-1,3-dione; and pharmaceutically acceptable salts, solvates and stereoisomers thereof. Still other specific PDE4 modulators include, but are not limited to, imido and amido-substituted acylhydroxamic acids (eg, (3- (1,3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl)) clothingnoylamino) propanoate described in WO 01/45702 and U.S. Patent No. 6,699,899, which are incorporated herein by reference, The compounds representative of the formula are: wherein: the designated carbon atom * constitutes a center of chirality, R4 is hydrogen or - (C = 0) -R12, each of R1 and R12, independently of one another, is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, pyridyl, methyl, pyridyl, imidazolylmethyl or CHR * (CH2) nNR * R °, wherein R * and R °, independently of each other, are hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, pyridylmethyl, pyridyl, i idazoyl or imidazolylmethyl, and n = 0, 1 or 2; R5 is C = 0, CH2, CH2-CO- or S02; each of R6 and R7, independently of the other, is nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6. carbon atoms, cycloalkoxy of 3 to 8 carbon atoms, halo, bicycloalkyl of up to 18 carbon atoms, tricycloalkoxy of up to 18 carbon atoms, 1-indanyloxy, 2-indanyloxy, cycloalkylidenemethyl of C-C8 or alkylidenemethyl of C3-C10; each of R8, R9, R10 and R11, independently of the others, is (i) hydrogen, nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to carbon atoms, halo, or (ii) one of R8, R9, R10 and R11 is acylamino, which comprises a lower alkyl, and the remainder of R8, R9, R10 and R11 are hydrogen, or (iii) hydrogen if R8 and R9 taken together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxole, 2-hydroxybenzimidazole, methylenedioxy, dialkoxy or dialkyl, or (iv) hydrogen if R10 and R11, taken together are benzo, quinoline, quinoxaline, benzimidazole, benzodioxole, 2- hydroxybenzimidazole, methylenedioxy, dialkoxy or dialkyl, or (v) hydrogen if R9 and R10 taken together are benzo. Still specific PDE4 modulators include, but are not limited to, 7-amido-isoindolyl compounds described in U.S. Patent Application No. 10 / 798,317, filed March 12, 2004, which is incorporated herein by reference. Representative compounds of the formula are: wherein: Y is -C (O) -, -CH2, -CH2C (0) - or S02; X is H; Z is (C04 alkyl) -C (0) R3, C! _ Alkyl, (C0_4 alkyl) -OH, (C_4 alkyl) -0 (C_4 alkyl), (Ci_4 alkyl) -S02 (CX-4 alkyl), (C0-) alkyl -SO (alkyl) of CX-4) -NH2, (C04 alkyl) -N (C? -8 alkyl), (C0-4 alkyl) -N (H) (OH) or CH2NS02 (C14 alkyl); Ri and R2 are independently C? _8 alkyl, cycloalkyl or (C? _4) cycloalkyl; R3 is NRR5, OH or O- (C? _ Alquilo alkyl); R4 is H; R5 is -OH or -0C (0) R6; R 6 is C 1 8 alkyl, amino (C 8 8 alkyl), C 8 alkyl) - (C 3-6 cycloalkyl), C 3-6 cycloalkyl, phenyl, benzyl or aryl; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof; or the formula: where: Y is -C (0) -, -CH2, -CH2C (0) - or S02; X is halogen, -CN, -NR7R8, -N02 or -CF3; Z is (C0-4 alkyl) -S02 (Cx_4 alkyl), (C0-4 alkyl) -CN, - (C0-4 alkyl) -C (O) R3, C? _ Alkyl, (alkyl) of C0 -_) OH, (C0_4 alkyl) O (C_4 alkyl), (C0_4 alkyl) SO (__4 alkyl), (C0_4 alkyl) NH2, (C0 alkyl. 4) N (C? -8) alkyl 2, (C0-4 alkyl) N (H) (OH), (C0-4 alkyl) -dichloropyridine or (C0-4 alkyl) NS02 (Ci alkyl) -4); W is C3_6 cycloalkyl, - (C? _8 alkyl) - (C3_6 cycloalkyl), - (C0-8 alkyl) - (C3_6 cycloalkyl) -NR7R8, (C0-8 alkyl) -NR7R8, - (C0-4 alkyl) -CHR9- (C0-4 alkyl) -NR7R8; Ri and R2 are independently C ?_8 alkyl, cycloalkyl or (C_4 alkyl) cycloalkyl; . R 3 is alkyl of C 1 S, NR 4 R 5, OH or O- (C__ β alkyl); R4 and R5 are independently H, C__8 alkyl (C0-8 alkyl) - (C3_6 cycloalkyl), OH or -OC (0) R6; R6 is C8_8alkyl, (C0_4alkyl) - (C3_s cycloalkyl), amino- (C_8_alkyl), phenyl, benzyl or aryl; R7 and R8 are each independently H, C? _8 alkyl, (C0-8 alkyl) - (C3.6 cycloalkyl), phenyl, benzyl, aryl or can be taken together with the atom by connecting them to form a heterocycloalkyl ring or 3 to 7 membered heteroaryl; R9 is C__4 alkyl, (C0-4 alkyl) aryl, (C0-) alkyl- (C3_6 cycloalkyl), (C0-) alkyl -heterocycle; or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. In another modality W is In another embodiment, the representative compounds of the formula so: wherein: Ri / R2 and 3 are independently H or Cx_8 alkyl, with the proviso that at least one of Rx, R2 and R3 is not H; and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates or prodrugs thereof. Still specific PDE4 modulators include, but are not limited to, isoindoline compounds described in U.S. Patent Application No. 10 / 900,332 filed July 28, 2004, which is incorporated herein by reference. Representative compounds are listed in Table 1 below, and pharmaceutically acceptable prodrugs, salts, solvates and stereoisomers thereof.

Table 1.

In another embodiment, this invention encompasses 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-dinitroisoindoline-1,3-dione and its acid addition salts. In a particular embodiment, this invention encompasses a hydrochloride salt of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl] -4,5-dinitroisoindoline-1,3-dione. Still specific PDE4 modulators include, but are not limited to, isoindoline compounds described in U.S. Patent Application No. 10 / 900,270 filed July 28, 2004, which is incorporated herein by reference. The representative compounds are. { 2- [l- (3-ethoxy-4-methoxy-phenyl) -2- [1,3,4] oxadiazol-2-yl-ethyl] -3-oxo-2,3-dihydro-lH-isoindol-4 -yl] -amide, which has the following chemical structure and pharmaceutically acceptable salts, solvates, prodrugs and stereoisomers thereof.

Still specific PDE4 modulators include, but are not limited to, isoindolyl N-alkyl-hydroxamic compounds described in US Provisional Application No. 60 / 454,149 filed March 12, 2003, and its North American provisional application entitled "N-alkyl" -hydroxamic acid-isoindolyl compounds and their pharmaceutical uses "which was presented on March 12, 2004, by Man et al. under the no. in series 10 / 798,372, each of which is incorporated herein by reference. Representative compounds of the formula are: wherein: Y is -C (O) -, -CH2, -CH2C (0) - or S02; Ri and R2 are independently C__8 alkyl; CF2H, -CF3, CH2CHF2, cycloalkyl or (__8 alkyl) cycloalkyl; Zx is H, C ?e alkyl, -NH 2, NR 3 R or OR 5; Z2 is H or C (0) R5; Xi, X2, X3 and X are each independently H, halogen, N02, OR3, CF3, C? _6 alkyl, (C0-4 alkyl) - (C3-S cycloalkyl), (C0-4 alkyl) -N- (R8R9), (C04 alkyl) -NHC (O) - (R8), (C0-) alkyl -NHC (O) CH (R8) (R9), (C0-C) -NHC alkyl (0) N (R8R9), (C0-4 alkyl) -NHC (O) O (R8), (C0-4 alkyl) -O-R8, (C0-4 alkyl) -imidazolyl, (alkyl) C0-4) -pyrrolyl, (C0-4 alkyl) oxadiazolyl, (C0-4 alkyl) -triazolyl or (C0_4 alkyl) -heterocycle; 3/4 and Rs are each independently H, C? _6 alkyl, C_s O-alkyl, phenyl, benzyl or aryl; R6 and 7 are independently H or C? _ Alkyl; R8 and R9 are each independently H, C? _g alkyl, C3_6 cycloalkyl, (C? _6 alkyl) - (C3_6 cycloalkyl), (C0-S alkyl) -N (R4R5), ? 6) -0R5, phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrrolidinyl, morpholino or C3_7 heterocycloalkyl; and or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. Still specific PDE4 modulators include, but are not limited to diphenylethylene compounds described in US Patent Application No. 10 / 934,974, filed September 3, 2004, as a CIP of US Patent Application No. 10 / 794,931, filed on March 5, 2004, which claims priority to the US provisional patent application No. 60 / 452,460, filed on March 5, 2003, which is incorporated herein by reference.

Representative compounds of the formula are: and pharmaceutically acceptable salts, solvates or hydrates thereof, wherein: Ri is halogen, -CN, lower alkyl, -COOH, C (0) -N (R9) 2, -C (O) -lower alkyl, -C (O) -benzyl, -C (0) 0-lower alkyl, -C (O) O-benzyl; R4 is -ll, -N02, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy, halogen, -OH, -C (O) (Rio) 2, -COOH, -NH2, -OC (O) - N (R_0) 2; R5 is substituted or unsubstituted lower alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkenyl; X is substituted or unsubstituted phenyl; substituted or unsubstituted pyridine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted imidizol, substituted or unsubstituted naphthalene, substituted or unsubstituted thiophene or substituted or unsubstituted cycloalkyl; each case of R9 is independently -H or substituted or unsubstituted lower alkyl; and each case of R0 is independently -H or substituted or unsubstituted lower alkyl. In another embodiment, the compounds representative of the formula are: and pharmaceutically acceptable salts, solvates or hydrates thereof, wherein: Ri and 2 are independently -H, -CN, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, NHC (O), ) 0R9, -COOH, -C (O) -lower alkyl, -C (0) 0-lower alkyl, -C (O) -N (Rg) 2, substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle; each case of Ra, Rb, Rc and Rd is independently -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, 0P0 (0H) 2, -N (R9) 2, -OC (0) -R? O, -OC (0) -Rxo-N (R10) 2, -C (0) N ( R10) 2, -NHC (O) -Rio, -NHS (0) 2-R? O, -S (0) 2 -R? O, -NHC (O) NH ~ R_0, NHC (0) N (R ? 0) 2, -NHC (0) NHS02-R? O, -NHC (O) -R10-N (Rio) 2, NHC (0) CH (R? O) (N (R9) 2) or -NHC (0) -R? 0-NH2; R3 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -0P0 (0H ) 2, -N (R9) 2, -OC (O) -R10, -OC (0) -R_0-N (R? O) 2, -0C (0) -R? O-NH2, -C (O) ) N (R10) 2, -NHC (O) -R10, -NHS (0) 2-R? O, -S (O) 2 -R10, -OS (O) 2 -R? 0, -OS (0 ) 2-NH2, -OS (0) 2-N (R10) 2, -S02NH2, -SO2-N (R10) 2, -NHC (0) 0-R? O, -NHC (O) NH-R? 0, -NHC (O) N (Rio) 2, -NHC (0) NHS02-R? O, -NHC (O) -R10-N (Rio) 2, -NHC (O) CH (Ri0) (N ( R9) 2) or -NHC (O) -R? 0-NH2, or R3 with either Ra or with R4, together form -OC (R_6R? 7) -O- or -O- (C (R_6-R? 7)) 2-0-; R 4 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -0P0 (0H ) 2, -N (R9) 2, -OC (O) -R? 0, -OC (O) -R_.0-N (R10) 2, -OC (0) R? O-NH2, -C ( O) N (R10) 2, -NHC (O) -R_0, -NHS (O) 2 -R10, -S (O) 2 -R? 0, -OS (0) 2 ~ R_o, -OS (0) 2-NH2, -OS (O) 2-N (R10) 2, -S02NH2, -SO2-N (R10) 2, -NHC (0) 0-R? O, -NHC (O) NH-R10, - NHC (O) N (Rio) 2 / -NHC (0) NHS02-R? O, -NHC (O) -R10-N (R10) 2, -NHC (O) CH (R10) (N (R9) 2 ) or -NHC (O) -R10-NH2; R5 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -OPO (OH ) 2, -N (R9) 2, -OC (O) -R? 0, -OC (O) -R_0-N (R? O) 2, -OC (0) -R? O-NH2, -C (0) N (R10) 2, -NHC (0) -R? O, -NHS (O) 2 -R10, -S (O) 2 -R? 0, -OS (0) 2-R? O, -OS (0) 2-NH2, -OS (0) 2-N (Rio) 2, -S02NH2, -S02-N (R? O) 2, -NHC (O) OR? 0, -NHC (0) NH-R10, -NHC (0) N (R10) 2, -NHC (0) NHS02-R? 0, -NHC (0) -R10-N (Ri0) 2, -NHC (0) CH (R10) ( N (R9) 2) or -NHC (0) -R? O-NH2; R6 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -OPO (OH ) 2, -N (R9) 2, -OC (O) -R_.0, -OC (O) -R10-N (R? O) 2, -OC (0) -R? O-NH2, -C (0) N (R10) 2, -NHC (O) -Rio, -NHS (O) 2-R? 0 -S (0) 2 -R? O, -OS (O) 2 -R10, -0S ( 0) 2-NH2, -OS (O) 2-N (R10) 2, -S02NH2, -SO2-N (R10) 2, -NHC (0) 0-R? O, -NHC (0) NH-R10 , -NHC (0) N (Rxo) 2, -NHC (0) NHS02-R? O, -NHC (O) -Ri0-N (R_0) 2, -NHC (O) CH (Rio) (N (Rg) ) 2) or -NHC (O) -R10-NH2; R7 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -0P0 (0H ) 2, -N (R9) 2, -OC (?) - R? 0, -OC (O) -R_0-N (Rao) 2, -OC (O) -R10-NH2, -C (O) N (R_0) 2, -NHC (O) -Rio, -NHS (0) 2 -R10, -S (0) 2 -R? O, -OS (0) 2 -R? O, -0S (G) 2 -NH2, -OS (O) 2-N (R10) 2, -S02NH2, -SO2-N (R10) 2, -NHC (0) 0-R? O, -NHC (0) NH-R_0, -NHC (0) N (Ri0) 2, -NHC (0) NHS02-R? O, -NHC (O) -R10 ~ N (Ri0) 2, -NHC (O) CH (R10) (N (R9) 2) O -NHC (O) -R? O-NH2; R8 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -0P0 (0H ) 2, -N (R9) 2, -OC (?) - R? 0, -OC (0) -R10-N (R? O) 2, -OC (0) -R? O-NH2, -C (0) N (R? 0) 2, -NHC (0) -Rio, -NHS (0) 2-R_0, -S (O) 2 -R? 0, -OS (0) 2-R? O, -OS (0) 2-NH2, -OS (O) 2-N (R_0) 2, -S02NH2, -SO2-N (R10) 2, -NHC (0) 0-R? O, -NHC (O) NH-R_0, -NHC (O) N (Ri0) 2, -NHC (O) NHSO2-R? 0, -NHC (O) -R10-N (Ri0) 2, -NHC (O) CH (R10) ( N (Rg) 2) or -NHC (O) -R? 0-NH2; or R8 with any of Rc or with R7, together form -O-C (R? 6R_7) -O- or -0- (C- (R_6R? 7)) 2 ~ 0-; each case of R9 is independently -H, substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl; each Rio case is independently substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted or unsubstituted lower hydroxyalkyl and a nitrogen to which it is attached form a substituted or unsubstituted heterocycle or Rio is -H where appropriate; and each case of R16 and R7 is independently -H or halogen. Still specific PDE4 modulators include, but are not limited to, substituted heterocyclic compounds described in U.S. Provisional Patent Application No. 60 / 607,408, filed September 3, 2004, which is incorporated herein by reference. Representative compounds of the formula are: and pharmaceutically acceptable salts, solvates or hydrates thereof, wherein: X is substituted or unsubstituted imidazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted thiophene, indole substituted or unsubstituted, 2,3-dihydrobenzofuran substituted or unsubstituted, 3,4-dihydro-2H-benzo (b) (1,4) oxazine substituted or unsubstituted, lH-benzo (d) (1, 2, 3 ) substituted or unsubstituted triazole, substituted or unsubstituted quinoline, substituted or unsubstituted benzofuran, substituted or unsubstituted benzo (d) oxazole-2 (3H) -one or substituted or unsubstituted pyrimidine; each case of Ri and R2 is independently -H, -CN, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -NHC (0) R9, -NHC (0) 0R9, - COOH, -C (O) -lower alkyl, -C (O) O-lower alkyl, -C (O) -N (Rg), substituted or unsubstituted aryl, or substituted or unsubstituted heterocycle; each case of Ra and Rb is independently -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, - OH, -0P0 (0H) 2, -N (R9) 2, -OC (0) -R? O, -OC (0) -R? ON (R? O) 2, -C (0) N (Rxo ) 2, -NHC (O) -R? 0, -NHS (0) 2-R? O, -S (O) 2 -R? 0, -S (0) 2-NH2, -S (O) 2 -N (R_0) 2 -NHC (0) NH-Rio, -NHC (O) N (R10) 2, -NHC (O) NHSO2-R? 0, -NHC (O) -R10-N (Rxo) 2 , -NHC (O) CH (Rio) (N (R_) 2) or -NHC (O) -R? 0-NH2; R3 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -0P0 (0H ) 2, -N (R9) 2, -OC (O) -R10, -OC (0) -R? 0-N (R? O) 2, -OC (0) -R? O-NH2, -C (0) N (R_0) 2, -NHC (O) -R? 0, -NHS (0) 2-R_0, -S (0) 2-R? O, -OS (0) 2-R? O, -S (0) 2-NH 2, -S (0) 2 -N (Rio) 2, -OS (0) 2-NH 2, -OS (0) 2 -N (R? O) 2, -NHC (0 ) 0-R ?o, -NHC (O) NH-R_0, -NHC (O) N (Rio) 2, -NHC (0) NHS02-R? O, -NHC (O) -R? 0-N ( Rio) 2, -NHC (O) CH (Ri0) (N (R9) 2) or -NHC (O) -R? 0-NH2, or R3 with either Ra or with R4, together form -0-C ( R? 6R? 7) -O-, -O- (C (R_6 ~ R? 7)) 2-0- or -O- (C (R? 6R_7)) 3-0-; R4 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -0P0 (0H ) 2, -N (R9) 2, -OC (O) -R_0, -OC (0) -R10-N (R? O) 2, -OC (0) -R? O-NH2, -C (O) ) N (R10) 2, -NHC (O) -R? 0, -NHS (0) 2-RX0, -S (0) 2-R? O, -OS (0) 2-R? O, -S (0) 2-NH2, -S (O) 2-N (Rio) 2, -OS (0) 2-NH2, -OS (0) 2-N (R? O) 2, -NHC (0) 0 -R? O, -NHC (O) NH-RX0, -NHC (O) N (Rxo) 2, -NHC (0) NHS02-R? O, -NHC (O) -R10-N (Rio) 2, -NHC (O) CH (R_0) (N (R9) 2) or -NHC (O) -R? O-NH2; R5 is -H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, halogen, cyano, -N02, -OH, -OPO (OH ) 2, -N (R9) 2, -OC (O) -R? 0, -OC (0) ~ RX0-N (R10) 2, -OC (0) -RXO-NH2, -C (O) N (Rxo) 2, -NHC (O) -RX0, -NHS (O) 2-R_0, -S (0) 2-Rao, -OS (0) 2-R? O, -S (0) 2-NH2 , -S (O) 2-N (R10) 2, -0S (0) 2-NH2, -OS (0) 2-N (R? O) 2, -NHC (0) 0-R? O, - NHC (0) NH-RX0, -NHC (O) N (Rxo) 2, -NHC (O) NHSO2-RX0, -NHC (0) -Rx0-N (Rxo) 2, -NHC (O) CH (Rxo) ) (N (R9) 2) or -NHC (0) -Rxo-NH2; each case of R9 is independently -H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted cycloalkyl; each Rxo case is independently substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted lower hydroxyalkyl, or Rx0 and a nitrogen to which it joins form a substituted or unsubstituted heterocycle, or Rx0 is -H where appropriate; and each case of Rxs and RX7 is independently -H or halogen.

The compounds of the invention can be purchased either commercially or prepared according to the methods described in the patents or patent publications described herein. In addition, optically pure compositions can be synthesized or analyzed using known solution agents or chiral columns as well as other techniques of standard synthetic organic chemistry. As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" embraces non-toxic acid and base addition salts of the compound to which the term refers. Non-toxic acid addition salts include those derived from the organic and inorganic acids or bases known in the art, which include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, acid tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid and the like. Compounds that are acidic by nature are capable of forming salts with several pharmaceutically acceptable bases. The bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those which form non-toxic base addition salts, ie, salts containing pharmacologically acceptable cations, such as, but not limited to, metal salts. alkali metal or alkaline earth metal and the salts of calcium, magnesium, sodium or potassium, in particular. Suitable organic bases include, but are not limited to, N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumain (N-methylglucamine), lysine and procaine. As used herein and unless otherwise indicated, the term "pro-drug" means a derivative of a compound that can hydrolyze, oxidize or otherwise react under biological conditions (in vi tro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of PDE4 modulators comprising biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides and biohydrolyzable phosphate analogues. Other examples of pro-drugs include derivatives of a PDE4 modulator comprising portions -NO, -N02, -ONO or -ON02. Pro-drugs can normally be prepared using well-known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolf ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985). As used herein and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureido" and "biohydrolyzable phosphate" mean an amide, an ester, a carbamate, a carbonate, a ureide or a phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound, but can confer on that compound advantageous in vivo properties, such as absorption, duration of action, or the beginning of the action; or 2) is biologically inactive, but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), esters of lower alkoxyacyloxyalkyl (such as esters of methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl) esters of alkoxyalkyl, choline esters, and acylamino alkylesters (such as acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkylamides, a-amino acid amides, alkoxyacylamides and alkylaminoalkylcarbonylamides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines. Several PDE4 modulators contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of PDE4 modulators can be used in methods and compositions of the invention. The purified (R) and (S) enantiomers of the specific compounds described herein can be used substantially free of their other enantiomer. As used herein and unless otherwise indicated, the term "stereomerically pure" means a composition that comprises a stereoisomer of a compound and is substantially free of another stereoisomer of that compound. For example, the stereomerically pure composition has a chiral center that will be substantially free of an opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical, stereomerically pure compound comprises more than about 80% by weight of a stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably more than about 90% by weight of a stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably more than about 95% by weight of a stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and more preferably more than about 97% by weight of a stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. As used herein and unless otherwise indicated, the term "stereomerically enriched" means a composition comprising more than about 60% by weight of a stereoisomer of a compound, preferably more than about 70% by weight, more preferably more than about 80% by weight of a stereoisomer of a compound. As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having a chiral center. Similarly, the term "enantiomerically enriched" means a stereomerically enriched composition of a compound having a chiral center. It should be noted that if there is a discrepancy between a structure described and a name given to that structure, the structure described will give more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated by, for example, bold or drawn lines, the structure or portion of the structure is to be construed as encompassing all stereoisomers thereof. 4. 2 SECONDS ACTIVE AGENTS A second active agent can be used in the methods and compositions of the invention together with a PDE4 modulator. It is believed that certain combinations work synergistically in the treatment of diseases or disorders related to asbestos. A PDE4 modulator can also work to alleviate adverse effects associated with certain second active agents, and some second active agents can be used to alleviate adverse effects associated with a PDE4 modulator. One or more second active agents can be used in the methods and compositions of the invention together with a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. Second active agents may be large molecules (eg, proteins) or small molecules (eg, organic, organometallic, organic, inorganic molecules). Examples of active agents of large molecules are biological molecules, such as proteins of natural origin or made artificially. Particular proteins include, but are not limited to: cytokines such as GM-CSF, interleukins such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12 e IL-18; and interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-la and interferon gamma-Ib. In one embodiment of the invention, the large molecule active agent reduces, eliminates or prevents an adverse effect associated with the administration of a PDE4 modulator. Depending on the disease or disorder being treated, adverse effects may include, but are not limited to, numbness, drowsiness, nausea, vomiting, gastrointestinal upset, diarrhea, and vasculitis. Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of a PDE4 modulator. Like some large molecules, many are believed to be capable of providing a synergistic effect when administered with (for example, before, after or at the same time) a modulator PDE4. Examples of second small molecule active agents include, but are not limited to anti-cancer agents, antibiotics, anti-inflammatory agents and steroids. Examples of anti-cancer agents include, but are not limited to, acivicin; aclarubicin; benzoyl hydrochloride; Acronine; 4- (amino) -2- (2,6-dioxo (3-piperidyl)) -isoindolin-1,3-dione (Actimid ™); adozelesina; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlina; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; Bizei bleomycin sulfate; sodium brequinar; biririmine; busulfan; cactinomycin; calusterona; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesina, - cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; Corylemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; decarbazine; Dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; Doxorubicin hydrochloride; droloxifene; Droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromato; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; sodium estramustine phosphate; etanidazole; etoposide; etoposide phosphate; etoprin; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; Fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; sodium fostriecin; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosin; iproplatin; Irinotecan; Irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansina; mechlorethamine hydrochloride; Megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; sodium methotrexate; metoprine; meturedepa; mitinomide; mitocarcin; mitochromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamiciña; ormaplatin; oxisuran; paclitaxel; pegaspargase; Peliomycin; pentamustine, peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; pentamethane; porfimer of sodium; porphyromycin; Prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; 3- (4-amino-l-oxo-l, 3-dihydro-isoindol-2-yl) -piperidin-2,6-dione (Revimid ™); riboprine; safingol; safingol hydrochloride; semustine; simtrazene; sodium esparfosate; Esparsomycin; Spirogérmanió hydrochloride, • Spiromustine; Spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalan; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; Teroxirone; testolactone; tiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamine; Toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidin sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zipiplatine; zinostatin; and zorubicin hydrochloride. Other anti-cancer drugs include, but are not limited to: 20-epi-l, 25-dihydroxyvitamin D3; 5-ethynyluracil abiraterone; aclarubicin; acilfulveno; adezpenole adozelesin; aldesleukin; ALL-TK antagonists altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrografol; inhibitors of angiogenesis; antagonist D; antagonist G, antarelix; morphogenetic protein 1 anti-dorsolization; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; afidicolin glycinate; modulators of the apoptosis gene; apoptosis regulators; Apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestana; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathirosine; Baccatin III derivatives; balanol batimastat; BCR / ABL antagonists; benzoclorins; benzoylstaurosporine; beta lactam derivatives; beta-aletine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylpermine; bisnafida; bistratene A; bizelesin; breflato; biririmine; budotitan; butionine sulfoximine; calcipotriol; calfostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; inhibitor derived from cartilage; carzelesin; inhibitors of casein kinase (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; colismicin A; colismicin B; combretastatin A4; combretastatin analogue; conagenina; crambescidin 816; crisnatol; cryptophycin 8; Cryptophycin A derivatives; curacin A; cyclopentantraquinones; Cycloplatam; cipemycin; cytarabine ocphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodyroid B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnospermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin CA; ebselen; ecomustine; edelfosin; Edrecolomab; eflornithine; elemena; emitefur; epirubicin; epristerida; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; Finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; ' galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulina; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifen; idramantone; ilmofosin; ilomastat; imatinib (for example, Gleevec®), imiquimod; immunostimulatory peptides; inhibitor of insulin-like growth factor-1 receptor agonists of interferon; interferons; interleukins iobenguan; iododoxorubicin; iporneano1; 4-; iroplact irsogladine; isobengazol; isohomohalicondrine B; itasetron jasplaquinolide; kahalaluro F; lamelarin-N lanreotide triacetate; leinamycin; lenograstim; lentinan leptolstatin sulfate; letrozole; Leukemia inhibition factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarosol; linear polyamine analog; lipophilic dysharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lyophilin; lytic peptides; Maytansine; Handstatin A; marimastat; masoprocol; maspina; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; they went meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; fibroblast growth factor of mitotoxin-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotropin; cell wall sk of A + monophosphoryl lipid mycobacterium; mopidamol; mustard anticancer agent; micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavina; nafterpina; nartograstim; nedaplatin; memorubicin; neridronic acid; nilutamide; nisamycin; Nitric oxide modulators; nitroxide antioxidant; nitrulin; oblimersen (Genasense®); 06-benzylguanine; octreotide; okicenona; oligonucleotides; onapristone; ondansetron; ondansetron; oracine; oral cytokine inducer, ormaplatin; osaterone; Oxaliplatin; oxaunomycin; paclitaxel; Paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrizoxin; pamidronic acid; panaxytriol; panomiphene; parabactin; pazeliptina; pegaspargase; peldesina; sodium pentosan polysulfate; pentostatin; pentrozole; perflubron; perfosfamide; perilic alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pir rubicina; piritrexim; placetina A; placetina B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer of sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; immune modulator based on protein A; inhibitor of protein kinase C; inhibitors of protein kinase C, microalgal; inhibitors of the protein tyrosine phosphatase; inhibitors of nucleoside purine phosphorylase; purpurins; pyrazoloacridine; pyridoxylated hemoglobin-polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras rasnesyl transferase protein inhibitors; ras inhibitors; ras-GAP inhibitor; Demethylated reteliptine; rhenium etidronate Re 186; rhizoxin; ribozymes; Retinamide RII, roitukine; romurtida; roquinimex; Rubiginone Bl; ruboxyl; safi? goal; saintopine; SarCNU; sarcofitol A; sargramostim; Sdi imitators 1; semustine; inhibitor 1 derived from senescence; sense oligonucleotides; inhibitors of signal transduction; sizofiran; Sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; Somatomedin binding protein; sonermin; Esparfosic acid; Spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stihadid; stromelysin inhibitors; Sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista suramin; suainsonin; talimustine; tamoxifen methiodide; tauromustine; tazarotene; sodium tecogalan; tegafur; telurapyrilio; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; Taliblastine; thiocoraline; thrombopoietin; thrombopoietin mimic; timalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulation hormone; ethyl etiopurpurine tin; tirapazamine; titanocene bichloride; topsentin; toremifene; Translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; Tyrphostins; UBC inhibitors; ubenimex; growth inhibitory factor derived from the urogenital sinus; Urokinase receptor antagonists; vapreotide; variolina B velaresol; veramina; verdins; verteporfin; vinorelbine vinxaltine; vitaxin; vorozole; zanoterone; zipiplatine zilascorb; and zinostatin estimalmer.

Second specific active agents include, but are not limited to anthracycline, platinum, alkylating agent, oblimersen (Genasense®), gemcitabine, cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, methotrexate, taxotere, irinotecan, topotecan, temozolomide , capecitabine, cisplatin, thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, Doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mepacrine, thiotepa, tetracycline, thalidomide and mitomycin C. 4. 3 METHODS OF TREATMENT AND HANDLING The methods of this invention encompass methods for treating, preventing and / or managing various types of diseases and disorders related to asbestos. As used herein, unless otherwise specified, the term "treating" refers to the administration of a PDE4 modulator or other additional active agent after the onset of symptoms of asbestos-related diseases or disorders, while that "prevent" refers to administration before the onset of symptoms, particularly to patients at risk of mesothelioma or other asbestos-related disorders. The term "prevent" includes inhibiting or avoiding a symptom of the particular disease or disorder. Symptoms of diseases or disorders related to asbestos include, but are not limited to, dyspnea, diaphragm obstruction, radiolucent sheet-like covering of the pleura, pleural effusion, pleural thickening, decreased breast size, chest ailment, chest pain, easy fatigability, fever, sweating and weight loss. Examples of patients at risk for diseases or disorders related to asbestos include, but are not limited to those who have been exposed to asbestos in the workplace and their family members who have been exposed to asbestos integrated into work clothes. Patients who have a family history of diseases or disorders related to asbestos are also preferred candidates for preventive regimens. As used herein and unless otherwise indicated, the term "management of asbestos-related diseases or disorders" includes preventing the recurrence of diseases or disorders in a patient who has suffered from the diseases or disorders, and / or the prolongation of time that a patient who has suffered from those stays in suspension. The methods encompassed by this invention comprise administering a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof to a patient (e.g., a human) who suffers, or could suffer from, diseases or disorders related to asbestos. Without being limited by theory, it is believed that the compounds of the invention can be administered prophylactically to prevent people who have been previously exposed to asbestos from developing diseases or disorders related to asbestos. This prophylactic method can avoid, in the first place, actually developing affections or disorders related to asbestos. Therefore, the invention encompasses a method for preventing diseases or disorders related to asbestos in people who are at risk of diseases or disorders related to asbestos, which comprises administering an effective amount of a PDE4 modulator, or a salt, solvate, hydrate, stereoisomer, clathrate or pharmaceutically acceptable prodrug thereof, to those in need thereof. Without being limited by theory, it is also believed that the compounds of the invention can inhibit the spread of asbestos-related diseases or disorders after diagnosis, because the compounds can affect the production of cytokines (e.g., TNF-a, IL-1/3 and IL12). The invention encompasses methods for treating, preventing and managing diseases or disorders related to asbestos 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, rounded atelectasis and bronchogenic carcinoma. It also includes methods for treating patients who have been previously treated for diseases or disorders related to asbestos, but were not sensitive enough or were not sensitive, as well as those who have not been previously treated for the diseases or disorders. Because patients have heterogeneous clinical manifestations and variable clinical outcomes, the treatment given to a patient may vary, depending on their prognosis. The medical specialist will be able to easily determine without undue experimentation specific secondary agents and types of physical therapy that can be effectively used to treat a particular patient. In one embodiment of the invention, a PDE4 modulator is administered orally and daily in an amount from about 1 mg to about 10,000 mg. More specifically, the daily dose is administered twice a day in equally divided doses. Specifically, a daily dose range can be from about 1 mg to about 5,000 mg per day, from about 10 mg to about 2,500 mg per day, from about 100 mg to about 800 mg per day, from about 100 mg to about 1,200 mg per day, or from approximately 25 mg to approximately 2,500 mg per day. In the management of the patient, the therapy should be started at a lower dose, perhaps about 1 mg to about 2,500 mg and increased if necessary to about 200 mg to about 5,000 mg per day either as a single dose or divided doses, depending of the patient's overall response. In a particular embodiment, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide can preferably be administered in an amount of about 400, 800, 1,200, 2,500, 5,000 or 10,000 mg per day as two divided doses. In a particular embodiment, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide is administered in an amount from about 400 to about 1,200. mg / d daily, or every alternate day. In a particular embodiment, a method for preventing asbestos-related diseases comprises administering 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide in a amount from approximately 400, 800 or 1,200 mg per day as two divided doses in people who have recognized that they have been exposed to asbestos. In a particular embodiment of the prophylactic regimen, 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide is administered in an amount of about 400 mg a day. 4. 3.1 Combination Therapy with a Second Active Agent Specific methods of the invention comprise administering a PDE4 modulator, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in combination with a second active agent. Examples of second active agents are described herein (see for example, section 4.2). The administration of a PDE4 modulator and the second active agents to a patient can occur at the same time or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (for example, if it can be administered orally without decomposition before entering the bloodstream) and the disease being treated. A preferred route of administration of a PDE4 modulator is oral. Preferred routes of administration for the second active agents of the invention are known to those of ordinary skill in the art, for example, in Physician's Desk Reference, 2003. The specific amount of the second active agent will depend on the specific agent used, the type , the severity and stage of the diseases or disorders that are treated or handled, and the or the amounts of PDE4 modulators and any additional optional active agents administered at the same time to the patient. In one embodiment, the second active agent is anthracycline, platinum, alkylating agent, oblimersen (Genasense®), cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, taxotere, irinotecan, capecitabine, cisplatin, thiotepa , fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil) ®), paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mecaprin, thiotepa, tetracycline and gemcitabine. In a specific embodiment, a PDE4 modulator is administered in combination with vinorelbine to patients with malignant mesothelioma or mesothelioma syndrome of malignant pleural effusion. In another embodiment, a PDE4 modulator is administered in combination with cyclophosphamide / adriamycin / cisplatin, cisplatin / methotrexate / vinblastine, cisplatin / gemcitabine, cisplatin / adriamycin / mitomycin C, bleomycin / intrapleural hyaluronidase, cisplatin / adriamycin, cisplatin / vinblastine / mitomycin C , gemcitabine / irinotecan, carboplatin / taxotere or carboplatin / pacilitaxel. 4. 3.2 Use with Conventional Therapy Standard methods of chemotherapy, radiation therapy, photodynamic therapy and surgery are used to treat or manage mesothelioma. Kaiser LR., Semin Thorac Cardiovasc Surg. Oct; 9 (4): 383-90, 1997. Intracavirus methods using target cytokines and gene therapy have been examined in patients with mesothelioma using intratumoral adenovirus gene transfer (rAd) recombinant containing the thymidine kinase gene of herpes simplex virus (HSVtk) in the pleural space of patients. Js. and Sterman DH, Hematol Oncol Clin North Am. Jun; 12 (3): 553-69, 1998. Certain embodiments of this invention encompass methods for treating and managing diseases or disorders related to asbestos, which comprise administering a PDE4 modulator, a salt, solvate, hydrate, stereoisomer, clathrate or pro pharmaceutically acceptable drug thereof, together with conventional therapy including (eg, before, during or after), but not limited to chemotherapy, surgery, photodynamic therapy, radiation therapy, gene therapy, immunotherapy or other non-drug based therapy currently used to treat or manage diseases or disorders. The combined use of a PDE4 modulator and conventional therapy can provide a single treatment regimen that is unexpectedly effective in certain patients. As discussed elsewhere herein, the invention encompasses a method for reducing, treating and / or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, chemotherapy, photodynamic therapy, surgery, radiation therapy, gene therapy. and immunotherapy. A PDE4 modulator and another active agent can be administered to a patient before, during or after the occurrence of the adverse effect associated with conventional therapy. Examples of adverse effects associated with chemotherapy and radiation therapy that can be treated or prevented by this method include, but are not limited to: gastrointestinal toxicity such as, but not limited to, diarrhea and flatulence of early and late formation; nausea; threw up; anorexy; leukopenia; anemia; neutropenia; asthenia; abdominal cramps; fever; pain; loss of body weight; dehydration; alopecia; dyspnoea; insomnia; dizziness, mucositis, dry mouth and renal failure. In one embodiment, a PDE4 modulator is administered in an amount of from about 1 mg to about 5,000 mg per day, from about 10 mg to about 2,500 mg per day, from about 100 mg to about 800 mg per day, from about 100 mg to about 1,200 mg per day, or from about 25 mg to about 2,500 mg per day only orally and daily, or in combination with a second active agent described herein (see for example, section 4.2) before, during, or after the use of conventional therapy. In a specific embodiment of this method, an effective amount of a PDE4 modulator and doxetaxol are administered to mesothelioma patients who were previously treated with radiation therapy. In one embodiment of this method, a PDE4 modulator is administered to patients with a disease or an asbestos-related disorder in combination with trimodality therapy. Trimodality therapy involves a combination of three standard strategies of surgery, chemotherapy and radiation therapy. In one modality of this method, extrapleural pneumonectomy is followed by a combination of chemotherapy using a PDE4 modulator and radiotherapy. In another embodiment of the trimodality treatment, a PDE4 modulator is administered in combination with different chemotherapeutic regimens including a combination of cyclophosphamide / adriamycin / cisplatin, carboplatin / paclitaxel or cisplatin / methotrexate / vinblastine. 4. 2.3 Cycle therapy In certain modalities, a PDE4 modulator is cyclically administered to a patient. Cycle therapy involves the administration of a PDE4 modulator over a period of time, followed by a break for a period of time, and repeating this sequential administration. Cycle therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improve the effectiveness of the treatment. Consequently, in a specific embodiment of the invention, a PDE4 modulator is administered daily in a single dose or divided into a cycle of four to six weeks with a rest period of approximately one week or two weeks. Typically, the number of cycles during which the combinatorial treatment is administered to a patient will be from about one to about 24 cycles, more usually from about two to about 16 cycles, and even more usually from about four to about six cycles. The invention also allows the frequency, number and duration of the dosing cycles to be increased. Thus, a specific embodiment of the invention encompasses the administration of a PDE4 modulator for more cycles that are typical when administered alone. In another specific embodiment of the invention, a PDE4 modulator is administered over a large number of cycles that would normally cause dose limiting toxicity in a patient who is not being administered a second active agent. In one embodiment, a PDE4 modulator is administered daily and continuously for three to four weeks in a dose of from about 400 to about 1,200 mg / d followed by a one or two week interval in a four to six week cycle. In another embodiment of the invention, a modulator PDE4 and a second active agent are administered orally, with the administration of a PDE4 modulator that occurs 30 to 60 minutes before a second active agent, during a cycle of four to six weeks. In another embodiment, a PDE4 modulator is administered with cisplatin in an amount of 100 mg / m2 on day 1 and gemcitabine in an amount of 1000 mg / m2 intravenously on days 1, 8 and day 15 of a cycle of 28 days for 6 cycles. 4. 4 PHARMACEUTICAL COMPOSITIONS AND NICAS UNIT DOSE FORMS Pharmaceutical compositions can be used in the preparation of single, single unit dosage forms. The pharmaceutical compositions and dosage forms of the invention comprise PDE4 modulators, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. The pharmaceutical compositions and dosage forms of the invention may further comprise one or more excipients. The pharmaceutical compositions and dosage forms of the invention may also comprise one or more additional active ingredients. Accordingly, the pharmaceutical compositions and dosage forms of the invention comprise the active agents described herein (e.g., PDE4 modulators, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent). Examples of optional additional active agents are described herein (see for example, section 4.2). The unique unit dosage forms of the invention are suitable for oral, mucosal administration (eg, nasal, sublingual, vaginal, buccal or rectal) or parenteral (eg, subcutaneous, intravenous, bolus injection, intramuscular or intraarterial), transdermal or transcutaneous to a patient. Examples of dosage forms include, but are not limited to: tablets; pills; capsules, such as soft elastic gelatin capsules; wafers; trociscos; pills; dispersions; suppositories; powder; aerosols (for example, sprays or nasal inhalers); gels, liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (eg, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline and amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient. The composition, form and type of dosage forms of the invention will normally vary depending on its use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active agents that it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active agents comprising an oral dosage form used to treat the same disease. These and other forms wherein the specific dosage forms encompassed by this invention will vary from one another will be readily apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990). Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. 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 will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suitable for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients comprising primary or secondary amines are particularly susceptible to such accelerated decomposition. Accordingly, this invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose other than mono- or di-saccharides. As used herein, the term "lactose free" means that the amount of lactose present, if any, is insufficient to substantially increase the rate of degradation of an active ingredient. The lactose-free compositions of the invention may comprise excipients that are well known in the art and are listed, for example, in the American Pharmacopoeia (USP) 25-NF20 (2002). In general, the lactose-free compositions comprise active ingredients, a binder / filler, and a lubricant in pharmaceutically acceptable amounts. Preferred free lactose dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate. This invention also encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (eg, 5%) is widely accepted in pharmaceutical techniques as a means to simulate long-term storage in order to determine characteristics such as shelf life of the stability of formulations over time. . See for example, Jens T., Carstensen, Drug Stabili ty: Principies & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. In this way, the effect of water in a formulation can be of greater significance since moisture and / or steam are commonly found during manufacturing, handling, packaging, storage, shipping and the use of formulations. The anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using low or anhydrous moisture containing ingredients and low humidity or low vapor conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if substantial contact with moisture and / or vapor during manufacture, packaging and / or storage is expected. An anhydrous pharmaceutical composition should be prepared and stored so that its anhydrous nature is maintained. Accordingly, the anhydrous compositions are preferably packaged using known materials to avoid exposure to water so that they can be included in suitable forms equipment. Examples of suitable packaging include, but are not limited to, hermetically sealed aluminum foil, plastics, dose unit containers (e.g., jars), blister packs and strip packaging. The invention further encompasses pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers", include, but are not limited to antioxidants such as ascorbic acid, pH buffers or saline buffers. As the amounts and types of excipients, the amounts and specific types of active ingredients in dosage form may differ depending on factors such as, but not limited to, the route by which they will be administered to patients. However, typical dosage forms of the invention comprise a PDE4 modulator or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in an amount from about 1 to about 10,000 mg. Typical dosage forms comprise a PDE4 modulator or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug thereof, in an amount of about 1, 2, 5, 10, 25, 50, 100, 200, 400, 800, 1,200, 2,500, 5,000 or 10,000 mg. In a particular embodiment, a preferred dosage form comprises 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide in an amount of about 400 , 800 or 1,200 mg. Typical dosage forms comprise the second active agent in an amount of from about 1 to about 3,500 mg, from about 5 to about 2,500 mg, from about 10 to about 500 mg, or from about 25 to about 250 mg. Of course, the specific amount of the second active agent will depend on the specific agent used, the type of disease or disorder being treated or handled, and the amounts of PDE4 modulators and any additional active agents administered to the patient at the same time. 4. 4.1 Oral Dosage Forms The pharmaceutical compositions of the invention which are suitable for oral administration may be presented as discrete dosage forms, such as, but not limited to, tablets (eg, chewable tablets), pills, capsules and liquids (e.g. , flavored syrups). Such dosage forms contain predeterm amounts of active agents, and can be prepared by pharmacy methods well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing Easton PA (1990). Typical oral dosage forms of the invention are prepared by combining the active ingredients in an intimate mixture with at least one excipient according to conventional pharmaceutical combination techniques. The excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents. Examples of suitable excipients for the use of solid oral dosage forms (eg, powders, tablets, capsules and tablets) include, but are not limited to, starches, sugars, microcrystallcellulose, diluents, granulating agents, lubricants, binders and disintegrating agents. . Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the pharmacy methods. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, fy divided solid carriers, or both, and then forming the product in the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding. Compressed tablets may be prepared by compressing in a suitable machthe active ingredients in a free-flowing form such as powders or granules, optionally mixed with an excipient. The molded tablets can be made by molding in a suitable macha mixture of the wetted powdered compound with an t liquid diluent. Examples of excipients that can be used in the oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose (eg, Nos. 2208, 2906, 2910) , microcrystallcellulose and mixtures thereof. Suitable forms of microcrystallcellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viseose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. A specific binder is a mixture of microcrystallcellulose and sodium carboxymethylcellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ™ and Starch 1500 LM. Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to,, talc, calcium carbonate (for example, granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch and mixtures thereof. The binder or filler in the pharmaceutical compositions of the invention is normally presented from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. Disintegrants are used in compositions of the invention that provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant can disintegrate in storage, while those that contain too little can not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of the disintegrant used varies based on the type of the formulation, and is easily discernible by those skilled in the ordinary art. Normal pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of the disintegrant, preferably from about 1 to about 5 weight percent of the disintegrant. Disintegrants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, sodium croscarmellose, crospovidone, potassium polacrilin, glycolate of sodium starch, potato starch or tapioca, other starches, pre-gelatinized starch, other starches, clays, other algin, other celluloses, gums and mixtures thereof. Lubricants that may be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate , ethyl oleate, ethyl laureate, agar and mixtures thereof. Additional lubricants include, for example, a siloid silica gel (AEROSIL200, manufactured by WR Grace Co., of Baltimore, MD), a synthetic silica coagulated aerosol (available from Degussa Co. of Plano, TX), CAB-O -SIL (a pyrogenic silica dioxide product sold by Cabot Co., of Boston, MA) and mixtures thereof. If used in all, the lubricants are normally used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms within which they are incorporated. A preferred solid oral dosage form of the invention comprises modulators PDE4, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin. 4. 4.2 Forms of Delayed Release Dosage Active agents of the invention can be administered by controlled release means or by delivery arrangement which are well known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses unique unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel capsules, and lozenges that are adapted for controlled release. All controlled-release pharmaceutical products have a common goal to improve drug therapy over what was achieved by their uncontrolled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance that is used to cure or control the condition in a minimum amount of time. Advantages of controlled release formulations include the extended activity of the drug, a reduced frequency of dose, and increased adherence of the patient. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thus can affect the occurrence of side effects (eg, adverse). Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that immediately produces the therapeutic effect, and gradually and continuously release other quantities of drug containing this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug that is metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by various conditions including, but not limited to pH, temperature, enzymes, water or other physiological or compound conditions. 4. 4.3 Parenteral Dosage Forms Parenteral dosage forms can be administered to patients by several routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular and intra-arterial. Because their administration normally deviates the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection and emulsions. Suitable carriers that can be used to provide the parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for USP Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Riot Injection; miscible vehicles in water such as, but not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate. Compounds that increase the solubility of one or more of the active ingredients described herein may also be incorporated in the parenteral dosage forms of the invention. For example, cyclodextrin and its derivatives can be used to increase the solubility of PDE4 modulators and their derivatives. See, for example, U.S. Patent No. 5,134,127, which is incorporated herein by reference. .4.4.4 Topical and Mucosal Dosage Forms The topical and mucosal dosage forms of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions or other forms known to one skilled in the art. See for example, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 __ 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed. , Read & Febiger, Philadelphia (1985). Suitable dosage forms for treating mucosal tissues within the oral cavity can be formulated as mouth rinses or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical art, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, pzopilenglycol, butan-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures thereof. to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants may also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See for example, Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990). The pH of a pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds, such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilic or lipophilic nature of one or more active ingredients so that delivery is improved. In this aspect, the stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or a surfactant, and as an agent that improves delivery or improves penetration. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition. 4. EQUIPMENT Normally, the active ingredients of the invention are not preferably administered to a patient at the same time or by the same route of administration. This invention therefore encompasses equipment which, when used by the practically physician, can simplify the administration of appropriate amounts of the active ingredients to a patient. A typical apparatus of the invention comprises a dosage form of PDE4 modulators, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, pro-drug or clathrate thereof. The equipment encompassed by this invention may further comprise additional active agents or a combination thereof. Examples of additional active agents include, but are not limited to anti-cancer agents, antibiotics, anti-inflammatory agents, spheroids, immunosuppressive agents, cytokines, immunosuppressive agents or other therapeutics discussed herein (see for example, section 4.2). The kits of the invention may further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to syringes, perfusion bags, patches and inhalers. The kits of the invention may further comprise pharmaceutically acceptable carriers that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the equipment may comprise a sealed container of a suitable vehicle wherein the active ingredient may be dissolved to form a sterile, particle-free solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: Water for USP Injection; aqueous vehicles such as, but not limited to, Sodium Chloride Injection; Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection and Lactated Ringer's Injection; miscible vehicles in water such as, but not limited to ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles, such as, but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

. EXAMPLES The following examples illustrate certain aspects of the invention, but do not limit its scope. . 1 PHARMACOLOGY STUDIES One of the biological effects normally exerted by PDE4 modulators is the reduction of TNF-a synthesis. Specific PDE4 modulators improve the degradation of TNF-α mRNA. In addition, the compounds may also have a modest inhibitory effect on IL1 / 3 and IL12 induced by LPS. Preferred compounds of the invention are potent PDE4 inhibitors. PDE4 is one of the largest phosphodiesterase isozymes found in myeloid and human lymphoid lineage cells. The enzyme plays a crucial part in regulating cellular activity by degrading the ubiquitous second cAMP messenger and maintaining it at low intracellular levels. The inhibition of PDE4 activity results in increased cAMP levels leading to the modulation of cytokines induced by LPS, including the inhibition of TNF-α production in monocytes as well as in lymphocytes. In a specific embodiment, the pharmacological properties of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide are characterized in in vitro studies. The studies examine the effects of the compound on the production of several cytokines. The inhibition of TNF-a production after stimulation by LPS of human PBMC and human whole blood by the compound is investigated in vi tro. The IC50 of the compound to inhibit the production of TNF-α are measured. In vi tro studies suggest a profile of pharmacological activity for 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide five to fifty times more potent than thalidomide. The pharmacological effects of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide can derive from its action as an inhibitor of the generation of inflammatory cytokines. . 2 CLINICAL STUDIES IN PATIENTS WITH MESOTHELIOMA Clinical trials with the administration of a PDE4 modulator in an amount from about 1 mg to about 1,000 mg, from about 1 mg to about 500 mg, or from about 1 mg to about 250 mg per day are conducted in patients with asbestosis, malignant mesothelioma or mesothelioma syndrome of malignant pleural effusion. In a specific embodiment, patients receive about 1 mg to about 1,000 mg / day of 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) - propionamide alone or in combination with vinorelbine. Patients who experience clinical benefits are allowed to continue treatment. Other clinical studies are performed using 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide in non-amputatable or recidivist mesothelioma patients who have not responded to conventional therapy. In one embodiment, 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide is administered in an amount of about 1 mg to about 1,000. mg / day to patients. Treatment with 400 mg as a continuous oral daily dose is well tolerated. Studies in patients with mesothelioma or asbestosis treated with a PDE4 modulator suggest that the drug has a therapeutic benefit in this disease. The embodiments of the invention described herein are only a sample of the scope of the invention. The entire scope of the invention is better understood with reference to the appended claims.

Claims

CLAIMS 1. A method for treating, preventing or managing a disease or disorder related to asbestos, comprising administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a PDE4 modulator, or a salt, pharmaceutically acceptable stereoisomer or solvate 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 a patient a therapeutically or prophylactically effective amount of a second active agent.
The method of claim 3, wherein the second active agent is an anti-cancer agent, an antibiotic, an anti-inflammatory agent, a steroid, an immunomodulatory agent, a cytokine, an immunosuppressive agent or a combination thereof .
The method of claim 4, wherein the second active agent is anthracycline, platinum, alkylating agent, interferon, oblimersen, cisplatin, cyclophosphamide, irinotecan, topotecan, temozolomide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, methotrexate, taxotere, capecitabine, cisplatin, thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, GM-CSF, IL-2, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, vincristine , doxorubicin, paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa, tetracycline or gemcitabine.
6. A method for treating, preventing or managing an asbestos-related disease or disorder, comprising administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a PDE4 modulator, or a salt, solvate or pharmaceutically acceptable stereoisomer thereof, before, during or after chemotherapy, photodynamic therapy, surgery, radiation therapy, gene therapy or immunotherapy.
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.
The method of claim 6, further comprising administering to a patient a therapeutically or prophylactically effective amount of a second active agent.
The method of claim 8, wherein the second active agent is an anti-cancer agent, an antibiotic, an anti-inflammatory agent, a steroid, an immunomodulatory agent, a cytokine, an immunosuppressive agent or a combination thereof .
The method of claim 9, wherein the second active agent is anthracycline, platinum, an alkylating agent, interferon, oblimersen, cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, irinotecan, topotecan, temozolomide, methotrexate , taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, trioxide arsenic, vincristine, doxorubicin, paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa, tetracycline or gemcitabine.
The method of claim 1, wherein the steroisomer of the PDE4 modulator is enantiomerically pure.
The method of claim 1, wherein the PDE4 modulator is 3- (3,4-dimethoxy-phenyl) -3- (1-oxo-l, 3-dihydro-isoindol-2-yl) -propionamide.
The method of claim 12, wherein the PDE4 modulator is enantiomerically pure.
14. The method of claim 1, wherein the PDE4 modulator is. { 2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl] -3-oxo-2,3-dihydro-lH-isoindol-4-yl} - Cyclopropanecarboxylic acid amide.
15. The method of claim 14, wherein the PDE4 modulator is enantiomerically pure.
16. The method of claim 1, wherein the PDE4 modulator is of the formula (I): (I) where n has a value of 1, 2 or 3; R5 is o-phenylene, substituted or unsubstituted with 1 to 4 substituents each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms and halo; R7 is (i) phenyl or phenyl substituted with one or more substituents each independently selected from the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino , alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo, (ii) substituted or unsubstituted benzyl with 1 to 3 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbotoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo, (iii) naphthyl and (iv) benzyloxy; R12 is -OH, alkoxy of 1 to 12 carbon atoms, or R8 is hydrogen or alkyl of 1 to 10 carbon atoms; and R9 is hydrogen, alkyl of 1 to 10 carbon atoms, -COR10 or -S02R10, wherein R10 is hydrogen, alkyl of 1 to 10 carbon atoms or phenyl.
17. The method of claim 16, wherein the PDE4 modulator is enantiomerically pure.
18. The method of claim 1, wherein the PDE4 modulator is of the formula (II): (H) wherein each of R1 and R2, when taken independently from each other, is hydrogen, lower alkyl, or R1 and R2, when taken together with the described carbon atoms to which each is attached, is o-phenylene, o-naphylene or cyclohexen-1,2-diyl, substituted or unsubstituted with 1 to 4 substituents, each independently selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy , carboxy, hydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halo; • R3 is phenyl substituted with one to four substituents selected from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, alkyl of 1 to 10 carbon atoms. carbon, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, cycloalkylidenemethyl of C4-C6, alkylidenemethyl of C3-CX0, indanyloxy and halo; R 4 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R4 'is hydrogen or alkyl of 1 to 6 carbon atoms; R5 is -CH2-, -CH2-CO-, -S02-, -S- or -NHCO-; and n has a value of 0, 1 or 2.
19. The method of claim 18, wherein the PDE4 modulator is enantiomerically pure.
The method of claim 1, wherein the PDE4 modulator is of the formula (III): (III) wherein the designated carbon atom * constitutes a center of chirality; Y is C = 0, CH2, S02 or CH2C = 0; each of R1, R2, R3 and R4 independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or -NR8R9; or any two of R1, R2, R3 and R4 on the adjacent carbon atoms, together with the described phenylene ring are naphthylidene; each of R 5 and R 6, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano or cycloalkoxy of up to 18 carbon atoms; R7 is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl or NR8'R9 '; each of R8 and R9 taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R8 and R9 is hydrogen and the other is -COR10 or -S0R10, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene or -CH2CH2X1CH2CH2- wherein X1 is -O-, -S- or -NH-; and each of R8 'and R9' taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or one of R8 'and R9' is hydrogen and the other is -COR10 'or -S02R10' , or R8 'and R9' taken together are tetramethylene, pentamethylene, hexamethylene or -CH2CH2X2CH2CH2- wherein X2 is -0-, -S- or -NH-.
21. The method of claim 20, wherein the PDE4 modulator is enantiomerically pure.
22. A pharmaceutical composition comprising a PDE4 modulator or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a second active agent capable of alleviating or reducing a symptom of a disease or disorder related to asbestos.
23. The pharmaceutical composition of claim 22, wherein the second active agent is an anti-cancer agent, an antibiotic, an anti-inflammatory agent, a steroid, a cytokine, an immunomodulatory agent, an immunosuppressive agent, or a combination thereof. . The pharmaceutical composition of claim 22, wherein the second active agent is anthracycline, platinum, an alkylating agent, interferon, oblimersen, cisplatin, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, methotrexate, taxotere, capecitabine, cisplatin, thiotepa, fludarabine, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonate, arsenic trioxide, irinotecan, topotecan, temozolomide , vincristine, doxorubicin, paclitaxel, ganciclovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa, tetracycline or gemcitabine.