MXPA06002234A - Method of treating cancer with hdac inhibitors - Google Patents

Abstract

The present invention relates to methods of treating cancers, e.g., mesothelioma or lymphoma. More specifically, the present invention relates to methods of treating mesothelioma or diffuse large B-cell lymphoma (DLBCL), by administration of pharmaceutical compositions comprising HDAC inhibitors, e.g., suberoylanilide hydroxamic acid (SAHA). The oral formulations of the pharmaceutical compositions have favorable pharmacokinetic profiles such as high bioavailability and surprisingly give rise to high blood levels of the active compounds over an extended period of time. The present invention further provides a safe, daily dosing regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo.

Description

METHOD FOR TREATING CANCER WITH DISHR.-HETONE HACITOR INHIBITORS (HDAC) DECLARATION OF GOVERNMENT INTEREST This invention was made in whole or in part with the support of the government under grant number 1R21 CA 096228-01, obtained by the National Cancer Institute. The government may have certain rights over the invention.

FIELD OF THE INVENTION The present invention relates to methods for treating cancers, for example, mesothelioma or lymphoma. More specifically, the present invention relates to methods for treating mesothelioma, diffuse large B-cell lymphoma or DLBCL (diffuse lymphoma of large B-lymphocytes), or other cancers or tumors by administration of compositions Pharmaceuticals comprising HDAC inhibitors, for example, suberoylanilide hydroxamic acid or SAHA (suberoylanilide hydroxamic acid, for its acronym in English). Oral formulations of the pharmaceutical compositions have favorable pharmacokinetic profiles such as high bioavailability and surprisingly, give rise to high levels in the blood of the active compounds for an extended period of time.

BACKGROUND OF THE INVENTION Through this specification, several publications are referenced by Arabic numerals within parentheses. Complete citations of these publications can be found at the end of the specification immediately before the claims. The descriptions of these publications in their entirety are incorporated herein by reference in this application, in order to more fully describe the state of the art to which the invention pertains. Cancer is a disorder in which a population of cells has become, to varying degrees, not sensitive to the control mechanisms tnormally govern proliferation and differentiation. Mesothelioma is a rare form of cancer, in which malignant (cancerous) cells are found in the mesothelium, a protective sac tcovers most of the internal organs of the body. The mesothelium is a membrane tcovers and protects most of the internal organs of the body. It is composed of two layers of cells: a layer timmediately surrounds the organ; the other forms a sack around it. The mesothelium produces a lubricating fluid tis released between these layers, allowing moving organs (such as the beating heart and lungs texpand and contract) to easily slide against adjacent structures. The mesothelium has different names, depending on its location in the body. The peritoneum is the mesothelial tissue tcovers most of the organs in the abdominal cavity. The pleura is the membrane tsurrounds the lungs and covers the wall of the chest cavity. The pericardium covers and protects the heart. The mesothelial tissue tsurrounds the male internal reproductive organs is called the testicular tunica vaginalis. The uterine serosal tunic covers the internal reproductive organs in women. Most cases of mesothelioma begin in the pleura or peritoneum. Malignant tumors arising from the pleural mesothelium are largely related to exposure to asbestos. Although the reported incidence rates have increased over the past 20 years, mesothelioma is still a relatively rare cancer. Approximately 2,000 new cases of mesothelioma are diagnosed in the United States each year. Mesothelioma occurs more frequently in men than in women, and the risk increases with age, but this disease can occur in both men and women at any age. Shortness of breath and pain in the chest due to an accumulation of fluid in the pleura are often symptoms of pleural mesothelioma. The symptoms of peritoneal mesothelioma include weight loss and abdominal pain and swelling due to an accumulation of fluid in the abdomen. Other symptoms of peritoneal mesothelioma may include intestinal obstruction, abnormalities in blood clot, anemia and fever. If the cancer has spread beyond the mesothelium to other parts of the body, the symptoms may include pain, difficulty swallowing, or swelling of the face or neck. The diagnosis of mesothelioma is bleak, with a poor response to radical surgery, current chemotherapy, radiation therapy and combination therapy. Microscopic dispersion of cancer cells in the chest wall and diaphragm is common even when such dispersion can not be detected by rou tes. Lymphoma is cancer of the lymphatic system, a network of lymph nodes, organs (including the spleen, thymus and tonsils), and vessels that are part of the immune system. There are many different types of lymphoma, and they can be divided into two categories: Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). The main difference between the two is the type of cells involved. The lymphatic system is part of the body's immune system, and helps fight infection. It is a complex system made up of organs, such as the bone marrow, the thymus and the spleen, and the lymphatic nodes (or lymphatic glands), which are connected by a network of small lymphatic vessels. The lymph nodes are found throughout the body. Lymphocytes are white blood cells that circulate through the lymphatic system; they are essential components of the body's immune system. There are two main types of lymphocytes: B lymphocytes and T lymphocytes. Most lymphocytes start growing in the bone marrow. The B lymphocytes continue to develop in the bone marrow, while the T lymphocytes go from the bone marrow to the thymus gland and mature there. Once they are mature, both B lymphocytes and T lymphocytes help the body fight infections. There are more than 20 different types of non-Hodgkin's lymphoma. Diffuse lymphoma of large B lymphocytes is a common type, constituting up to 40% of all cases. It is a cancer of B lymphocytes. Diffuse lymphoma of B lymphocytes can occur at any time from adolescence to old age. It is slightly more common in men than in women. Non-Hodgkin lymphomas are also divided into one of two groups: low and high grade. Low-grade lymphomas usually grow slowly, and high-grade lymphomas tend to grow more quickly. Diffuse lymphoma of large B-lymphocytes is a high-grade lymphoma and needs prompt treatment. The main treatment for diffuse large B-cell lymphoma is chemotherapy. The type of chemotherapy depends on the grade of the lymphoma and other factors, such as age and general health. The two drugs that are usually given to treat diffuse lymphoma of large B-lymphocytes are called doxorubicin and cyclophosphamide. Usually, other anticancer drugs are given together. Currently, the most widely used combination is called the "CHOP" regime. This includes the drugs vincristine and prednisolone, as well as doxorubicin and cyclophosphamide. Chemotherapy can usually be given as an outpatient in the hospital and continues for four to six months. In addition, high-dose chemotherapy with infusions of bone marrow or germ cells has been effective in some patients whose lymphoma has relapsed. This type of treatment involves having very intense chemotherapy and sometimes radiotherapy. Since the side effects can be severe, some types of transplants are not given to people over 45-50 years, and others can be given to people up to 65 years old, who are adequate enough to have the treatment. The intensity of the treatment increases the risks of serious side effects for people over this age. Radiation therapy can also be used when the lymphoma cells are contained in one or two areas of lymph nodes in the same part of the body (Stage 1 or 2). It can also occur in addition to chemotherapy. Another treatment that has been treated is a monoclonal antibody called rituximab. For many years there have been two main strategies for the chemotherapeutic treatment of cancer: 1) block the proliferation of tumor cells dependent on hormones by interfering with the production or peripheral action of sex hormones; and 2) destroy the cancer cells directly by exposing them to cytotoxic substances, which injure both the neoplastic and normal cell populations. Despite many advances in the field of oncology, most solid tumors remain incurable in the advanced stages. Cytotoxic therapy is used in most cases, however, it frequently causes significant morbidity to the patient without significant clinical benefit. Less toxic and more specific agents are needed to treat and control advanced malignancies. An alternative procedure for chemotherapy for cancer is the induction of terminal differentiation of neoplastic cells (1). In cell culture models, differentiation has been reported by exposing the cells to a variety of stimuli, including: cyclic AMP and retinoic acid (2, 3), aclarubicin, and other anthracyclines (4). There is abundant evidence that neoplastic transformation does not necessarily destroy the potential of cancer cells to differentiate (1, 5, 6). There are many examples of tumor cells that do not respond to the normal regulators of proliferation, and appear to be blocked for the expression of their differentiation program, and can still be induced to differentiate and stop replicating. A variety of agents, including some relatively simple polar compounds (5, 7-9), vitamin D derivatives and retinoic acid (10-12), steroidal hormones (13), growth factors (6, 14), proteases (15 , 16), tumor promoters (17, 18), and inhibitors of DNA or RNA synthesis (4, 19-24), can induce several transformed cell lines and explants of primary human tumors to express more differentiated characteristics. Previous studies identified a series of polar compounds that were effective inducers of differentiation in several transformed cell lines (8, 9). Of these, the most effective inducer was the hybrid polar / apolar compound N, Nf-hexamethylene bisacetamide or HMBA (N, N '-hexamethylene bisacetamide, for its acronym in English) (9). The use of this polar / apolar compound to induce the cells of murine erythroleukemia or MELC (cells of murine erythroleukemia) to undergo erythroid differentiation with the suppression of oncogenicity, proved to be a useful model to study the differentiation mediated by the inducer of the transformed cells (5, 7-9). The terminal erythroid differentiation of the MELC induced by HMBA is a multi-step process. After the addition of the HMBA to the MELC (745A-DS19) in culture, there is a latent period of 10 to 12 hours before the commitment to terminal differentiation is detected. Commitment is defined as the ability of cells to express terminal differentiation despite the elimination of the inducer (25). After continuous exposure to the HMBA, there is a progressive recruitment of the cells to differentiate. The present inventors have reported that MELC cell lines resistant to relatively low levels of vincristine, become markedly more sensitive to the inducing action of HMBA and can be induced to differentiate with little or no latent period (26). HMBA is able to induce phenotypic changes consistent with differentiation in a wide variety of cell lines (5). The characteristics of the effect induced by the drug have been studied more extensively in the cellular system of murine erythroleukemia (MELC) (5, 25, 27, 28). The induction of differentiation of the MELC is both time and concentration dependent. The minimum concentration required to demonstrate an in vitro effect in most strains is 2 to 3 mM; the minimum duration of continuous exposure generally required to induce differentiation in a substantial portion (> 20%) of the population without continuing exposure to the drug is approximately 36 hours. The primary action goal of the HMBA is not known. There is evidence that protein kinase C is involved in the trajectory of differentiation mediated by the inducer (29). In vitro studies provide a basis for evaluating the potential of HMBA as an agent for cytodifferentiation in the treatment of human cancers (30). Several phase I clinical trials with HMBA have been completed (31-36). Clinical trials have shown that this compound can induce a therapeutic response in patients with cancer (35, 36). However, these phase I clinical trials have also shown that the potential efficacy of HMBA is limited, in part, by dose-related toxicity, which avoids reaching optimal blood levels and by the need for intravenous administration of large doses. quantities of the agent, for extended periods. It has been reported that several of the compounds related to HMBA with polar groups separated by apolar bonds, on a molar basis, are as active (37) or 100 times more active than HMBA (38). As a class, however, it has been found that symmetric dimers such as HMBA and related compounds are not the best agents for cytodifferentiation. It has unexpectedly been found that the best compounds comprise two polar end groups separated by a flexible chain of methylene groups, wherein one or both of the polar end groups is a large hydrophobic group. Preferably, the polar end groups are different and only one is a large hydrophobic group. These compounds are unexpectedly a thousand times more active than HMBA and ten times more active than compounds related to HMBA. Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA), belong to this class of agents that have the ability to induce growth arrest, differentiation and / or apoptosis of tumor cells (39). These compounds are directed towards the mechanisms inherent in the ability of a neoplastic cell to become malignant, since they do not appear to have effective dose toxicity for the inhibition of tumor growth in animals (40). There are several lines of evidence that acetylation and deacetylation with histone are mechanisms through which transcriptional regulation in a cell is achieved (41). It is thought that these effects occur through changes in the croatin structure, altering the affinity of histone proteins for DNA wrapped in a nucleosome. There are five types of histones that have been identified (designated Hl, H2A, H2B, H3 and H4). The histones H2A, H2B, H3 and H4 are found in the nucleosomes and Hl is a linker located between the nucleosomes. Each nucleosome contains two of each type of histone within its nucleus, except for Hl, which is present alone in the outer portion of the nucleosome structure. It is believed that when the histone proteins are hypoacetylated, there is a higher affinity of histone for the phosphate backbone of the DNA. This affinity causes DNA to bind tightly to histone, and makes DNA inaccessible to the elements and machinery of transcriptional regulation. The regulation of acetylated states occurs through the balance of activity between two enzyme complexes, the HAT (histone acetyl transferase, for its acronym in English) and the HDAC (histone deacetylase, for its acronym in English). It is thought that the hypoacetylated state inhibits the transcription of the associated DNA. This hypoacetylated state is catalyzed by large complexes of multiple proteins including the HDAC enzymes. In particular, HDACs have been shown to catalyze the removal of acetyl groups from the histones of the chromatin nucleus. It is thought that the inhibition of HDAC by SAHA occurs through direct interaction with the catalytic site of the enzyme, as demonstrated by X-ray crystallography studies (42). It is not believed that the result of HDAC inhibition has a generalized effect on the genome, but instead only affects a small subset of the genome (43). The evidence provided by DNA microarrays using malignant cell lines grown with an HDAC inhibitor, shows that there is a finite number (1-2%) of genes whose products are altered. For example, cells treated in culture with HDAC inhibitors, show a consistent induction of the p21 inhibitor of cyclin-dependent kinase (44). This protein plays an important role in the arrest of the cell cycle. It is thought that HDAC inhibitors increase the transcription rate of p21, propagating the hyperacetylated state of histones in the p21 gene region, thereby making the gene accessible to the transcriptional machinery. Genes whose expression is not affected by HDAC expression do not show changes in the acetylation of associated regional histones (45). It has been shown in several cases that the interruption of HAT activity or HDAC is involved in the development of a malignant phenotype. For example, in acute pro ielocítica leukemia, the oncoprotein produced by the fusion of PML and RAR alpha, seems to suppress the specific transcription of the gene through the recruitment of HDAC (46). In this way, the neoplastic cell is unable to complete the differentiation and leads to an excessive proliferation of the leukemic cell line. U.S. Patent Nos. 5,369,108, 5,932,616, 5,700,811, 6,087,367 and 6,511,990, issued to some of the present inventors, describe compounds useful for selectively inducing terminal differentiation of neoplastic cells, compounds which have two polar end groups separated by a flexible chain of methylene groups or by a rigid phenyl group, wherein one or both of the polar end groups is a large hydrophobic group. Some of the compounds have an additional large hydrophobic group at the same end of the molecule as the first hydrophobic group, which additionally increases the differentiation activity approximately 100-fold in an enziotic assay and approximately 50-fold in a cell differentiation assay. The methods for synthesizing the compounds used in the methods and pharmaceutical compositions of this invention are fully described in the patents mentioned above, the total content of which is incorporated herein by reference. In addition to their biological activity as antitumor agents, the compounds described in the aforementioned patents have recently been identified as being useful for treating or preventing a wide variety of diseases and conditions mediated by thioredoxin (TRX), such as inflammatory diseases, allergic diseases, autoimmune diseases, diseases associated with oxidative aggressions of diseases characterized by cellular hyperproliferation (U.S. Application No. 10 / 369,094, filed on February 15, 2003. In addition, these compounds have been identified as useful for treating nervous system disease central nervous system (CNS), such as neurodegenerative diseases and to treat brain cancer (See, U.S. Application No. 10,273,401, filed on October 16, 2002). describe specific oral formulations of the inhibitor it is from the HDAC or dosages and specific dosage schemes of the exposed compounds, which are effective to treat cancer, for example, mesothelioma or lymphoma. Importantly, the aforementioned patents do not disclose oral formulations that have favorable pharmacokinetic profiles such as high bioavailability, which result in high blood levels of the active compounds for an extended period of time. There is an urgent need to discover suitable dosages and dosage schedules of these compounds, and to develop formulations, preferably oral formulations, which result in stable, therapeutically effective blood levels of the active compounds, over a period of time. extended, and effective to treat cancer.

SUMMARY OF THE INVENTION The present invention relates to methods for treating cancers, for example, mesothelioma or lymphoma. More specifically, the present invention relates to methods for treating mesothelioma or diffuse large B-cell lymphoma (DLBCL), by administering pharmaceutical compositions comprising HDAC inhibitors, for example, suberoylanilide hydroxamic acid (SAHA). In particular aspects, the methods of the invention are used to treat mesothelioma. In other aspects, the methods of the invention are used to treat lymphoma, for example, DLBCL. Oral formulations of the pharmaceutical compositions have favorable pharmacokinetic profiles such as high bioavailability and surprisingly, give rise to high blood levels of the active compounds for an extended period of time. The present invention further provides a safe, daily dosage regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo. In one embodiment, the present invention provides a method for treating mesothelioma or DLBCL in a subject in need thereof, by administering to the subject a pharmaceutical composition comprising an effective amount of suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate. thereof, as described herein. The SAHA can be administered in a total daily dose of up to 800 mg, preferably orally, once, twice or three times a day, continuously (every day) or intermittently (for example, 3-5 days a week). Oral SAHA has been safely administered in phase I clinical studies to patients suffering from mesothelioma or DLBCL. In addition, the present invention provides a method for treating mesothelioma or DLBCL in a subject in need thereof, by administering to the subject a pharmaceutical composition comprising an effective amount of an HDAC inhibitor as described herein, or a salt thereof. or pharmaceutically acceptable hydrate thereof. The HDAC inhibitor can be administered in a total daily dose of up to 800 mg, preferably orally, once, twice or three times a day, continuously (ie, every day) or intermittently (e.g. , 3-5 days a week). The HDAC inhibitors and methods of the present invention are useful in the treatment of a wide variety of cancers, for example, lymphoma, including Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). In one embodiment, HDAC inhibitors are useful for treating mesothelioma or large cell lymphoma, including diffuse large B-cell lymphoma (DLBCL). As defined herein, "large cell lymphoma" is a lymphoma that is characterized by unusually large cells. HDAC inhibitors suitable for use in the present invention include, but are not limited to, hydroxamic acid derivatives, Short Chain Fatty Acids or SCFA (Short Chain Fatty Acids), cyclic tetrapeptides, derivatives of benzamide or electrophilic ketone derivatives, as described herein. Specific non-limiting examples of HDAC inhibitors suitable for use in the methods of the present invention are: A) Derivatives of hydroxamic acid selected from the bishydroxamide of m-carboxycinnamic acid or CBHA (bishydroxamide of m-carboxycinnamic acid, by its acronyms), Trichostatin A (TSA), Trichostatin C, Salicylic Hydroxamic Acid, Bishydroxamic Acid Azelaic or ABHA (Bishydroxamic Azelaic Acid, for its acronym in English), Azelaic-l-Hydroxamate-9-Anilide or AAHA (Azelaic-1-Hydroxamate-9-Anilide), 6- (3-Chlorophenylureido) carpoic acid Hydroxamic acid (3C1-UCHA), Oxamflatine, A-161906 , Scriptaid, PXD-101, LAQ-824, CHAP, MW2796 and M 2996; B) Cyclic tetrapeptides selected from Trapoxin A (TPX) cyclic tetrapeptide (cyclo- (L-phenylalanyl-L-phenylalanyl-D-pipecolinyl-L-2-amino-8-oxo-9,10-epoxy decanoyl); FR901228 (FK 228, Depsipeptide), cyclic tetrapeptide FR225497, cyclic tetrapeptide Apicidin [cyclo (NO-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)]; Apicidin la, Apicidin Ib , Apicidina le, Apicidina lia and Apicidina Ilb; CHAP, cyclic tetrapeptide of HC toxin; Cyclic WF27082; and Clamidocin; C) Short Chain Fatty Acids (SCFA), selected from Sodium Butyrate, Isovaleriato, Valeriato, 4-Phenyl or 4-PBA butyrate (4- Phenyl butyrate), Phenyl butyrate or PB (Phenyl butyrate, for its acronym in English), propionate, Butyramide, Isobutyramide, Phenyl Acetate, 3-Bromopropionate, Tributyrin, Valproic Acid and Valproate and Pivanex ™; D) Benzamide derivatives selected from CI-994, MS-27-275 (MS-275) [N- (2-aminophenyl) -4- [N- (pyridin-3-ylmethoxycarbonyl) to inomethyl] benzamide] and a derivative 3'-amino of MS-27-275; E) Electrophilic Ketone Derivatives, selected from trifluoromethyl ketone and an α-keto amide, such as an N-methyl-α-ketoamide; and F) Miscellaneous HDAC inhibitors, including natural products, psammaplins and Depudecin. Specific inhibitors of HDAC include, for example: Suberoylanilide hydroxamic acid (SAHA), which is represented by the following structural formula: Piroxamide, which is represented by the following structural formula: M-carboxycinnamic acid bis-hydroxamide (CBHA), which is represented by the structural formula: Other non-limiting examples of HDAC inhibitors that are suitable for use in the methods of the present invention are: A compound represented by the structure: wherein R3 and R4 are independently an alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy or unsubstituted or substituted, branched or unbranched pyridine, a cycloalkyl, aryl, aryloxy, arylalkyloxy or pyridine group, or R3 and R4 are joined together to form a piperidine group; R2 is a hydroxylamino group; and n is an integer from 5 to 8. A compound represented by the structure: O or R ICI NH (CH2) n- - ICI NHOH wherein R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3- pyridine or 4-pyridine and n is an integer from 4 to 8. A compound represented by the structure: wherein A is an amide moiety, Ri and R2 are each selected from unsubstituted or substituted aryl, arylalkyl, naphthyl, pyridinamino, 9-purin-6-amino, thiazolamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R is hydrogen, a halogen, a phenyl or cycloalkyl portion and n is an integer from 3 to 10. In one embodiment, pharmaceutical compositions comprising the HDAC inhibitor are administered orally, for example, within a gelatin capsule. In a further embodiment, the pharmaceutical compositions further comprise microcrystalline cellulose, croscarmellose sodium and magnesium stearate. HDAC inhibitors can be administered in a total daily dose that can vary from patient to patient, and can be administered to varying dosage schedules. Suitable dosages are a total daily dosage of between about 25-4000 mg / m2 administered orally once a day, twice a day or three times a day, continuously (every day) or intermittently (e.g. -5 days a week) . In addition, the compositions can be administered in cycles, with periods of rest between the cycles (for example, treatment of two to eight weeks with a rest period of up to one week between treatments). In one embodiment, the composition is administered once a day at a dose of approximately 200-600 mg. In another embodiment, the composition is administered twice a day at a dose of approximately 200-400 mg. In another embodiment, the composition is administered twice daily at a dose of about 200-400 mg intermittently, for example, three, four or five days per week. In another embodiment, the composition is administered three times a day at a dose of approximately 100-250 mg. In one modality, the daily dose is 200 mg, which can be administered once a day, twice a day, or three times a day. In one embodiment, the daily dose is 300 mg, which can be administered once a day or twice a day. In one modality, the daily dose is 400 mg, which can be administered once a day or twice a day.

The present invention also provides methods for selectively inducing terminal differentiation, the arrest of cell growth and / or apoptosis of neoplastic cells, for example, lymphoma cells in a subject, thereby inhibiting the proliferation of such cells. in the subject, administering to the subject a pharmaceutical composition comprising an effective amount of an HDAC inhibitor, eg, SAHA, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent. An effective amount of an HDAC inhibitor in the present invention can be up to a total daily dose of 800 mg. The present invention also provides methods for inhibiting the activity of a histone deacetylase in a subject by administering to the subject a pharmaceutical composition comprising an effective amount of an HDAC inhibitor, eg, SAHA, or a pharmaceutically acceptable salt or hydrate thereof. , and a pharmaceutically acceptable carrier or diluent. An effective amount of an HDAC inhibitor in the present invention can be up to a total daily dose of 800 mg. The present invention also provides in vitro methods for selectively inducing terminal differentiation, the arrest of cell growth and / or apoptosis of neoplastic cells, for example, lymphoma cells, thereby inhibiting the proliferation of such cells, contacting the cells with an effective amount of an HDAC inhibitor, e.g., SAHA, or a pharmaceutically acceptable salt or hydrate thereof. The present invention also provides in vitro methods for inhibiting the activity of a histone deacetylase, by histone deacetylase with an effective amount of an HDAC inhibitor, eg, SAHA, or a pharmaceutically acceptable salt or hydrate thereof. The present invention further provides a safe, daily dosage regimen of the formulation of pharmaceutical compositions comprising an HDAC inhibitor, which is easy to follow and adhere to. These pharmaceutical compositions are suitable for oral administration and are useful for treating cancer, for example, mesothelioma, lymphoma, or other cancers or tumors, selectively inducing terminal differentiation, arrest of cell growth, and / or apoptosis of cells neoplastic, and / or inhibiting histone deacetylase (HDAC).

BRIEF DESCRIPTION OF THE FIGURES The foregoing and other objects, features and advantages of the invention, will be apparent from the following more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, in which the characters of Similar reference refers to the same parties through the different views. The drawings are not necessarily to scale, instead emphasis is made on illustrating the principles of the invention. Figure 1 is a photograph of a Western blot (upper panel), showing the amounts of acetylated histone-4 (a-AcH4) in the blood plasma of patients after an oral or intravenous (IV) dose of SAHA. SAHA IV was administered at 200 mg infused for two hours. Oral SAHA was administered in a single capsule at 200 mg. The amount of a-AcH4 is shown at the indicated measurement points. Bottom panel: staining with Coomassie blue. Bottom panel: staining with Coomassie blue. Figure 2 is a photograph of a Western blot (upper panels), showing the amounts of acetylated histone-4 (a-AcH4) in the blood plasma of patients having a solid tumor, after an oral or intravenous dose (IV ) of SAHA. The SAHA IV and Oral was administered as in Figure 1. The amount of a-AcH4 is shown at the indicated measurement points. The experiment is shown in duplicate (Figure 2A and Figure 2B). Lower panels: staining with Coomassie blue. Figure 3 is a photograph of a Western blot (upper panels) showing the amounts of acetylated histone-4 (a-AcH4) (Figure 3A) and acetylated histone-3 (a-AcH3) (Figures 3B-E) in the blood plasma of patients after an oral or intravenous (IV) dose of SAHA, on Day 1 and on Day 21. SAHA IV and Oral was administered as in Figure 1. The amount of a-AcH4 or a-AcH3 is shown at the indicated measurement points. Lower panels: staining with Coomassie blue. Figure 4 is a photograph of a Western blot (upper panels) showing the amounts of acetylated histone-3 (a-AcH3) in the blood plasma of patients having a solid tumor, after an oral or intravenous (IV) dose of SAHA. The SAHA IV and Oral was administered as in Figure 1. The amount of a-AcH3 is shown at the indicated measurement points. Bottom panel: staining with Coomassie blue. Figure 5 is a photograph of a Western blot (upper panels) showing the amounts of acetylated histone-3 (ct-AcH3) in the blood plasma of patients after an oral or intravenous (IV) dose of SAHA. SAHA IV was administered at 400 mg infused for two hours. Oral SAHA was administered in a single capsule at 400 mg. The amount of a-AcH4 is shown at the indicated measurement points. The experiment is shown in triplicate (Figure 5A and B). Lower panels: staining with Coomassie blue. Figure 6 is a photograph of a Western blot (upper panel) showing the amounts of acetylated histone-3 (a-AcH3) in the blood plasma of patients having a solid tumor, after an oral or intravenous (IV) dose. of SAHA. SAHA IV and Oral was administered as in Figure 5. The amount of a-AcH3 is shown at the indicated measurement points. Bottom panel: staining with Coomassie blue. Figure 7 is a photograph of a Western blot (upper panels) showing the amounts of acetylated histone-3 (a-AcH3) in the blood plasma of patients having a solid tumor after an oral or intravenous (IV) dose of SAHA, on Day 1 and on Day 21. SAHA IV and Oral was administered as in Figure 4. The amount of a-AcH4 or a-AcH3 is shown at the indicated measurement points. The experiments are shown in triplicate (Figure 7A-C). Lower panels: staining with Coomassie blue. Figure 8 is a photograph of a Western blot (upper panels) showing the amounts of acetylated histone-3 (a-AcH3) in the blood plasma of patients after an oral or intravenous (IV) dose of SAHA. SAHA IV and Oral was administered as in Figure 5. The amount of a-AcH3 is shown at the indicated measurement points. Lower panels: staining with Coomassie blue. Figures 9A-C are graphs showing average plasma concentrations of SAHA (ng / ml) at the indicated measurement points after administration. Figure 9A: Oral dose (200 mg and 400 mg) under fasting conditions on Day 8. Figure 9B: Oral dose (200 mg and 400 mg) with food on Day 9. Figure 9C: IV dose on day 1. Figure 10 shows the apparent half-life of an oral SAHA dose of 200 mg and 400 mg on Days 8, 9 and 22. Figure 11 shows the AUC (ng / ml / hr) of an oral SAHA dose of 200 mg and 400 mg on Days 8, 9 and 22. Figure 12 shows the bioavailability of SAHA after an oral dose of 200 mg and 400 mg on Days 8, 9 and 22. Figure 13 is a CT Scan of a mesothelioma tumor of a patient, before (left) and after (right) six months of treatment with SAHA at a dose of 300 mg twice a day, 3 days a week.

Figure 14 is a CT scan taken of a patient with Large Cell Diffuse Lymphoma, before treatment (A) and r (B) of 2 months of treatment with SAHA at a dose of 400 mg BID (twice a day) for 1 month, followed by 400 mg QD (every day) for one month. Figure 15 is a PET scan taken of a patient with Large Cell Diffuse Lymphoma, before treatment (A) and r (B) of 2 months of treatment with SAHA at a dose of 400 mg BID (twice a day) for 1 month, followed by 400 mg QD (every day) for one month. Figure 16 is a CT scan taken of a patient with Large Cell Diffuse Lymphoma, before treatment (A) and r (B) of 1 month of treatment with SAHA at a dose of 600 mg QD (every day). Figure 17 is a PET scan taken from a patient with Large Cell Diffuse Lymphoma, before treatment (A) and r (B) of 2 months of treatment with SAHA at a dose of 200 mg BID (twice a day) .

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods for treating cancers, for example, mesothelioma or lymphoma. More specifically, the present invention relates to methods for treating mesothelioma or diffuse large B-cell lymphoma (DLBCL), by administering pharmaceutical compositions comprising HDAC inhibitors, for example, suberoylanilide hydroxamic acid (SAHA). In specific aspects, the methods of the invention are used to treat mesothelioma. In other aspects, the methods of the invention are used to treat lymphoma, including DLBCL. Oral formulations of the pharmaceutical compositions of the invention have favorable pharmacokinetic profiles, such as high bioavailability and surprisingly, give rise to high blood levels of the active compounds for an extended period of time. Thus, the present invention further provides a safe, daily dosage regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo. Accordingly, in one embodiment, the present invention provides a method for treating mesothelioma or DLBCL in a subject in need thereof, by administering to the subject a pharmaceutical composition comprising an effective amount of an HDAC inhibitor as described in present, or a pharmaceutically acceptable salt or hydrate thereof. The HDAC inhibitor can be administered in a total daily dose of up to 800 mg, preferably orally, once, twice or three times a day, continuously (ie, every day) or intermittently (e.g. , 3-5 days a week). In one embodiment, the HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA). In another embodiment, the HDAC inhibitor is a hydroxamic acid derivative as described herein. In another embodiment, the HDAC inhibitor is represented by any of the structures of formulas 1-51, described herein. In another embodiment, the HDAC inhibitor is a benzamide derivative as described herein. In another embodiment, the HDAC inhibitor is a cyclic tetrapeptide as described herein. In another embodiment, the HDAC inhibitor is a Short Chain Fatty Acid (SCFA) as described herein. In another embodiment, the HDAC inhibitor is an electrophilic ketone as described herein.

In another embodiment, the HDAC inhibitor is depudecin. In another embodiment, the HDAC inhibitor is a natural product. In another embodiment, the HDAC inhibitor is a psammaplin. In a particular embodiment, the present invention provides a method for treating mesothelioma or DLBCL in a subject in need thereof, by administering to the subject a pharmaceutical composition comprising an effective amount of suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate. acceptable thereof, as described herein. SAHA can be administered at a total daily dose of up to 800 mg, preferably orally, once, twice or three times a day, continuously (every day) or intermittently (eg, 3-5 days a week) . The SAHA is represented by the following structure: In another particular embodiment, the present invention relates to a method for treating mesothelioma or DLBCL in a subject, comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase inhibitor (HDAC). , represented by any of the structures described herein, by the formulas 1-51 described herein, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent, wherein the amount of the histone inhibitor Deacetylase is effective in treating mesothelioma or DLBCL in the subject. The term "treating" in its various grammatical forms in relation to the present invention, refers to preventing (ie, chemoprevention), curing, reversing, alleviating, minimizing, suppressing or arresting the damaging effects of a disease state, progression of the disease, causal agent of the disease (for example, bacteria or virus) or other abnormal condition. For example, the treatment may involve alleviating a symptom (ie, not necessarily all symptoms) of a disease or attenuating the progression of a disease. Because some of the inventive methods involve the physical removal of the etiological agent, the skilled artisan will recognize that they are equally effective in situations where the inventive compound is administered prior to, or concurrently with exposure to, the etiological agent. (prophylactic treatment), and in situations where the inventive compounds are administered after (even much later) exposure to the etiological agent.

Cancer treatment, as used herein, refers to inhibiting, delaying or partially or totally preventing the progression of cancer, including cancer metastasis; inhibit, delay or prevent the recurrence of cancer, including cancer metastasis; or preventing the onset or development of cancer (chemoprevention) in a mammal, for example, a human. As used herein, the term "therapeutically effective amount" is intended to encompass any amount that will achieve the desired biological response. In the present invention, the desired biological response is the inhibition, delay or partial or total prevention of cancer progression, including cancer metastasis; inhibition, delay or prevention of cancer recurrence, including cancer metastasis; or preventing the onset or development of cancer (chemoprevention) in a mammal, for example, a human. The method of the present invention is intended for the treatment or chemoprevention of human patients with cancer. However, it is also likely that the method is effective in the treatment of cancer in other mammals.

Histone Deacetylases and Histone Deacetylase Inhibitors Histone deacetylase inhibitors (HDACs), as that term is used herein, are enzymes that catalyze the removal of the acetyl groups from the lysine residues in the amino terminal tails of the histones of the nucleosomal nucleus. Therefore, HDACs, together with histone acetyl transferases (HAT), regulate the histone acetylation state. Acetylation of histone affects gene expression and inhibitors of HDAC, such as the hybrid polar compound based on hydroxamic acid, suberoylanilide hydroxamic acid (SAHA), induces growth arrest, differentiation and / or apoptosis of transformed cells in vitro, and inhibit tumor growth in vivo. HDACs can be divided into three classes based on their structural homology. The HDAC of Class I (HDAC 1, 2, 3 and 8), have similarity with the protein RPD3 of yeast, are located in the nucleus and are found in complexes associated with transcriptional correpressors. Class II HDACs (HDAC 4, 5, 6, 7, and 9) are similar to yeast HDAl protein, and have both a nuclear and a cytoplasmic subcellular location. Both Class I and Class II HDAC are inhibited by HDAC inhibitors based on hydroxynamic acid, such as SAHA. HDACs of Class III form a structurally distant class of NAD-dependent enzymes that are related to yeast SIR2 proteins, and are not inhibited by HDAC inhibitors based on hydroxamic acid. Histone deacetylase inhibitors or HDAC inhibitors, as that term is used herein, are compounds that are capable of inhibiting deacetylation of histones in vivo, in vitro or both. Therefore, inhibitors of HDAC inhibit the activity of at least one histone deacetylase. As a result of inhibiting the deacetylation of at least one histone, an increase in the acetylated histone occurs and the accumulation of the acetylated histone is a suitable biological marker to assess the activity of the HDAC inhibitors. Therefore, procedures that can prove the accumulation of acetylated histones can be used to determine the HDAC inhibitory activity of the compounds of interest. It is understood that compounds that can inhibit the activity of histone deacetylase also bind to other substrates and can therefore inhibit other biologically active molecules such as enzymes. It should also be understood that the compounds of the present invention are capable of inhibiting any of the histone deacetylases discussed above, or any other histone deacetylases. For example, in patients receiving HDAC inhibitors, the accumulation of acetylated histones in peripheral mononuclear cells, as well as in tissue treated with HDAC inhibitors, can be determined against adequate control. The HDAC inhibitory activity of a particular compound can be determined in vitro using, for example, enzymatic assays that show inhibition of at least one histone deacetylase. In addition, the determination of the accumulation of acetylated histones in cells treated with a particular composition can be determinant of the HDAC inhibitory activity of a compound. Assays for the accumulation of acetylated histones are well known in the literature. See, for example, Marks, P. A. et al., J. Nati. Cancer Inst., 92: 1210-1215, 2000, Butler, L.M. et al., Cancer Res. 60: 5165-5170 (2000), Richon, V.M. et al., Proc. Nati Acad. Sci., USA, 95: 3003-3007, 1998 and Yoshida, M. et al. J. Biol. Chem., 265: 17174-17179, 1990. For example, an enzymatic assay for determining the activity of an HDAC inhibitor compound can be carried out as follows. Briefly, the effect of an HDAC inhibitor compound on the affinity of purified human HDACl, labeled with an epitope (Flag), can be tested by incubating the enzyme preparation in the absence of the substrate on ice for approximately 20 minutes with the amount indicated of the inhibitor compound. The substrate (histone derived from murine erythroleukemia cells labeled with [3H] acetyl) can be added and the sample can be incubated for 20 minutes at 37 ° C in a total volume of 30 μL. The reaction can then be stopped and the released acetate can be extracted and the amount of radioactivity released determined by scintillation counting. An alternative assay useful for determining the activity of an HDAC inhibitor compound is the "HDAC Fluorescent Activity Assay"; Drug Discovery Equipment-AK-500"available from BIOMOL® Research Laboratories, Inc., Plymouth Meeting, Pa. In vivo studies may be conducted as follows Animals, for example, mice, may be injected intraperitoneally with an inhibitory compound of the HDAC Selected tissues, eg brain, spleen, liver, etc., can be isolated at predetermined times after administration Histones can be isolated from tissues essentially as described by Yoshida et al., J. Biol. Chem. 265: 17174-17179, 1990. Equal amounts of histones (approximately 1 μg) can be electrophoresed in 15% SDS-polyacrylamide gels and can be transferred to Hybond-P filters (available from Amersham) .The filters can be blocked with milk at 3% and can be probed with a purified polyclonal antibody of rabbit antiacetylated histone H4 (a-Ac-H4) and antiacetylated histone H3 antibody (a-Ac-H3) (Upstate Biotechnology, Inc.). Acetylated isone can be visualized using a goat anti-rabbit antibody conjugated with horseradish peroxidase (1: 5000) and the SuperSignal chemiluminescent substrate (Pierce). As a loading control for the histone protein, parallel gels can be run and stained with Coomassie Blue or CB (Coomassie Blue, for its acronym in English). In addition, HDAC inhibitors based on hydroxamic acid have been shown to upregulate the expression of the p21WAF1 gene. The p21AF1 protein is induced within 2 hours of culture with HDAC inhibitors in a variety of transformed cells, using standard methods. Induction of the? 21AF1 gene is associated with the accumulation of acetylated histones in the chromatin region of this gene. The induction of p21AF1 can therefore be recognized as being involved in the arrest of the Gl cell cycle caused by the HDAC inhibitors in the transformed cells. Typically, HDAC inhibitors fall into five general classes: 1) hydroxamic acid derivatives; 2) Short Chain Fatty Acids (SCFA); 3) cyclic tetrapeptides; 4) benzamides and 5) electrophilic ketones. Thus, the present invention includes within its broad aspect, compositions comprising HDAC inhibitors that are 1) hydroxamic acid derivatives; 2) Short Chain Fatty Acids (SCFA); 3) cyclic tetrapeptides; 4) benzamides and 5) electrophilic ketones and / or other class of compounds capable of inhibiting histone deacetylases, for use in the inhibition of histone deacetylase, inducing terminal differentiation, the arrest of cell growth and / or apoptosis in cells neoplastic and / or inducing differentiation, the arrest of cell growth and / or the apoptosis of tumor cells in a tumor. Non-limiting examples of such HDAC inhibitors are discussed below. It is understood that the present invention includes any salts, crystalline structures, amorphous structures, hydrates, derivatives, metabolites, stereoisomers, structural isomers and prodrugs of the HDAC inhibitors described herein. A. Derivatives of Hydroxamic Acid, such as suberoylanilide hydroxamic acid (SAHA) (Richon et al., Proc.Nat.Acid.Sci.USA 95, 3003-3007 (1998)); m-carboxycinic acid bishydroxamide (CBHA) (Richon et al., supra); pyroxamide; trichostatin analogs such as trichostatin • A (TSA) and trichostatin C (Koghe et al., 1998. Biochem Pharmacol 56: 1359-1364); salicydehydroxamic acid (Andrews et al., International J. Parasitology 30, 761-768 (2000)); suberoil bishydroxamic acid or SBHA (suberoil bishydroxamic acid, for its acronym in English) (U.S. Patent No. 5,608,108); bishydroxamic azelaic acid (ABHA) (Andrews et al., supra); azelaic-1-hydroxamate-9-anilide (AAHA) (Qiu et al., Mol. Biol. Cell 11, 2069-2083 (2000)); 6- (3-chlorophenyl) acid carpoic hydroxamic acid (3C1-UCHA); oxamflatine [(2E) -5- [3- [(phenylsufonyl) aminol-phenyl] -pent-2-en-4-yl-hydroxamic acid] (Ki et al., Oncogene, 18: 2461-2470 (1999)); A-161906, Scriptaid (Su et al., 2000 Cancer Research, 60: 3137-3142); PXD-101 (Prolifix); LAQ-824; CHAP; MW2796 (Andrews et al., Supra); MW2996 (Andrews et al., Supra); or any of the hydroxamic acids described in U.S. Patent Nos. 5,369,108, 5,932,616, 5,700,811, 6,087,367 and 6,511,990. B. Cyclic tetrapeptides such as trapoxin A (TPX) -cyclic tetrapeptide (cyclo- (L-phenylalanyl-L-phenylalanyl-D-pipecolinyl-L-2-amino-8-oxo-9, 10-epoxy decanoyl)) (Kijima et al., J Biol. Chem. 268, 22429-22435 (1993)); FR901228 (FK 228, depsipeptide) (Nakajima et al., Ex. Cell Res. 241, 126-133 (1998)); FR225497 cyclic tetrapeptide (H. Mori et al., PCT Application WO 00/08048 (February 17, 2000)); cyclic tetrapeptide apicidin [Cyclo (N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)] (Darkin-Rattray et al., Proc.

Nati Acad. Sci. USA 93, 13143-13147 (1996)); apicidin la, apicidin Ib, apicidin le, apicidin lia and apicidin Ilb (P. Dulski et al., PCT Application WO 97/11366); CHAP, cyclic tetrapeptide of the HC toxin (Bosch et al., Plant Cell 7, 1941-1950 (1995)); cyclic tetrapeptide WF27082 (PCT application WO 98/48825) and clamidocin (Bosch et al., Supra). C. Derivatives of short chain fatty acids (SCFA) such as: sodium butyrate (Cousens et al., J. Biol. Chem. 254, 1716-1723 (1979)); isovaleriato (McBain et al., Biochem. Pharm 53: 1357-1368 (1997)); valeriato (McBain et al., Supra); 4-phenyl butyrate (4-PBA) (Read and Tulsyan, Anticancer Research, 15, 879-873 (1995)); phenyl butyrate (PB) (Wang et al., Cancer Research, 59, 2766-2799 (1999)); propionate (McBain et al., supra); butyramide (Lea and Tulsyan, supra); isobutyramide (Lea and Tulsyan, supra); phenyl acetate (Lea and Tulsyan, supra); 3-bromopropionate (Read and Tulsyan, supra); tributyrin (Guan et al., Cancer Research, 60, 749-755 (2000)); valproic acid, valproate and Pivanex ™.

D) Benzamide derivatives such as CI-994, MS-275 [N- (2-aminophenyl) -4- [N- (pyridin-3-ylmethoxycarbonyl) -aminomethyl] benzamide] (Saito et al., Proc. Nati. Acad. Sci. USA 96, 4592-4597 (1999)) and a 3'-amino derivative of MS-275 (Saito et al., Supra). E) Electrophilic Ketone Derivatives, such as trifluoromethyl ketone (Frey et al, Bioorganic &Med.Chem.Lett. (2002), 12, 3443-3447; US 6,511,990) and an α-keto amide, such as N-methyl -a-ketoamides. F. Other HDAC Inhibitors such as natural products, psammaplins and Depudecin (Kwon et al., 1998. PNAS 95: 3356-3361). Preferred HDAC inhibitors based on hydroxamic acid are suberoylanilide hydroxamic acid (SAHA), bishydroxamide of m-carboxycinnamic acid (CBHA) and pyroxamide. SAHA has been shown to bind directly in the catalytic receptacle of the enzyme histone deacetylase. SAHA induces cell cycle arrest, differentiation and / or apoptosis of transformed cells in culture and inhibits tumor growth in rodents. SAHA is effective in inducing these effects in both solid tumors and hematologic cancers. It has been shown that SAHA is effective to inhibit tumor growth in animals without toxicity to the animal. The inhibition of tumor growth induced by SAHA is associated with an accumulation of acetylated histones in the tumor. SAHA is effective in inhibiting the development and continuous growth of mammary tumors induced by a carcinogen (N-methylnitrosourea) in rats. SAHA was administered to the rats in their diet during the 130 days of the study. A) Yes, SAHA is a non-toxic, orally active antitumor agent whose mechanism of action involves the inhibition of histone deacetylase activity. Preferred HDAC inhibitors are those described in U.S. Patent Nos. 5,369,108, 5,932,616, 5,700,811, 6,087,367 and 6,511,990, issued to some of the present inventors, which describe compounds, the total content of which is incorporated herein by reference , the non-limiting examples of which are set forth below: In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 1, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (1) where Ri and R2 may be the same or different; when Ri and R2 are the same, each is an arylamino, cycloalkylamino, pyridinamino, piperidino, 9-purin-6-amine or substituted or unsubstituted thiazolamino group; when Ri and R2 are different R? = R3-N-R4, wherein each of R3 and R4 are independently the same or different from each other and are a hydrogen atom, a hydroxyl group, an alkyl, alkenyl group , cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy or substituted or unsubstituted, branched or unbranched pyridine, or R3 and R4 are joined together to form a piperidine group, R2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group and n is an integer from about 4 to about 8. In a particular embodiment of formula 1, Ri and R2 are the same and are a substituted or unsubstituted thiazolamino group; and n is an integer from about 4 to about 8. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 2, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (2) wherein each of R3 and R4 are independently the same or different from each other, and are a hydrogen atom, a hydroxyl group, an alkyl, alkenyl, cycloalkyl, arylalkyloxy, aryloxy, arylalkyloxy or pyridine group substituted or unsubstituted, branched or unbranched, or R3 and R4 are joined together to form a piperidine group, R2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group and n is an integer from about 4 to about 8. In a particular embodiment of formula 2, each of R3 and R4 are independently the same or different from each other, and are a hydrogen atom, a hydroxyl group, an alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy group , arylalkyloxy or substituted or unsubstituted, branched or unbranched pyridine, or R3 and R4 are joined together to form a piperidine group; R2 is a hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group; n is an integer from 5 to 7; and R3-N-R4 and R2 are different. In another particular embodiment of formula 2, n is 6. In yet another embodiment of formula 2, R 4 is a hydrogen atom, R 3 is a substituted or unsubstituted phenyl, and n is 6. In yet another embodiment of formula 2, R 4 is a hydrogen atom, R3 is a substituted phenyl and n is 6, wherein the phenyl substituent is selected from the group consisting of a methyl, cyano, nitro, trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro, bromo, iodo group , 2, 3-difluoro, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, 3,5-difluoro, 2,6-difluoro, 1,2,3-trifluoro, 2, 3, 6 -trifluoro, 2,4,6-trifluoro, 3,4,5-trifluoro, 2,3,5,6-tetrafluoro, 2, 3, 4, 5, 6-pentafluoro, azido, hexyl, t-butyl, phenyl , carboxyl, hydroxyl, methoxy, phenyloxy, benzyloxy, phenylaminoxy, phenylaminocarbonyl, methoxycarbonyl, methylaminocarbonyl, dimethylamino, dimethylaminocarbonyl or hydroxylaminocarbonyl. In another embodiment of formula 2, n is 6, R 4 is a hydrogen atom, and R 3 is a chlorohexyl group. In another embodiment of formula 2, n is 6, R 4 is a hydrogen atom, and R 3 is a methoxy group. In another embodiment of formula 2, n is 6 and R3 and R are joined together to form a piperidine group. In another embodiment of formula 2, n is 6, R is a hydrogen atom, and R 3 is a benzyloxy group. In another embodiment of formula 2, R4 is a hydrogen atom and R3 is a? -pyridine group. In another embodiment of formula 2, R 4 is a hydrogen atom and R 3 is a β-pyridine group.

In another embodiment of formula 2, R 4 is a hydrogen atom and R 3 is an a-pyridine group. In another form of formula 2, n is 6, and R3 and R are both methyl groups. In another embodiment of formula 2, n is 6, R 4 is a methyl group and R 3 is a phenyl group. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 3, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. wherein n is an integer from 5 to about 8. In a preferred embodiment of formula 3, n is 6. According to this embodiment, the HDAC inhibitor is SAHA (4), or a pharmaceutically acceptable salt or hydrate thereof. , and a pharmaceutically acceptable carrier or excipient. The SAHA can be represented by the following structural formula: (4) In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 5, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (5) In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 6 (pyroxamide), or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. .

In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 7, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (7) In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 8, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (8) In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 9, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (9) In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 10, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. wherein R3 is hydrogen and R4 is a cycloalkyl, aryl, aryloxy, arylalkyloxy or pyridine group, or R3 and R4 are joined together to form a piperidine group; R2 is a hydroxylamino group; and n is an integer from 5 to about 8. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 11, or a pharmaceutically acceptable salt or hydrate thereof, and a carrier or pharmaceutically acceptable excipient. wherein R3 and R4 are independently an alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy or unsubstituted or substituted, branched or unbranched pyridine, a cycloalkyl, aryl, aryloxy, arylalkyloxy or pyridine group, or R3 and R4 are joined together to form a piperidine group; R2 is a hydroxylamino group; and n is an integer from 5 to about 8. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 12, or a pharmaceutically acceptable salt or hydrate thereof, and a carrier or pharmaceutically acceptable excipient. (12) wherein each of X and Y are independently the same or different from each other, and are a hydroxyl, amino or hydroxylamino group, an alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxy, aryloxyamino, unsubstituted or substituted alkyloxyalkylamino or aryloxyalkylamino; R is a hydrogen atom, a hydroxyl group, an unsubstituted or substituted alkyl, arylalkyloxy or aryloxy group; and each of m and n are independently the same or different from each other and are each an integer from about 0 to about 8. In a particular embodiment, the HDAC inhibitor is a compound of formula 12, wherein X, Y and R are each hydroxyl and both of m and n are 5. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 13, or a pharmaceutically acceptable salt or hydrate thereof. , and a pharmaceutically acceptable carrier or excipient. (13) wherein each of X and Y are independently the same or different from each other, and are a hydroxyl, amino or hydroxylamino group, an alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylaryl group substituted or unsubstituted aryloxyalkylamino or aryloxyalkylamino; each of Ri and R2 are independently the same or different from one another, and are a hydrogen atom, a hydroxyl group, an alkyl, aryl, substituted or unsubstituted alkyloxy or aryloxy group; and each of m, n and o are independently the same or different from each other and each is an integer from about 0 to about 8. In a particular embodiment of formula 13, each of X and Y is a hydroxyl group and each of Ri and R2 is a methyl group. In another particular form of formula 13, each of X and Y is a hydroxyl group, each of Ri and R2 is a methyl group, each of nyo is 6, and m is 2. In one embodiment, the HDAC inhibitor useful in the methods of present invention is represented by the structure of formula 14, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (14) wherein each of X and Y are independently the same or different from each other, and are a hydroxyl, amino or hydroxylamino group, an alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino group or substituted or unsubstituted aryloxyalkylamino; each of Ri and R2 are independently the same or different from one another, and are a hydrogen atom, a hydroxyl group, an alkyl, aryl, substituted or unsubstituted alkyloxy or aryloxy group; and each of m and n are independently the same or different from each other and each is an integer from about 0 to about 8. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 15, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (15) wherein each of X and Y are independently the same or different from each other, and are a hydroxyl, amino or hydroxylamino group, an alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylaryl group .no or substituted or unsubstituted aryloxyalkylamino; and each of m and n are independently the same or different from each other and each is an integer from about 0 to about 8. In a particular embodiment of formula 15, each of X and Y is a hydroxyl group and each of myn is 5.

In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 16, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (16) wherein each of X and Y are independently the same or different from each other, and are a hydroxyl, amino or hydroxylamino group, an alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino group or substituted or unsubstituted aryloxyalkylamino; Ri and R2 are independently the same or different from each other and are a hydrogen atom, a hydroxyl group, an unsubstituted or substituted alkyl, arylalkyloxy or aryloxy group; and each of m and n are independently the same or different from each other and each is an integer from about 0 to about 8. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 17, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (17) wherein each of X and Y are independently the same or different from each other, and are a hydroxyl, amino or hydroxylamino group, an alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino or aryloxyalkyla substituted or unsubstituted group replaced; and n is an integer from about 0 to about 8. In a particular embodiment of formula 17, each of X and Y is a hydroxylamino group; Ri is a methyl group, R2 is a hydrogen atom; and each of m and n is 2. In another particular embodiment of formula 17, each of X and Y is a hydroxylamino group; Ri is a carbonyl idroxylamino group, R2 is a hydrogen atom; and each of m and n is 5. In another particular embodiment of formula 17, each of X and Y is a hydroxylamino group; each of Ri and R2 is a fluoro group; and each of m and n is 2. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 18, or a pharmaceutically acceptable salt or hydrate thereof, and a carrier or excipient pharmaceutically acceptable. (18) wherein each of X and Y are independently the same or different from each other, and are a hydroxyl, amino or hydroxylamino group, an alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino group or substituted or unsubstituted aryloxyalkylamino; each of Ri and R2 are independently the same or different from one another, and are a hydrogen atom, a hydroxyl group, an alkyl, aryl, alkyloxy, aryloxy, substituted or unsubstituted carbonyl or hydroxy or hydroxy group; and each of m and n are independently the same or different from each other and each is an integer from about 0 to about 8. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 19, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (19) wherein each of Ri and R2 are independently the same or different from each other, and are a hydroxy, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkylaminoamino, aryloxyamino, alkyloxyalkylamino or aryloxyalkylamino. In a particular embodiment, the HDAC inhibitor is a compound of structural formula 19, wherein Rx and R2 are both hydroxylamino. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 20, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (twenty) wherein each of Ri and R2 are independently the same or different from one another, and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group. In a particular embodiment, the HDAC inhibitor is a compound of structural formula wherein Ri and R2 are both hydroxylamino. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 21, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (21) wherein each of Ri and R2 are independently the same or different from each other, and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino or aryloxyalkylamino group . In a particular embodiment, the HDAC inhibitor is a compound of structural formula 21, wherein Ri and R2 are both hydroxylamino. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 22, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (22) wherein R is a phenylamino group substituted with a cyano, methylcyano, nitro, carboxyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, trifluoromethyl, hydroxylaminocarbonyl, N-hydroxylaminocarbonyl, methoxycarbonyl, chloro, fluoro, methyl, methoxy, 2, 3- group difluoro, 2,4-difluoro, 2,5-difluoro, 2,6-difluoro, 3,5-difluoro, 2,3,6-trifluoro, 2,4,6-trifluoro, 1,2,3-trifluoro, 3, 4, 5-trifluoro, 2,3,4,5-tetrafluoro or 2, 3, 4, 5, 6-pentafluoro; and n is an integer from 4 to 8. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 23 (m-carboxycinnamic acid bishydroxamide-CBHA), or a salt or pharmaceutically acceptable hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (23) In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 24, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (24) In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 25, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (25) wherein R is phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine, substituted or unsubstituted and n is an integer from about 4 to about 8. In a particular embodiment of formula 25, R is a substituted phenyl group. In another particular embodiment of formula 25, R is a substituted phenyl group, wherein the substituent is selected from the group consisting of a methyl group, cyano, nitro, uncle, trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro, bromo, iodine, 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, 3,5-difluoro, 2,6-difluoro, 1, 2, 3-trifluoro, 2, 3, 6-trifluoro, 2,4,6,6-trifluoro, 3,4,5-trifluoro, 2,3,5,6-tetrafluoro, 2,3,4,5,6-pentafluoro, azido, hexyl, t-butyl, phenyl, carboxyl, hydroxyl, methyloxy, phenyloxy, benzyloxy, phenylaminoxy, phenylaminocarbonyl, methyloxycarbonyl, methylaminocarbonyl, dimethylamino, dimethylaminocarbonyl, or hydroxylaminocarbonyl. In another particular embodiment of formula 25, R is 2-pyridine, 3-pyridine or substituted or unsubstituted 4-pyridine and n is an integer from about 4 to about 8. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 26, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. o o R HN ICI NH (CH2) n ICI NHOH (26) wherein R is a substituted or unsubstituted phenyl, pyridine, piperidine or thiazole group and n is an integer from about 4 to about 8 or a pharmaceutically acceptable salt thereof. In a particular embodiment of formula 26, R is a substituted phenyl group. In another particular embodiment of formula 26, R is a substituted phenyl group, wherein the substituent is selected from the group consisting of a methyl group, cyano, nitro, thio, trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro, bromo, iodine, 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, 3,5-difluoro, 2,6-difluoro, 1, 2, 3-trifluoro, 2, 3, 6-trifluoro, 2,4,6,6-trifluoro, 3,4,5-trifluoro, 2,3,5,6-tetrafluoro, 2,3,4,5,6-pentafluoro, azido, hexyl, t-butyl, phenyl, carboxyl, hydroxyl, methoxy, phenyloxy, benzyloxy, phenylaminoxy, phenylaminocarbonyl, methyloxycarbonyl, methylaminocarbonyl, dimethylamino, dimethylaminocarbonyl, or hydroxylaminocarbonyl. In another particular embodiment of formula 26, R is phenyl and n is 5. In another embodiment, n is 5 and R is 3-chlorophenyl. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 27, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (27) wherein each of Ri and R2 is attached directly or through a linker and is an aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, cycloalkyl, cycloalkylamino, pyridinamino, piperidino, 9- purin-6-amino, thiazolamino, hydroxyl, substituted or unsubstituted, alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridyl or quinolinyl or branched or unbranched isoquinolinyl; n is an integer from about 3 to about 10 and R3 is a hydroxamic, hydroxylamino, hydroxyl, amino, alkylamino or alkyloxy group. The binder can be an amide portion, for example, O-, -S-, -NH-, NR5, -CH2-, - (CH2) m-, - (CH = CH) -, phenylene, cycloalkylene or any combination of the same, wherein R 5 is a substituted or unsubstituted C 1 -C 5 alkyl. In certain embodiments of formula 27, Rx is -NH-R4, wherein R4 is an aryl (eg, phenyl), arylalkyl (eg, benzyl), naphthyl, cycloalkyl, cycloalkylamino, pyridinamino, piperidino, 9-purin-6. -amino, thiazolamino, hydroxyl, substituted or unsubstituted, alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridyl, quinolinyl or branched or unbranched isoquinolinyl. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 28, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient. (28) wherein each of W \ and R2 is an aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, cycloalkyl, cycloalkylamino, pyridinamino, piperidino, 9- purin-6 -anri.no, thiazolamino, hydroxyl, substituted or unsubstituted, alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridyl, quinolinyl or branched or unbranched isoquinolinyl; R3 is a group of hydroxamic, hydroxylamino, hydroxyl, amino, alkylamino or alkyloxy; R 4 is hydrogen, halogen, phenyl or a cycloalkyl portion; and A may be the same or different and represents an amide moiety, 0-, -S-, -NH-, NR5, -CH2-, - (CH2) m-, - (CH = CH) -, phenylene, cycloalkylene, or any combination thereof, wherein R5 is a substituted or unsubstituted C1-C5 alkyl; ynym are each an integer from 3 to 10. In a further particular embodiment, the compounds having a more specific structure within the scope of compounds 27 or 28 are: In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 29: (29) wherein A is an amide moiety, Ri and R2 are each selected from aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridinamino, 9-purin-6-amino, thiazolamino, aryloxy , substituted or unsubstituted arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; and n is an integer from 3 to 10. For example, the compound of formula 29 may have structure 30 or 31: (30) (31) wherein Ri, R2, and n have the meanings of formula 29. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 32: (32) wherein R7 is selected from aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridinamino, 9-purin-6-amino, thiazolamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or substituted or unsubstituted isoquinolinyl; n is an integer from 3 to 10 and Y is selected from: In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 33: where n is an integer from 3 to 10, and is selected from and R7 'is selected from In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 34: (34) aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridinamino, 9-purin-6-atoyl, thiazolamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; n is an integer from 3 to 10 and R7 'is selected from In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 35: (35) wherein A is an amide moiety, Ri and R2 are each selected from aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridinamino, 9-purin-6-amino, thiazolamino, aryloxy , substituted or unsubstituted arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; R 4 is hydrogen, a halogen, a phenyl or cycloalkyl portion and n is an integer from 3 to 10. For example, the compound of formula 35 may have structure 36 or 37 (36) (37) wherein Ri, R2, R4 and n have the meanings of formula 35. In one embodiment, the HDAC inhibitor useful in the methods of the present invention is represented by the structure of formula 38: (38) wherein L is a binder selected from the group consisting of an amide moiety, O-, -S-, -NH-, NR5, -CH2-, (CH2) m-, - (CH = CH) -, phenylene, cycloalkylene or any combination thereof, wherein R5 is a substituted or unsubstituted C1-C5 alkyl; and wherein each of R and Ra are independently an aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridinamino, 9-purin-6-amino, thiazolamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl, substituted or unsubstituted; n is an integer from 3 to 10 and m is an integer from 0-10. For example, a compound of formula 38 can be represented by the structure of formula (39): (39) Other HDAC inhibitors suitable for use in the methods of the present invention include those shown in the following more specific formulas: A compound represented by the structure: (40) wherein n is an integer from 3 to 10, or an enantiomer thereof. In a particular embodiment of formula 40, n = 5.

A compound represented by the structure: (41) wherein n is an integer from 3 to 10, or an enantiomer thereof. In a particular embodiment of formula 41, n = 5. A compound represented by the structure: (42) wherein n is an integer from 3 to 10 or an enantiomer thereof. In a particular embodiment of formula 42, n = 5. A compound represented by the structure: (43) wherein n is an integer from 3 to 10, or an enantiomer thereof. In a particular embodiment of formula 43, n = 5. A compound represented by the structure: (44) where n is an integer from 3 to 10 or an enantiomer thereof. In a particular embodiment of formula 44, n = 5. A compound represented by the structure: (45) wherein n is an integer from 3 to 10, or an enantiomer thereof. In a particular embodiment of formula 45, n = 5. (46) wherein n is an integer from 3 to 10 or an enantiomer thereof. In a particular embodiment of formula 46, n = 5. A compound represented by the structure: (47) wherein n is an integer from 3 to 10, or an enantiomer thereof. In a particular embodiment of formula 47, n = 5. A compound represented by the structure: (48) wherein n is an integer from 3 to 10, or an enantiomer thereof. In a particular embodiment of formula 48, n = 5. A compound represented by the structure: (49) wherein n is an integer from 3 to 10, or an enantiomer thereof. In a particular embodiment of formula 49, n = 5. A compound represented by the structure: (50) wherein n is an integer from 3 to 10, or an enantiomer thereof. In a particular embodiment of formula 50, n = 5. A compound represented by the structure: (51) wherein n is an integer from 3 to 10, or an enantiomer thereof. In a particular embodiment of formula 51, n = 5. Other examples of such compounds and other HDAC inhibitors can be found in U.S. Patent No. 5,369,108, issued November 29, 1994, U.S. Pat. No. 5,700,811, issued December 23, 1997, U.S. Patent No. 5,773,474, issued June 30, 1998, U.S. Patent No. 5,932,616, issued August 3, 1999 and the U.S. Pat. from United States No. 6,511,990, issued January 28, 2003, all from Breslow et al .; U.S. Patent No. 5,055,608, issued October 8, 1991, U.S. Patent No. 5,175,191, issued December 29, 1992, and U.S. Patent No. 5,608,108, issued March 4 , from 1997, all by Marks et al .; as well as Yoshida, M., et al., Bioassays 17, 423-430 (1995); Saito, A., et al., PNAS USA 96, 4592-4597, (1999); Furamai, R. et al., PNAS USA 98 (1), 87-92 (2001); Komatsu, Y., et al., Cancer Res. 61 (11), 4459-4466 (2001); Su, G. H., et al., Cancer Res. 60, 3137-3142 (2000); Lee, B. I. et al., Cancer Res. 61 (3), 931-934; Suzuki, T., et al., J. Med. Chem. 42 (15), 3001-3003 (1999); the published PCT Application WO 01/18171, published on March 15, 2001, of the Sloan-Kettering Institute for Cancer Research and the Columbia University Board of Administration; the published PCT Application WO02 / 246144 by Hoffmann-La Roche; the published PCT Application WO02 / 22577 of Novartis; the published Application of PCT WO02 / 30879 of Prolifix; PCT Published Requests WO 01/38322 (published May 31, 2001), WO 01/70675 (published September 27, 2001) and WO 00/71703 (published November 30, 2000), all from Methylgene, Inc .; PCT Published Application WO 00/21979, published October 8, 1999 by Fujisawa Pharmaceutical Co., Ltd.; PCT Published Application WO 98/40080, published March 11, 1998 by Beacon Laboratories, L. L. C .; and Curtin M. (current patent status of the HDAC inhibitors Expert Opin, Ther.Patents (2002) 12 (9): 1375-1384 and references cited therein). The SAHA or any of the other HDACs may be synthesized according to the methods set forth in the Experimental Details Section, or in accordance with the method set forth in U.S. Patent Nos. 5,369,108, 5,700,811, 5,932,616 and 6,511,990, the contents of which are incorporated herein by reference. of which is incorporated as a reference in its entirety, or according to any other method known to a person skilled in the art. Specific non-limiting examples of HDAC inhibitors are provided in the following Table. It should be noted that the present invention encompasses any compounds that are structurally similar to the compounds depicted below, and that are capable of inhibiting histone deacetylases.

Oxamflatine Trichostatin C The compounds of the present invention are useful for selectively inducing terminal differentiation, the arrest of cell growth and / or apoptosis of neoplastic cells and therefore, assist in the treatment of cancer in patients, as described in detail in the I presented.

Chemical Definitions An "aliphatic group" is a non-aromatic group, consisting solely of carbon and hydrogen, and which may optionally contain one or more unsaturation units, for example, double and / or triple bonds. An aliphatic group can be straight chain, branched or cyclic. When it is straight or branched chain, an aliphatic group typically contains between about 1 and about 12 carbon atoms, more typically between about 1 and about 6 carbon atoms. When cyclic, an aliphatic group typically contains between about 3 and about 10 carbon atoms, more typically between about 3 and about 7 carbon atoms. The aliphatic groups are preferably straight or branched chain C?-C12 alquilo alkyl groups (i.e., fully saturated aliphatic groups), more preferably straight or branched chain Ci-Cß alkyl groups. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl and tert-butyl. An "aromatic group" (also referred to as an "aryl group"), as used herein, includes carbocyclic aromatic groups, heterocyclic aromatic groups (also referred to as "heteroaryl") and fused polycyclic aromatic annual systems as defined in I presented. A "carbocyclic aromatic group" is an aromatic ring of 5 to 14 carbon atoms, and includes a carbocyclic aromatic group fused with a 5 or 6 membered cycloalkyl group, such as indane. Examples of carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, eg, 1-naphthyl and 2-naphthyl; anthracenyl, for example, 1-anthracenyl, 2-anthracenyl; phenanthrenyl; fluorenonyl, for example, 9-fluorenonyl, indanyl and the like. A carbocyclic aromatic group is optionally substituted with a designated number of substituents, described below. A "heterocyclic aromatic group" (or "heteroaryl") is a monocyclic, bicyclic or tricyclic aromatic ring with from 5 to 14 carbon atoms in the ring, and from one to four heteroatoms selected from 0, N or S. The examples of heteroaryl include, in a non-exclusive manner, pyridyl, for example, 2-pyridyl (also referred to as -pyridyl), 3-pyridyl (also referred to as β-pyridyl) and 4-pyridyl (also referred to as β-pyridyl); thienyl, for example, 2-thienyl and 3-thienyl; furanyl, for example, 2-furanyl and 3-furanyl; pyrimidyl, for example, 2-pyrimidyl and 4-pyrimidyl; imidazolyl, for example, 2-imidazolyl; pyranyl, for example, 2-pyranyl and 3-pyranyl; pyrazolyl, for example, 4-pyrazolyl and 5-pyrazolyl; thiazolyl, for example, 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; thiadiazolyl; isothiazolyl; oxazolyl, for example, 2-oxazoyl, 4-oxazoyl and 5-oxazoyl; isoxazoyl; pyrrolyl; pyridazinyl; pyracinyl and the like. The heterocyclic (or heteroaryl) aromatic group as defined above, may be optionally substituted with a designated number of substituents, as described below for the aromatic groups.

A "fused polycyclic aromatic" ring system is a carbocyclic or heteroaryl aromatic group fused to one or more other heteroaryls or non-aromatic heterocyclic rings. Examples include, quinolinyl and isoquinolinyl, for example, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl, 1-isoquinolinyl, 3-quinolinyl, 4-isoquinolinyl , 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl; benzofuranyl, for example, 2-benzofuranyl and 3-benzofuranyl; dibenzofuranyl, for example, 2,3-dihydrobenzofuranyl; dibenzothiophenyl; benzothienyl, for example, 2-benzothienyl and 3-benzothienyl; indolyl, for example, 2-indolyl and 3-indolyl; benzothiazolyl, for example, 2-benzothiazolyl; benzooxazolyl, for example, 2-benzooxazolyl; benzimidazolyl, for example, 2-benzoimidazolyl; isoindolyl, for example, 1-isoindolyl and 3-isoindolyl; benzotriazolyl; purinyl; tianaftenilo and the similar. The fused polycyclic aromatic ring systems may be optionally substituted with a designated number of substituents, as described herein. An "aralkyl group" (arylalkyl) is an alkyl group substituted with an aromatic group, preferably a phenyl group. A preferred aralkyl group is a benzyl group. Suitable aromatic groups are described herein and suitable alkyl groups are described herein. Suitable substituents for an aralkyl group are described herein. An "aryloxy group" is an aryl group that is linked to a compound via an oxygen (e.g., phenoxy). An "alkoxy group" (alkyloxy), as used herein, is a straight or branched chain C _-C? 2 alkyl group or cyclic C C-C???? Que which is connected to a compound via a carbon atom. oxygen. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy and propoxy. An "arylalkoxy group" (arylalkyloxy), is an arylalkyl group that is linked to a compound via an oxygen in the alkyl portion of the arylalkyl (e.g., phenylmethoxy). An "arylamino group" as used herein, is an aryl group that is attached to a compound via a nitrogen. As used herein, an "arylalkylamino group" is an arylalkyl group that binds to a compound via a nitrogen in the alkyl portion of the arylalkyl. As used herein, many portions or groups refer to or are "substituted or unsubstituted." When referring to a portion as being substituted, it denotes that any portion of the portion known to one of skill in the art to be available for substitution can be substituted. For example, the substitutable group can be a hydrogen atom that is replaced with a group that is different from hydrogen (i.e., a substituent group). Multiple substituent groups may be present. When multiple substituents are present, the substituents may be the same or different, and the substitution may be at any of the substitutable sites. Such means for substitution are well known in the art. For purposes of exemplification, which should not be construed as limiting the scope of this invention, some examples of the groups which are substituents are: alkyl groups (which may also be substituted, with one or more substituents, such as CF3), groups alkoxy (which may also be substituted, such as 0CF3), a halogen group or halo (F, Cl, Br, I), hydroxy, nitro, oxo, -CN, -COH, -COOH, amino, azido, N-alkylamino or N, N-dialkylamino (in which the alkyl groups may also be substituted), esters (-C (O) -OR, where R may be a group such as alkyl, aryl, etc., which may be substituted ), aryl (most preferred is phenyl, which may be substituted), arylalkyl (which may be substituted) and aryloxy.

Stereotyping Many organic compounds exist in optimally active forms that have the ability to rotate the plane of polarized light in the plane. When describing an optimally active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule around its chiral center. The prefixes d and 1 or (+) and (-), are used to designate the sign of the rotation of the polarized light in the plane by the compound, with (-) or 1 meaning that the compound is levogyratory. A compound with the prefix (+) or d, is dextrogiratorio. For a given chemical structure, these compounds, called stereoisomers, are identical, except that they are mirror images that can not overlap one with respect to the other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein have one or more chiral centers, and therefore, may exist in different enantiomeric forms.

If desired, a chiral carbon can be designated with an asterisk (*). When the bonds to the chiral carbon are described as straight lines in the formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are encompassed within of the formula. As used in the art, when it is desired to specify the absolute configuration around a chiral carbon, one of the bonds to the chiral carbon can be described as a wedge (links to atoms above the plane), and the others can be described as a series or wedge of short parallel lines (links to the atoms below the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon. When the HDAC inhibitors of the present invention contain a chiral center, the compounds exist in two enantiomeric forms, and the present invention includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture, referred to as the racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, for example, by the formation of diastereomeric salts that can be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes that can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer with a specific reagent of the enantiomer, for example, enzymatic esterification; or gaseous-liquid or liquid chromatography in a chiral medium, for example, on a chiral support, for example, silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted to another chemical entity by one of the separation methods described above, an additional step is required to release the desired enantiomeric form. Alternatively, the specific enantiomers can be synthesized by asymmetric synthesis using optimally active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other or by asymmetric transformation. The designation of a specific absolute configuration of a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in an enantiomeric excess (ee), or in other words, is substantially free of the other enantiomer . For example, the "R" forms of the compounds are substantially free of the "S" forms of the compounds and are, therefore, in an enantiomeric excess of the "S" forms. Inverse, the "S" forms of the compounds are substantially free of the "R" forms of the compounds and are therefore in an enantiomeric excess of the "R" forms. Enantiomeric excess, as used herein, is the presence of a particular enantiomer to more than 50%. For example, the enantiomeric excess may be about 60% or more, such as about 70% or more, for example, about 80% or more, such as about 90% or more. In a particular embodiment, when the specific absolute configuration is designated, the enantiomeric excess of the described compounds is at least about 90%. In a more particular embodiment, the enantiomeric excess of the compounds is at least about 95%, such as at least about 97.5%, for example, at least 99% enantiomeric excess. When a compound of the present invention has two or more chiral carbons, it may have more than two optical isomers, and may exist in diastereomeric forms. For example, when there are two chiral carbons, the compounds can have up to 4 optical isomers and 2 pairs of enantiomers ((S, S) / (R, R) and (R, S) / (S, R)). The pairs of enantiomers (e.g., (S, S) / (R, R)), are stereoisomers of mirror images of one another. Stereoisomers that are not mirror images (e.g., (S, S) and (R, S)), are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example, chromatography or crystallization, and the individual enantiomers within each pair can be separated as described above. The present invention includes each diastereomer of such compounds and mixtures thereof. As used herein, "a," "an," and "the," include singular and plural references unless the context clearly dictates otherwise. Thus, for example, the reference to "an active agent" or "a pharmacologically active agent", includes a single active agent, as well as two or more different active agents in combination, the reference to "one carrier" includes mixtures of two or more carriers, as well as a single carrier, and the like. This invention is also intended to encompass the prodrugs of the HDAC inhibitors described herein. A prodrug of any of the compounds can be made using well-known pharmacological techniques. This invention, in addition to the compounds listed above, is intended to encompass the use of homologs and analogs of such compounds. In this context, homologs are molecules that have substantial structural similarities to the compounds previously described, and analogs are molecules that have substantial biological similarities regardless of structural similarities. The invention also encompasses pharmaceutical compositions comprising pharmaceutically acceptable salts of HDAC inhibitors with organic and inorganic acids, for example, acid addition salts which may, for example, be hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid , maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid and the like. Pharmaceutically acceptable salts can also be prepared from the treatment with inorganic bases, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and organic bases such as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like . The invention also encompasses pharmaceutical compositions comprising the hydrates of HDAC inhibitors. The term "hydrate" includes, in a non-exclusive manner, hemihydrate, monohydrate, dihydrate, trihydrate and the like. This invention also encompasses pharmaceutical compositions comprising any solid or liquid physical form of SAHA or any of the other HDAC inhibitors. For example, the HDAC inhibitors can be in crystalline form, in amorphous form and have any particle size. The particles of the HDAC inhibitor can be micronized, or they can be agglomerated granules, particulates, powders, oils, oily suspensions or any other form of a solid or liquid physical form.

Therapeutic Uses of HDAC Inhibitors 1. Cancer Treatment As demonstrated herein, the HDAC inhibitors of the present invention are useful for the treatment of cancer. Accordingly, in one embodiment, the invention relates to a method of treating cancer in a subject in need of treatment, which comprises administering to the subject a therapeutically effective amount of a histone deacetylase inhibitor described herein. The term "cancer" refers to any cancer caused by the proliferation of neoplastic cells, such as solid tumors, neoplasms, carcinomas, sarcomas, leukemias, mesotheliomas, lymphomas and the like. For example, cancers include, but are not limited to: mesotheliomas such as mesothelioma of the pleura, peritoneal mesothelioma, and benign fibrous mesothelioma; leukemias, including acute leukemias and chronic leukemias, such as acute lymphocytic leukemia or ALL (acute lymphocytic leukemia), acute non-lymphocytic leukemia, acute myeloid leukemia or AML (acute myeloid leukemia), chronic lymphocytic leukemia or CLL (chronic lymphocytic leukemia), chronic myelogenous leukemia or CML (chronic myelogenous leukemia) and hairy cell leukemia; lymphomas such as cutaneous lymphomas of the T lymphocytes or CTCL (cutaneous lymphomas of the T lymphocytes, for its acronym in English), non-cutaneous lymphomas of the peripheral T lymphocytes, lymphomas associated with the lymphotrophic virus of human T lymphocytes or HTLV (lymphotrophic virus of human T lymphocytes, by its acronym English), such as adult lymphocyte / lymphocyte T lymphocytes or ATLL (leukemia / lymphocyte T lymphocytes in adults), Hodgkin's disease and non-Hodgkin's lymphomas, large cell lymphomas, diffuse lymphoma of large B lymphocytes (DLBCL); Burkitt's lymphoma; primary lymphoma of the central nervous system (CNS); multiple myeloma; solid tumors of childhood, such as brain tumors, neuroblastoma, retinoblast a, Wilm's tumor, bone tumors and soft tissue sarcomas, solid tumors common in adults such as head and neck cancers (eg, oral, laryngeal and esophageal) , genitourinary cancers (eg, prostate, bladder, kidney, uterine, ovarian, testicular, rectal and colon), lung cancer, breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, tumors brain, liver cancer and thyroid cancer. 2. Treatment of Mesothelioma and Lymphoma As demonstrated herein, HDAC inhibitors are useful for the treatment of mesothelioma and various forms of lymphoma, including diffuse large B-cell lymphoma (DLBCL). There are several types of mesotheliomas. Mesotheliomas of the pleura and peritoneum (malignant) include mesothelial tissue tumors associated with exposure to asbestos. Histologically, these tumors are composed of epithelioid, sarcomatoid or fibrous cells, or mixed cell types (also called biphasic type). Benign fibrous mesothelioma is a rare solid tumor of the pleura that produces chest pain, dyspnea, fever and hypertrophic osteoarthropathy. A staging system used for mesothelioma is the Butchart system. This system is based mainly on the extension of the primary mass of the malignant tumor, and divides the mesotheliomas in stages I to IV.

Stage I: Mesothelioma is present on one side of the chest only and is not growing towards the chest wall. Stage II: Mesothelioma invades the chest wall or involves the esophagus (passage of food that connects the throat to the stomach), the heart, or has grown in the pleura on the other side of the chest. Lymph nodes of the chest may be involved too. Stage III: Mesothelioma has grown through the diaphragm into the peritoneum (covering the abdominal cavity) or has spread to the lymph nodes beyond those in the chest. Stage IV: Mesothelioma has spread through the bloodstream to other organs (metastasis).

Another staging system has recently been developed by the International Mesothelioma Interest Group. In this system, information about the tumor, lymph nodes and metastases are combined in a process called staging.

Stage I: The disease is confined within the capsule of the parietal pleura: ipsilateral pleura, lung, pericardium and diaphragm. Stage II: All stage I with positive intrathoracic lymph nodes (Ni or N2). Stage III: Local extension of the disease in the following: pectoral or mediastinal wall; heart or through the diaphragm, peritoneum; with or without involvement of the extrathoracic or contralateral lymph nodes (N3). Stage IV: Distant metastatic disease, There are many different types of lymphoma, and they can be divided into two categories: Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). The main difference between the two is the type of cells involved. There are two main types of lymphocytes: B lymphocytes and T lymphocytes. Most lymphocytes start growing in the bone marrow. The B lymphocytes continue to develop in the bone marrow, while the T lymphocytes go from the bone marrow to the thymus gland and mature in it. Once they are mature, both B lymphocytes and T lymphocytes help the body fight infections. There are more than 20 different types of non-Hodgkin's lymphoma. Diffuse lymphoma of large B lymphocytes is a common type, constituting up to approximately 40% of all cases. It is a cancer of B lymphocytes. Diffuse lymphoma of B lymphocytes can occur at any time from adolescence to old age. It is slightly more common in men than in women. A large cell lymphoma is a lymphoma that is characterized by unusually large cells. Both Hodgkin's disease and NHL are classified by the same categories of stages. The majority of lymphomas in HIV-positive people involve B lymphocytes, as opposed to T lymphocytes. The stage of lymphoma is very important and can help determine the prognosis and the course of treatment. The four stages are: Stage I: There is a site with cancer. There is no implication of the bone marrow. Stage II: There are two sites, amboe > They are above or below the diaphragm. There is no implication of the bone marrow. Stage III: There are sites above and below the diaphragm. There is no involvement of the bone membrane.

Stage IV: The bone marrow is affected or the cancer cells have dispersed outside the lymphatic system. In Hodgkin's disease, the classification by stages is further classified as follows: Classifications of Hodgkin's Disease B: presence of fever, weight loss or night sweats A: absence of fever, weight loss or night sweats E: the disease has spread to the organs outside the lymphatic system Classification by grade For practical purposes, non-Hodgkin's lymphomas are also divided into one of two groups: low and high grade. Low-grade lymphomas usually grow slowly and high-grade lymphomas tend to grow faster. Diffuse lymphoma of B lymphocytes is a high-grade lymphoma. As contemplated herein, the HDAC inhibitors of the present invention are useful for treating all stages of mesothelioma and lymphoma, ie, stages I, II, III and IV indicated above, as well as steps A, B and E of HD. In addition, HDAC inhibitors are useful for treating low and high grade lymphomas.

As demonstrated herein, the HDAC inhibitors of the present invention are particularly useful for treating mesothelioma and diffuse large B-cell lymphoma (DLBCL). 3. Other uses of HDAC inhibitors HDAC inhibitors are effective in treating a wider range of diseases characterized by the proliferation of neoplastic diseases, such as any of the cancers described herein above. However, the therapeutic utility of HDAC inhibitors is not limited to the treatment of cancer. Instead, there is a wide range of diseases for which HDAC inhibitors have been found useful. For example, HDAC inhibitors, in particular SAHA, have been found useful in the treatment of a variety of acute and chronic inflammatory diseases, autoimmune diseases, allergic diseases, diseases associated with oxidative stress and diseases characterized by cellular hyperproliferation. Non-limiting examples are inflammatory conditions of a joint, including rheumatoid arthritis (RA) and psoriatic arthritis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including psoriasis mediated by T lymphocytes) and inflammatory dermatoses, such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (for example, necrotizing, cutaneous and hypersensitivity vasculitis); eosinophilic myositis, eosinophilic fasciitis; cancers with infiltration of leukocytes from the skin or organs, ischemia (for example, brain injury as a result of trauma, epilepsy, hemorrhage or stroke, each of which can lead to neurodegeneration); HIV, heart failure, chronic liver disease, acute or malignant, autoimmune thyroiditis; systemic lupus erythematosus, Sjorgren's syndrome, lung diseases (eg, ARDS); acute pancreatitis; amyotrophic lateral sclerosis or ALS (amyotrophic lateral sclerosis, for its acronym in English); Alzheimer disease; cachexia / anorexia; asthma; atherosclerosis; chronic fatigue syndrome, fever; diabetes (for example, diabetes by insulin or juvenile onset diabetes); glomerulonephritis; rejection of the graft versus the host (for example, in transplants); hemorrhagic shock; hyperalgesia; inflammatory bowel disease; multiple sclerosis; myopathies (eg, metabolism of muscle protein, esp. in sepsis); osteoporosis; Parkinson's disease; pain; premature birth; psoriasis; reperfusion injury; cytokine-induced toxicity (eg, septic shock, endotoxic shock); Lateral effects of radiation therapy, temporary mandibular joint disease, tumor metastasis or an inflammatory condition resulting from distention, sprain, cartilage damage, trauma such as burn, orthopedic surgery, infection or other disease processes. Allergic diseases and conditions, including, but not limited to, allergic respiratory diseases such as asthma, allergic rhinitis, lung hypersensitivity diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), hypersensitivity of the type delayed, interstitial lung diseases or ILD (interstitial lung diseases, for its acronym in English) (for example, idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, multiple sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (eg, penicillin, cephalosporins), allergies to insect bites and the like. For example, it has been found that HDAC inhibitors, and in particular SAHA, are useful in the treatment of a variety of neurodegenerative diseases, a non-exhaustive list of which is: I. Disorders characterized by progressive dementia in the absence of other prominent neurological signs, such as Alzheimer's disease; senile dementia of the Alzheimer type and Pick disease (lobular atrophy). II. Syndromes that combine progressive dementia with other prominent neurological abnormalities, such as A) syndromes that appear mainly in adults (eg, Huntington's disease, multiple system atrophy that combines dementia with ataxia and / or manifestations of Parkinson's disease, progressive supranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy body disease and corticodentatonigral degeneration) and B) syndromes that occur mainly in children or young adults (eg, Hallervorden-Spatz disease and progressive familial myoclonic epilepsy). III. Syndromes gradually develop abnormalities of posture and movement such as parkinsonism (Parkinson's disease), estratonigral degeneration, progressive supranuclear palsy, torsional dystonia (torsion spasm); muscle dystonia deforming), spasmodic torticollis and other dyskinesis, familial tremor and Gilles de la Tourette syndrome. IV. Progressive ataxia syndromes such as cerebellar degenerations (eg, cerebellar cortical degeneration and olivopontocerebellar atrophy or OPCA (olivopontocerebellar atrophy)) and spinocerebellar degeneration (Friedreich's ataxia and related disorders). V. Autonomic central nervous system failure syndrome (Shy-Drager syndrome). SAW . Syndromes of weakness and muscular wasting without sensory changes (motor neuron disease such as amyotrophic lateral sclerosis, spinal muscular atrophy (eg, childhood spinal muscular atrophy) (Werdnig-Hoffman), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander) and other forms of familial muscular atrophy), primary lateral sclerosis and hereditary spastic paraplegia. VII. Syndromes that combine muscle weakness and wasting with sensory changes (progressive neural muscle atrophy, chronic familial polyneuropathies) such as peroneal muscle atrophy (Charcot-Marie-Tooth), hypertrophic interstitial polyneuropathy (Dejerine-Sottas) and miscellaneous forms of chronic progressive neuropathy. VIII. Syndromes of progressive visual loss such as pigment degeneration of the retina (retinitis pigmentosa) and hereditary optic atrophy (Leber's disease). Combination Therapy The methods of the present invention may also comprise administering initially to the subject, an antitumor agent to render the neoplastic cells of the subject resistant to the antitumor agent and subsequently administering an effective amount of any of the compositions of the present invention, effective to induce selectively, terminal differentiation, arrest of cell growth and / or apoptosis of such cells, or to treat cancer or provide chemoprevention. The antitumor agent can be one of numerous agents for chemotherapy, such as an alkylating agent, an antimetabolite, a hormonal agent, an antibiotic, colchicine, an alkaloid vinca, L-asparaginase, procarbazine, hydroxyurea, mitotane, nitrosoureas or an imidazole carboxamide. Suitable agents are those agents that promote the demoralization of tubulin. Preferably, the antitumor agent is colchicine or an alkaloid vinca; vinblastine and vincristine are especially preferred.

In embodiments wherein the antitumor agent is vincristine, the cells are preferably treated so that they are resistant to vincristine at a concentration of about 5 mg / ml. The treatment of the cells to render them resistant to an antitumor agent can be effected by contacting the cells with an agent for a period of at least 3 to 5 days. The contacting of the resulting cells with any of the above compounds is carried out as previously described. Other than the above chemotherapy agents, the compounds may also be administered in conjunction with radiation therapy.

Dosages and Dosage Schemes The dosage regimen that uses HDAC inhibitors can be selected according to a variety of factors including the type, species, age, weight, sex and type of cancer being treated; the severity (ie, stage) of the cancer to be treated; the administration route; the renal and hepatic function of the patient and the particular compound or salt thereof that is used. A physician or veterinarian with ordinary experience can easily determine and prescribe the effective amount of the drug required to treat, for example, to prevent, inhibit (totally or partially) or arrest the progress of the disease. Suitable dosages are a total daily dosage of between about 25-4000 mg / m2 administered orally once a day, twice a day or three times a day, continuously (every day) or intermittently (e.g. -5 days a week) . For example, SAHA or any of the HDAC inhibitors can be administered in a total daily dose of up to 800 mg. The HDAC inhibitor can be administered once a day (QD), or divided into multiple daily doses, such as twice a day (BID), and three times a day (TID). The HDAC inhibitor can be administered at a total daily dosage of up to 800 mg, for example, 150 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg, which can be administered in a daily dose or can be divided into multiple doses. daily doses as described above. Preferably, the administration is oral. In a modality, the composition is administered once a day at a dose of approximately 200-600 mg. In another embodiment, the composition is administered twice a day at a dose of approximately 200-400 mg. In another embodiment, the composition is administered twice daily at a dose of about 200-400 mg intermittently, for example, three, four or five days per week. In another embodiment, the composition is administered three times a day at a dose of approximately 100-250 mg. In one modality, the daily dose is 200 mg, which can be administered once a day, twice a day, or three times a day. In one modality, the daily dose is 300 mg, which can be administered once a day, twice a day or three times a day. In one modality, the daily dose is 400 mg, which can be administered once a day or twice a day. In one embodiment, the daily dose is 150 mg, which can be administered twice a day or three times a day. In addition, the administration can be continuous, that is, every day or intermittently. The terms "intermittent" or "intermittently," as used herein, mean stopping and starting at regular or irregular intervals. For example, intermittent administration of an HDAC inhibitor may be administration one to six days per week or may mean administration in cycles (eg, daily administration for two to eight consecutive weeks, then a rest period without administration). for up to a week) or may mean administration on alternate days. The SAHA or any of the HDAC inhibitors can be administered to the patient at a total daily dosage of between 25-4000 mg / m2. A currently preferred treatment protocol comprises continuous (i.e., daily) administration, once, twice or three times daily at a total daily dose in the range of about 200 mg to about 600 mg. Another currently preferred treatment protocol comprises intermittent administration of three to five days a week, once, twice or three times a day at a total daily dose in the range of about 200 mg to about 600 mg. In a particular embodiment, the HDAC inhibitor is administered continuously once a day at a dose of 400 mg or twice a day at a dose of 200 mg. In another particular embodiment, the inhibitor of HDAC is administered intermittently three days a week, once a day at a dose of 400 mg or twice a day at a dose of 200 mg. In another particular embodiment, the HDAC inhibitor is administered intermittently four days a week, once a day at a dose of 400 mg or twice a day at a dose of 200 mg. In another particular embodiment, the inhibitor of HDAC is administered intermittently five days a week, once a day at a dose of 400 mg or twice a day at a dose of 200 mg. In a particular embodiment, the HDAC inhibitor is administered continuously once a day at a dose of 600 mg, twice a day at a dose of 300 mg or three times a day at a dose of 200 mg. In another particular embodiment, the inhibitor of HDAC is administered intermittently three days a week, once a day at a dose of 600 mg, twice a day at a dose of 300 mg or three times a day at a dose of 200 mg. In another particular embodiment, the inhibitor of HDAC is administered intermittently four days a week, once a day at a dose of 600 mg, twice a day at a dose of 300 mg or three times a day at a dose of 200 mg. In another particular embodiment, the inhibitor of HDAC is administered intermittently five days a week, once a day at a dose of 600 mg, twice a day at a dose of 300 mg or three times a day at a dose of 200 mg. In addition, the HDAC inhibitor can be administered according to any of the schemes described above, consecutively for a few weeks, followed by a rest period. For example, the HDAC inhibitor can be administered according to any of the schemes described above for two to eight weeks, followed by a rest period of one week or two times a day at a dose of 300 mg for three to five days a week. In another particular embodiment, the HDAC inhibitor is administered three times a day for two consecutive weeks, followed by a week of rest. It will be apparent to a person skilled in the art that the various dosages and dosage schemes described herein simply state the specific embodiments and should not be construed as limiting the broad scope of the invention. Any permutations, variations and combinations of dosages and dosage schemes are included within the scope of the present invention. The present invention provides a safe, daily dosage regimen of these formulations, which is safe to follow and adhere to. The formulations of the present invention are therefore useful to selectively induce terminal differentiation, arrest of cell growth and / or apois of neoplastic cells and therefore, aid in the treatment of tumors in patients.

Pharmaceutical Compositions The compounds of the invention, and the pharmaceutically acceptable derivatives, fragments, analogs, homologs, salts or hydrates thereof, can be incorporated into pharmaceutical compositions suitable for oral administration, together with a pharmaceutically acceptable carrier or excipient. Such compositions typically comprise a therapeutically effective amount of any of the above compounds, and a pharmaceutically acceptable carrier. Preferably, the effective amount is an amount effective to selectively induce the terminal differentiation of suitable neoplastic cells and less than the amount that causes toxicity in a patient. The compositions of the present invention can be formulated in any unit dosage form (liquid or solid) suitable for oral administration, for example, in the form of a granule, a tablet, a coated tablet, a capsule, a gelatin capsule, a solution, a suspension or a dispersion. In a currently preferred mode, the composition is in the form of a gelatin capsule. Any inert excipient that is commonly used as a carrier or diluent can be used in the formulations of the present invention, such as for example, a gum, a starch, a sugar, a cellulosic material, an acrylate or mixtures thereof. A preferred diluent is microcrystalline cellulose. The compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate), and in addition, may comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, an agent that increases the viscosity or any combination thereof. In addition, the compositions of the present invention may be in the form of controlled release or immediate release formulations. One embodiment is a pharmaceutical composition for oral administration, comprising an HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. Another modality has SAHA as the inhibitor of HDAC. Another embodiment comprises 50-70% by weight of an HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, 20-40% by weight of microcrystalline cellulose, 5-15% by weight of croscarmellose sodium and 0.1-5% by weight. Weight of magnesium stearate. Another embodiment comprises approximately 50-200 mg of an HDAC inhibitor.

In one embodiment, the pharmaceutical compositions are administered orally, and are therefore formulated in a form suitable for oral administration, i.e., as a solid or liquid preparation. Suitable solid oral formulations include tablets, capsules, pills, granules, pellets and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment of the present invention, the composition is formulated in a capsule. According to this embodiment, the compositions of the present invention further comprise the HDAC inhibitor active compound and the inert carrier or diluent, a hard gelatin capsule. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and those that delay absorption and the like, compatible with pharmaceutical administration, such as sterile, pyrogen-free water. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such diluent carriers include, but are not limited to, water, saline, ringer's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils can also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as some conventional medium or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. The solid carriers / diluents include, but are not limited to, a gum, a starch (e.g., corn starch, pregelatinized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. , microcrystalline cellulose), an acrylate (e.g., polymethyl acrylate), calcium carbonate, magnesium oxide, talc or mixtures thereof. For liquid formulations, pharmaceutically acceptable carriers can be solutions, aqueous or non-aqueous, suspensions, emulsions or oils. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol and injectable organic esters, such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including physiological saline and buffered medium. Examples of oils are those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil and fish liver oil. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, physiological saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid or EDTA (ethylenediaminetetraacetic acid, for its acronym in English); buffers such as acetates, citrates or phosphates, and agents for tonicity adjustment, such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. In addition, the compositions may comprise binders (e.g., acacia, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., corn starch, potato starch)., alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers (for example, tris-HCl, acetate, phosphate) of various pH and ionic strengths, additives such as albumin or gelatin for avoid absorption to surfaces, detergent (eg, Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (eg, sodium lauryl sulfate), permeation enhancers, agents solubilizers (e.g., glycerol, polyethylene glycerol), a glidant (e.g., colloidal silicon dioxide), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose), agents that increase viscosity (eg, carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum), sweeteners (eg, sucrose, aspartame, citric acid), flavoring agents (e.g., peppermint, methyl salicylate or orange flavoring), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate) , flow aids (eg, colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymeric coatings (e.g. poloxamers or poloxamines), coating and film forming agents (for example, ethyl cellulose, acrylates, polymethacrylates) and / or adjuvants. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for the preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used (including liposomes directed to cells infected with monoclonal antibodies to viral antigens) as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811. It is especially advantageous to formulate the oral compositions in a unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein, refers to physically discrete units suitable as unit dosages for the subject to be treated; each unit contains a predetermined amount of an active compound, calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention is dictated and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the inherent limitations in the art of the composition of such active compound for the treatment of individuals. The pharmaceutical compositions can be included in a container, package or dispenser together with instructions for administration. Daily administration can be repeated continuously for a period of several days to several years. Oral treatment can continue for between one week and the patient's life. Preferably, administration takes place for five consecutive days, after which time the patient can be evaluated to determine if additional administration is required. The administration can be continuous or intermittent, that is, treatment during a number of consecutive days followed by a rest period. The compounds of the present invention can be administered intravenously on the first day of treatment, with oral administration on the second day and all subsequent consecutive days. The compounds of the present invention can be administered for the purpose of preventing the progression of the disease or stabilizing tumor growth. The preparation of pharmaceutical compositions containing an active component is well understood in the art, for example, by mixing, granulating or tabletting processes. The therapeutic active ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, the active agents are mixed with additives customary for this purpose, such as vehicles, stabilizers or inert diluents, and are converted by customary methods into forms suitable for administration, such as tablets, coated tablets, capsules hard and soft gelatin, aqueous, alcoholic or oily solutions and the like, as detailed above. The amount of the compound administered to the patient is less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of the compound that is administered to the patient is less than the amount that causes a concentration of the compound in the patient's plasma to equal or exceed the toxic level of the compound. Preferably, the concentration of the compound in the patient's plasma is maintained at approximately 10 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 25 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 50 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 100 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 500 nM. In another modality, the concentration of the compound in the patient's plasma is maintained at approximately 1000 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 2500 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at approximately 5000 nM. It has been found with the HMBA that administration of the compound in an amount of about 5 gm / m2 / day to about 30 gm / m2 / day, in particular about 20 gm / m2 / day, is effective without causing toxicity in the patient. The optimum amount of the compound to be administered to the patient in the practice of the present invention will depend on the particular compound used and the type of cancer being treated. In a currently preferred embodiment of the present invention, the pharmaceutical composition comprises a histone deacetylase inhibitor (HDAC); microcrystalline cellulose as a carrier or diluent; croscarmellose sodium as a disintegrant and magnesium stearate as a lubricant. In another currently preferred embodiment, the HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA). Another currently preferred embodiment of the invention is a solid formulation of SAHA with microcrystalline cellulose, NF (Avicel Ph 101), croscarmellose sodium, NF (AC-Di-Sol) and magnesium stearate, NF, contained in a gelatin capsule. The percentage of the active ingredient and the various excipients in the formulation may vary. For example, the composition may comprise between 20 and 90%, preferably between 50-70% by weight of histone deacetylase (HDAC). In addition, the composition may comprise between 10 and 70%, preferably between 20-40% by weight of microcrystalline cellulose as a carrier or diluent. In addition, the composition may comprise between 1 and 30%, preferably 5-15% by weight of croscarmellose sodium as a disintegrant. In addition, the composition may comprise between 0.1-5% by weight of magnesium stearate as a lubricant. In another preferred embodiment, the composition comprises about 50-200 mg of the HDAC inhibitor (e.g., 50 mg, 100 mg and 200 mg for the HDAC inhibitor, e.g., SAHA). In a particularly preferred embodiment, the composition is in the form of a gelatin capsule. A currently preferred embodiment is 200 mg of solid SAHA with 89.5 mg of microcrystalline cellulose, 9 mg of croscarmellose sodium and 1.5 mg of magnesium stearate, contained in a gelatin capsule.

Methods ± n vitro The present invention also provides in vitro methods for selectively inducing terminal differentiation, the arrest of cell growth and / or apoptosis of neoplastic cells, for example, lymphoma cells, thereby inhibiting the proliferation of such cells by contacting the cells with an effective amount of an HDAC inhibitor, eg, SAHA, or a pharmaceutically acceptable salt or hydrate thereof. The present invention also provides in vitro methods for inhibiting the activity of a histone deacetylase, by histone deacetylase with an effective amount of an HDAC inhibitor, eg, SAHA, or a pharmaceutically acceptable salt or hydrate thereof. Although the methods of the present invention can be practiced in vitro, it is contemplated that the preferred embodiment for methods of selectively inducing terminal differentiation, arresting cell growth and / or apoptosis of neoplastic cells, and inhibiting HDAC , will comprise contacting the cells in vivo, that is, by administering the compounds to a subject harboring neoplastic cells or tumor cells, in need of treatment. Thus, the present invention also provides methods for selectively inducing the terminal differentiation, the arrest of cell growth and / or the apoptosis of neoplastic cells, for example, lymphoma cells in a subject, thereby inhibiting the proliferation of such cells in the subject, administering to the subject a pharmaceutical composition comprising an effective amount of an HDAC inhibitor, eg, SAHA, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent. An effective amount of an HDAC inhibitor in the present invention can be up to a total daily dose of 800 mg. The present invention also provides methods for inhibiting the activity of a histone deacetylase in a subject by administering to the subject a pharmaceutical composition comprising an effective amount of an HDAC inhibitor, eg, SAHA, or a pharmaceutically acceptable salt or hydrate thereof. , and a pharmaceutically acceptable carrier or diluent. An effective amount of an HDAC inhibitor in the present invention can be up to a total daily dose of 800 mg.

EXAMPLES The invention is illustrated in the following Examples. This section is set forth to assist in the understanding of the invention, but is not intended, and should not be construed as limiting the invention in any way, as set forth in the claims that follow thereafter.

EXAMPLE 1 Synthesis of the SAHA The SAHA can be synthesized according to the method set forth below, or according to the method set forth in U.S. Patent 5,369,108, the content of which is incorporated by reference in its entirety or in accordance with any other method.

Synthesis of SAHA Step 1 - Synthesis of suberanilic acid In a 22 L flask, 3,500 g (20.09 moles) of suberic acid were placed, and the acid was melted with heat. The temperature was raised to 175 ° C, and then 2.040 g (21.92 moles) of aniline was added. The temperature was raised to 190 ° C and maintained at that temperature for 20 minutes. The melt was poured into a Nalgene tank containing 4.017 g of potassium hydroxide dissolved in 50 L of water. The mixture was stirred for 20 minutes after the addition of the melt. The reaction was repeated on the same scale, and the second most melted was poured into the same potassium hydroxide solution. After the mixture was completely stirred, the agitator was turned off and the mixture allowed to settle. The mixture was then filtered through a pad of Celite (4,200 g) the product was filtered to remove the neutral by-product (from the attack of the aniline at both ends of the suberic acid). The filtrate contained the salt of the product, and also the unreacted salt of the suberic acid. The mixture was allowed to settle because the filtration was very slow, taking several days. The filtrate was acidified using 5 L of concentrated hydrochloric acid; the mixture was stirred for one hour, and then allowed to settle overnight. The product was collected by filtration, and washed in the funnel with deionized water (4 x 5 L). The wet filter cake was placed in a 72 L flask with 44 L of deionized water, the mixture was heated to 50 ° C, and the solid was isolated by hot filtration (the desired product was contaminated with suberic acid, which It has a much higher solubility in hot water Several hot triturations were made to remove the suberic acid The product was verified by NMR [D6DMSO], to verify the elimination of suberic acid). The hot crushing was repeated with 44 L of water at 50 ° C. The product was again isolated by filtration, and rinsed with 4 L of hot water. It was dried over the weekend in a vacuum oven at 65 ° C using a Nash pump as the source of the vacuum (the Nash pump is a pump with a liquid ring (water), and it draws a vacuum of approximately 736.6 millimeters (29 inches) of mercury, an intermittent argon purge was used to help remove the water); 4,182.8 g of suberanilic acid were obtained. The product still contained a small amount of suberic acid; therefore, the hot crushing was done in portions at 65 ° C, using approximately 300 g of the product at a time. Each portion was filtered and rinsed thoroughly with the addition of hot water (a total of about 6 L). This was repeated to purify the entire lot. This completely eliminated the suberic acid from the product. The solid product was combined in a flask and stirred with 6 L of methanol / water (1: 2), and then isolated by filtration and air dried on the filter over the weekend. It was placed in trays and dried in a vacuum oven at 65 ° C for 45 hours, using the Nash pump and an argon purge. The final product had a weight of 3,278.4 g (32.7% yield).

Step 2 - Synthesis of Methyl Suberanilate H O O H O O -N I C II- - (CH 2) 6 -C OH -N C II (CH 2) β C II OCH 3 To a 50 L flask equipped with a mechanical stirrer and a condenser were placed 3,229 g of suberanilic acid from the previous step, 20 L of methanol, and 398.7 g of Dowex 50WX2-400 resin. The mixture was heated to reflux and refluxed for 18 hours. The mixture was filtered to remove the beads from the resin, and the filtrate was brought to a residue in a rotary evaporator. The residue from the rotary evaporator was transferred into a 50 L flask equipped with a condenser and a mechanical stirrer. To the flask was added 6 L of methanol, and the mixture was heated to give a solution. Next, 2 L of deionized water was added and the heat stopped. The stirred mixture was allowed to cool, and then the flask was placed in an ice bath, and the mixture was cooled. The solid product was isolated by filtration, and the filter cake was rinsed with 4 L cold methanol / water (1: 1). The product was dried at 45 ° C in a vacuum oven using a Nash pump for a total of 64 hours to provide 2,850.2 g (84% yield) of methyl suberanilate, CSL Lot # 98-794-92-3 1.

Step 3 - Synthesis of crude SAHA -? N? C (CH2) 6 fC OCH3 + NH.OH »HCl« -? N? C (CH2) S? C TN OH To a 50 L flask with a mechanical stirrer, a thermocouple and an inlet for an inert atmosphere, were added 1,451.9 g of hydroxylamine hydrochloride, 19 L of anhydrous methanol and 3.93 L of a 30% sodium methoxide solution in methanol Then, the flask was charged with 2,748.0 g of methyl suberanilate, followed by 1.9 L of a 30% sodium methoxide solution in methanol. The mixture was allowed to stir for 16 hours and 10 minutes. Approximately half of the reaction mixture was transferred from the reaction flask (flask 1) to a 50 L flask (flask 2), equipped with a mechanical stirrer. Next, 27 L of deionized water was added to flask 1 and the mixture was stirred for 10 minutes. The pH was taken using a pH meter; the pH was 11.56. The pH of the mixture was adjusted to 12.02 by the addition of 100 ml of a 30% sodium methoxide solution in methanol; this provided a clear solution (the reaction mixture at this time contained a small amount of solid.The pH was adjusted to provide a clear solution, from which the product would precipitate). The reaction mixture in flask 2 was diluted in the same manner; 27 L of deionized water was added, and the pH was adjusted by the addition of 100 ml of a 30% sodium methoxide solution to the mixture, to provide a pH of 12.01 (clear solution). The reaction mixture in each flask was acidified by the addition of glacial acetic acid to precipitate the product. The flask 1 had a final pH of 8.98, and the flask 2 had a final pH of 8.70. The product from both flasks was isolated by filtration using a Buchner funnel and a filter cloth. The filter cake was washed with 15 L of deionized water, and the funnel was covered and the product partially dried in the funnel under vacuum for 15.5 hours. The product was removed and placed in five glass trays. The trays were placed in a vacuum oven, and the product was dried at constant weight. The first drying period was 22 hours at 60 ° C, using a Nash pump as the empty source with an argon purge. The trays were removed from the vacuum oven and weighed. The trays were returned to the oven and the product was dried for an additional 4 hours and 10 minutes using an oil pump as the vacuum source and without argon purge. The material was packed in double polyethylene bags of 0.1016 millimeters (4 mils), and placed in an external plastic container. The final weight after taking the samples was 2633.4 g (95.6%).

Step 4 - Recrystallization of crude SAHA The crude SAHA was recrystallized from methanol / water. A 50 L flask with a mechanical stirrer, a thermocouple, a condenser and an inlet for an inert atmosphere was charged with the crude SAHA to be crystallized (2.525.7 g), followed by 2.625 ml of deionized water and 15.755 ml of methanol. The material was heated to reflux to provide a solution. Then, 5.250 ml of deionized water was added to the reaction mixture. The heat stopped, and the mixture was allowed to cool. When the mixture had cooled sufficiently so that the flask could be handled safely (28 ° C), the flask was removed from the heating mat, and placed in a tub for use as a cooling bath. Ice / water was added to the tank to cool the mixture to -5 ° C. The mixture was kept below that temperature for 2 hours. The product was isolated by filtration, and the filter cake was washed with 1.5 L cold methanol / water (2: 1). The funnel was covered, and the product was partially dried under vacuum for 1.75 hours. The product was removed from the funnel and placed in 6 glass trays. The trays were placed in a vacuum oven and the product was dried for 64.75 hours at 60 ° C using a Nash pump as the vacuum source and using an argon purge. The trays were removed for weighing and returned to the oven and dried for an additional 4 hours at 60 ° C to give a constant weight. The vacuum source for the second drying period was in an oil pump and no argon purge was used. The material was packed in double polyethylene bags of 0.1016 millimeters (4 mils), and placed in an external plastic container. The final weight after taking the samples was 2540.9 g (92.5%).

EXAMPLE 2 Oral Dosing of Suberoylanilide Hydroxamic Acid (SAHA) Background: Treatment with hybrid polar differentiation agents resulted in inhibition of growth of cell lines derived from a solid human tumor and xenografts. The effect is mediated in part by the inhibition of histone deacetylase. SAHA is a potent inhibitor of histone deacetylase that has been shown to induce growth arrest of tumor cells, differentiation and apoptosis in the laboratory and preclinical studies. Objectives: To define a SAHA safe daily oral regimen that can be used in Phase II studies. In addition, the pharmacokinetic profile of the oral SAHA formulation was evaluated. The oral bioavailability of SAHA in humans in the fasting state vs. without fasting and the anti-tumor effects of the treatment. In addition, the biological effects of SAHA on normal tissues and tumor cells were assessed and responses were documented with respect to histone acetylation levels. Patients: Patients with solid tumors in advanced stage, primary or metastatic histologically documented adults, who are difficult to treat with standard therapy or for whom there is no standard curative therapy. Patients must have a Kamofsky Performance Status of > 70%, and a suitable hematologic, hepatic and renal function. Patients should have at least four weeks from any prior chemotherapy, radiation therapy or other anticancer drugs in research. Dosage Scheme: On the first day, patients were first treated with 200 mg of SAHA administered intravenously. Starting on the second day, patients were treated with daily doses of oral SAHA according to Table 1. Each cohort received a different dose of SAHA. "QD" indicates dosing once a day; "Q12 hours" indicates dosing twice a day. For example, patients in Cohort IV received two doses of 800 mg SAHA per day. The doses were administered to the patients daily and continuously. Blood samples were taken on day one and on day 21 of the oral treatment. Patients stopped treatment with oral SAHA due to disease progression, tumor regression, unacceptable side effects, or treatment with other therapies.

Table 1: Oral SAHA Dosage Schedule Results: The comparison of serum plasma levels shows a high bioavailability of orally administered SAHA, when the patient fasted and when the patient did not fast, in comparison with the SAHA administered intravenously (SAHA IV). The "AUC" is an estimate of the bioavailability of SAHA at (ng / ml) minute, where 660 ng / ml equals 2.5 μM SAHA. The AUC taken together with the half-life (t_./2), shows that the total bioavailability of oral SAHA is better than that of SAHA IV. Cmax is the maximum concentration of SAHA observed after administration. SAHA IV was administered at 200 mg infused for two hours. Oral SAHA was administered in a single 200 mg capsule. Tables 2 and 3 summarize the results of an HPLC assay (LCMS using a deuterated standard), which quantifies the amount of SAHA in the patients' blood plasma versus time; using acetylated histone-4 (a- AcH4) as a marker.

Table 2: Serum Plasma Levels of Oral-Patient SAHA # 1 Table 3: Serum Plasma Levels of Oral-Patient SAHA # 2 Figures 1 to 8 are slides of the HPLC showing the amount of -AcH4 in patients in Cohorts I and II, measured up to 10 hours after receiving the oral dose, compared to the levels of a-AcH4 when the SAHA It is administered intravenously. Figure 9 shows the average plasma concentration of SAHA (ng / ml) at the indicated measurement points after administration. Figure 9A: Oral dose (200 mg and 400 mg) under fasting on Day 8. Figure 9B: Oral dose (200 mg and 400 mg) with food on Day 9. Figure 9C: IV dose on day 1. Figure 10 shows the apparent half-life of an oral dose of SAHA of 200 mg and 400 mg, on Days 8, 9 and 22. Figure 11 shows the AUC (ng / ml / hour) of an oral SAHA dose of 200 mg and 400 mg, on Days 8, 9 and 22. Figure '12 shows the bioavailability of SAHA after an oral dose of 200 mg and 400 mg, on Days 8, 9 and 22.

EXAMPLE 3 Oral Dosing of Suberoylanilide Hydroxamic Acid (SAHA) -Increase of Dose In another experiment, twenty-five patients with solid tumors in the A branch were enrolled, thirteen patients with Hodgkin's or non-Hodgkin's lymphomas enrolled in the B branch, and a patient with acute leukemia and a patient with myelodysplastic syndrome enrolled in branch C, as shown in Table 4.

Table 4: Scheme of Increase in Dosage and Number of Patients in Each Dose Level * Branch A = solid tumor, branch B = lymphoma, branch C = leukemia Results: Among the eleven patients treated in Cohort II, one patient experienced DLT of grade 3 diarrhea and grade 3 dehydration during the first treatment cycle. Nine patients entered Cohort III. Two patients were not evaluated for 28-day toxicity assessment due to early termination of the study due to rapid progression of the disease. Of the remaining seven patients, five experienced DLT during the first treatment cycle: diarrhea / dehydration (n = 1), fatigue / dehydration (n = 1), anorexia (n = 1), dehydration (n = 1) and anorexia / dehydration (n = 1). These five patients recovered in about a week after the study drug was maintained. Subsequently, the dose was reduced to 400 mg QD, which appeared to be well tolerated. The median number of days with 400 mg BID for all patients in Cohort III was 21 days. Based on these findings, it was considered that the dosing schedule of 400 mg ql2 hours had exceeded the maximum tolerated dose. After amendment of the protocol, the accumulation continued in cohort IV at a dose of 600 mg once a day. Of the seven patients enrolled in the IV cohort, two were not evaluated for 28-day toxicity assessment due to early termination of the study due to a progression of the disease. Three patients experienced DLT during the first treatment cycle: anorexia / dehydration / fatigue (n = 1), and diarrhea / dehydration (n = 2). Therefore, it was considered that the 600 mg dose had exceeded the maximum tolerated dose and the 400 mg dose once a day was defined as the maximum tolerated dose for oral administration once a day. The protocol was amended to evaluate the levels of additional doses of a dosing schedule twice daily with 200 mg BID and 300 mg BID administered continuously. The interim pharmacokinetic analysis was based on 18 patients treated with the dose levels of 200 mg QD, 4Q0 mg QD and 400 mg BID. In general, the average estimates of Cmax and AUC? Nf of SAHA administered orally under fasting conditions or with food, were increased proportionally with a dose in the range of a dose of 200 mg to 400 mg. In general, the fraction of AUC? Nf due to extrapolation was 1% or less. The estimated means for apparent half-life were available through the dose groups under fasting or with food conditions, ranging from 61 to 114 minutes. The mean Cmax estimates range from 233 ng / ml (0.88 μM) to 570 ng / ml (2.3 μM). The bioavailable fraction of the SAHA, calculated from the AUCinf values after the IV and oral infusion routes, was found to be approximately 0.48. Peripheral blood mononuclear cells were collected before therapy, immediately after infusion and 2-10 hours after oral ingestion of SAHA capsules to assess the effect of SAHA on the degree of acetylation of histone in a normal host cell. Histones were isolated and probed with antiacetylated histone antibody (H3) followed by secondary HRP antibody. Preliminary analyzes showed an increase in accumulation of acetylated histones in peripheral mononuclear cells that could be detected up to 10 hours after ingestion of SAHA capsules at a dose level of 400 mg per day. Thirteen patients continued treatment for 3-12 months with responsive or stable disease: thyroid (n = 3), sweat gland (n = 1), kidney (n = 2), larynx (n = 1), prostate (n = 1), Hodgkin's lymphoma (n = 2), non-Hodgkin's lymphoma (n = 2), and leukemia (n = 1). Six patients had tumor shrinkage on C scans. Three of these six patients met the partial response criterion (one patient with metastatic laryngeal cancer and two patients with non-Hodgkin's lymphoma). These partial responses occurred at the dose levels of 400 mg BID (n = 2) and 600 mg QD (n = 1). The dosages described above were also administered twice daily intermittently. Patients received SAHA twice a day, three to five days per week. The patient's response was observed with the administration of SAHA twice daily at 300 mg for three days a week.

EXAMPLE 4 Intravenous Dosage of SAHA Table 5 shows a dosing schedule for patients receiving SAHA intravenously. Patients begin in Cohort I, receiving 300 mg / m2 of SAHA for five consecutive days in a week for a week, for a total dose of 1500 mg / m2. The patients were observed for a period of two weeks, and continued to Cohort II, then progressed through the Cohorts unless the treatment was terminated due to disease progression, tumor regression, unacceptable side effects or the patient received another treatment.

Table 5: Increase in Standard Dose for SAHA Administered intravenously fHematological patients started at a dose III level.

EXAMPLE 5 Treatment of Mesothelioma with SAHA Three patients with mesothelioma enrolled in Phase I studies with SAHA. Patients were given SAHA twice a day at a dose of 300 mg or 400 mg for three days a week. A partial response was observed after treatment with SAHA according to the previous regimen for 6 months. Figure 13 is a CT scan of a mesothelioma tumor of a patient, before (PRE-left panel) and after (POST-right panel) of SAHA treatment twice a day at a dose of 300 mg three days a week for 6 months . The data show that SAHA is effective in treating mesothelioma tumors in patients.

EXAMPLE 6 Treatment of Diffuse Lymphoma of Large B-lymphocytes (DLBCL) with SAHA A phase I study of oral SAHA was performed in sixty-eight patients with advanced cancer, including hematologic cancer and solid tumors. Patients received SAHA orally (po) at 200, 400 or 600 mg QD daily, 200, 300 or 400 mg BID daily, 300 mg or 400 mg (BID) intermittently 3 days a week, or 100 mg TID (2 weeks). Seven patients with diffuse Large B-Lymphocyte Lymphoma (DLBCL) were enrolled in the study.

Results: A. Complete response (CR) to treatment with oral SAHA: One patient, a 66-year-old woman, diagnosed with stage I small lymphocytic (plasmacytoid) lymphoma; received bleomycin, CPT and local XRT with complete response; developed recurrent disease (breast / subcutaneous nodule, and pulmonary nodules) and was treated with Fludarabine / mitoxantrone, rituximab, CEPT, doxorubicin liposomal. It was transformed to DBLCL, subsequently treated with Rituximab, Anti-Bl, CTX / liposomal doxorubicin / pred / vincristine. The patient referred to Phase I with oral SAHA with subcutaneous nodules, diffuse adenopathy, large gastrohepatic mass, bilateral pulmonary nodules, involvement of the bone marrow by the lymphoma. The patient received SAHA at 400 mg BID for 1 month, the dose was subsequently reduced to 400 mg QD, and she was on SAHA treatment for a total of 1 year.

Figure 14 is a CT scan taken before (Figure 14A) and after (Figure 14B) of 2 months of treatment with SAHA, demonstrating the shrinkage of the Gastrohepatic mass. A complete resolution of the Gastrohepatic mass was observed after 2 cycles of treatment (4 months). Figure 15 is a PET scan taken before (Figure 15A) and after (Figure 15B) of 2 months of treatment with SAHA, demonstrating tumor regression after treatment. A complete response (CR) was achieved (fulfilling the Cheson Criteria) after 4 months of treatment with SAHA. The complete response (CR) has lasted up to 14 months, and the patient is still in CR.

B. Partial Response (PR) to treatment with oral SAHA: A patient with DLBCL received 600 mg QD of SAHA orally, and was in treatment with SAHA for a total of five months. Figure 16 is a CT scan taken before (Figure 16A) and after (Figure 16B) 1 month of treatment with SAHA, demonstrating shrinkage of the tumor after treatment. A partial response (RR) was achieved (fulfilling Cheson's Criterion) after 5 months of treatment with SAHA.

C. Tumor regression after treatment with oral SAHA: One patient, a 75-year-old woman, who initially presented a follicular lymphoma with evidence of transformation. It was originally treated with 6 cycles of cyclophosphamide, doxorubicin, etoposide and prednisone. He then underwent a splenectomy, which showed DLBCL, for which he was treated with Zevalin. He later received two courses of rituximab and finally pentostatin, cyclophosphamide and rituximab. The patient received 200 mg BID of SAHA orally, and was on SAHA treatment for six months. Figure 17 is a PET scan taken before (Figure 17A) and after (Figure 17B) of 2 months of treatment with SAHA. As observed, the patient achieved an excellent negative response with PET after 2 months with SAHA with continuous reduction in her disease. Although this invention has been shown and described particularly with reference to the preferred embodiments thereof, it will be understood by those skilled in the art that various changes and details may be made therein, without departing from the meaning of the disclosed invention. The scope of the invention includes the subject matter of the following claims. All patents, patent applications and publications cited herein are incorporated herein by reference.

References 1. Sporn, M.B., Roberts, A.B., and Driscoll, J.S. (1985) in Cancer: Principles and Practice of Oncology, eds. Hellman, S., et al., Ed. 2, (J.B. Lippincott, Philadelphia), P. 49. 2. Breitman, T.R., Selonick, S.E., and Collins, S.J. (1980) Proc. Nati Acad. Sci. USA 77: 2936-2940. 3. Olsson, I. L. and Breitman, T. R. (1982) Cancer Res. 42: 3924-3927. 4. Schwartz, E. L. and Sartorelli, A.C. (1982) Cancer Res. 42: 2651-2655. 5. Marks, P.A., Sheffery, M., and Rifkind, R.A. (1987) Cancer Res. 47: 659. 6. Sachs, L. (1978) Nature (Lond.) 274: 535. 7. Friend, C, Scher, W., Holland, J. W., and Sato, T. (1971) Proc. Nati Acad. Sci. (USA) 68: 378-382. 8. Tanaka, M., Levy, J., Terada, M., Breslow, R., Rifkind, R.A., and Marks, P.A. (1975) Proc. Nati Acad. Sci. (USA) 72: 1003-1006. 9. Reuben, R.C., Wife, R.L., Breslow, R., Rificind, R.A., and Marks, P.A. (1976) Proc. Nati Acad. Sci. (USA) 73: 862-866. 10. Abe, E., Miyaura, C, Sakagami, H., Takeda, M., Konno, K., Yamazaki, T., Yoshika, S., and Suda, T. (1981) Proc. Nati Acad. Sci. (USA) 78: 4990-4994. 11. Schwartz, E.L., Snoddy, J.R., Kreutter, D., Rasmussen, H., and Sartorelli, A.C. (1983) Proc. Am. Assoc. Cancer Res. 24:18. 12. Tanenaga, K., Hozumi, M., and Sakagami, Y. (1980) Cancer Res. 40: 914-919. 13. Lotem, J. and Sachs, L. (1975) Int. J. Cancer 15: 731-740. 14. Metcalf, D. (1985) Science, 229: 16-22. 15. Scher, W., Scher, B.M., and Waxman, S. (1983) Exp. Hematol. 11: 490-498. 16. Scher,., Scher, B. M., and Waxman, S. (1982) Biochem. & Biophys. Res. Comm. 109: 348-354. 17. Huberman, E. and Callaham, M. F. (1979) Proc. Nati Acad. Sci. (USA) 76: 1293-1297. 18. Lottem, J. and Sachs, L. (1979) Proc. Nati Acad. Sci. (USA) 76: 5158-5162. 19. Terada, M., Epner, E., Nudel, U., Salmon, J., Fibach, E., Rifkind, R.A., and Marks, P.A. (1978) Proc. Nati Acad. Sci. (USA) • 75: 2795-2799.

. Morin, M. J. and Sartorelli, A.C. (1984) Cancer Res. 44: 2807-2812. 21. Schwartz, E.L., Brown, B.J., Nierenberg, M., Marsh, J.C., and Sartorelli, A.C. (1983) Cancer Res. 43: 2725-2730. 22. Sugano, H., Furusawa, M., Kawaguchi, T., and Ikawa, Y. (1973) Bibl. Hematol. 39: 943-954. 23. Ebert, P. S., Wars, I., and Buell, D. N. (1976) Cancer Res. 36: 1809-1813. 24. Hayashi, M., Okabe, J., and Hozumi, M. (1979) Gann 70: 235-238. 25. Fibach, E., Reuben, R.C., Rifkind, R.A., and Marks, P.A. (1977) Cancer Res. 37: 440-444. 26. Melloni, E., Pontremoli, S., Damiani, G., Viotti, P., Weich, N., Rifkind, R.A., and Marks, P. (1988) Proc. Nati Acad. Sci. (USA) 85: 3835-3839. 27. Reuben, R., Khanna, P.L., Gazitt, Y., Breslow, R., Rifkind, R.A., and Marks, P.A. (1978) J. Biol. Chem. 253: 4214-4218. 28. Marks, P. A. and Rifkind, R. A. (1988) Int.

Journal of Cell Cloning 6: 230-240. 29. Melloni, E., Pontremoli, S., Michetti, M., Sacco, O., Cakiroglu, A.G., Jackson, J.F., Rifkind, R.

A., and Marks, P. A. (1987) Proc. Nati Acad. Sciences (USA) 84: 5282-5286.

. Marks, P.A. and Rifkind, R.A. (1984) Cancer 54: 2766-2769. 31. Egorin, M.J., Sigman, L.M. VanEcho, D.A., Forrest, A., Whitacre, M.Y., and Aisner, J. (1987) Cancer. Res. 47: 617-623. 32. Rowinsky, E. W., Ettinger, D.S., Grochow, L.B., Brundrett, R.B., Cates, A.E., and Donehower, R.C. (1986) J. Clin. Oncol. 4: 1835-1844. 33. Rowinsky, E. L. Ettinger, D. S., McGuire, W. P., Noe, D. A., Grochow, L. B., and Donehower, R. C. (1987) Cancer Res. 47: 5788-5795. 34. Callery, P. S., Egorin, M.J., Geelhaar, L.A., and Nayer, M.SB. (1986) Cancer Res. 46: 4900-4903. 35. Young, C. W. Fanucchi, M. P., Walsh, T. B., Blatzer, L., Yaldaie, S., Stevens, Y. W., Gordon, C, Tong, W., Rifkind, R.A., and Marks, P.A. (1988) Cancer Res. 48: 7304-7309. 36. Andreeff, M., Young, C, Clarkson, B., Fetten, J., Rifkind, R.A., and Marks, P.A. (1988) Blood 72: 186a. 37. Marks, P. A., Breslow, R., Rifkind, R.A., Ngo, L., and Singh, R. (1989) Proc. Nati Acad. Sci. (USA) 86: 6358-6362. 38. Breslow, R., Jursic, B., Yan, Z. F., Friedman, E., Leng, L., Ngo, L., Rifkind, R.A., and Marks, P.A. (1991) Proc. Nati Acad. Sci. (USA) 88: 5542-5546. 39. Richon, V.M., Webb, Y., Merger, R., et al. (1996) PNAS 93: 5705-8. 40. Cohen, L.A., Amin, S., Marks, P.A., Rifkind, R.A., Desai, D., and Richon, V.M. (1999) Anticancer Research 19: 4999-5006. 41. Grunstein, M. (1997) Nature 389: 349-52. 42. Finnin, M.S., Donigian, J.R., Cohen, A., et al. (1999) Nature 401: 188-193. 43. Van Lint, C, Emiliani, S., Verdín, E. (1996) Gene Expression 5: 245-53. 44. Archer, S. Shufen, M. Shei, A., Hodin, R. (1998) PNAS 95: 6791-96. 45. Dressel, U., et al. (2000) Anticancer Research 20 (2A): 1017-22. 46. Lin, R.J., Nagy, L., Inoue, S., et al. (1998) Nature 391: 811-14.

Claims (17)

1. CLAIMS: 1. The use of suberoylanilide hydroxamic acid (SAHA) is represented by the following structural formula: or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent, for the preparation of a medicament for administration to a person for treatment against mesothelioma or diffuse lymphoma of large B lymphocytes.
2. 2. The use according to claim 1, for the treatment of mesothelioma in the person.
3. 3. The use according to claim 1, for the treatment of diffuse lymphoma of large B lymphocytes in the person.
4. 4. The use according to claim 2, wherein the medicament is administered orally.
5. The use according to claim 4, wherein the medicament is administered twice a day in a dose of 300 mg at regular intervals.
6. 6. The use according to claim 5, wherein the medicament is administered three to five days per week.
7. The use according to claim 6, wherein the medicament is administered three days per week.
8. The use according to claim 4, wherein the composition is administered once a day in a 400 mg dose.
9. The use according to claim 8, wherein the composition is administered for 14 days followed by a rest period of 7 days without administration.
10. The use according to claim 4, wherein the composition is administered once a day in a dose of 300 mg.
11. The use according to claim 10, wherein the composition is administered for 14 days followed by a rest period of 7 days without administration.
12. 12. The use according to any of claims 1 to 11, wherein the SAHA is the active ingredient in the composition.
13. 13. A pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) which is represented by the following structural formula: or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment against mesothelioma or diffuse lymphoma of large B lymphocytes.
14. 14. A kit comprising at least one pharmaceutically effective unit dosage of SAHA or a pharmaceutically effective salt or hydrate thereof, wherein the pharmaceutically effective unit dosage is about 300 mg, and instructions for the treatment of mesothelioma with oral administration of according to a continuous schedule of 300 mg / day.
15. 15. The use of suberoylanilide hydroxamic acid (SAHA) which is represented by the following structural formula: or a pharmaceutically acceptable salt or hydrate thereof and a pharmaceutically acceptable carrier or diluent, for the preparation of a medicament for administration to a person for treatment against T-lymphocyte cutaneous lymphomas, wherein oral administration of SAHA is 400 mg / day in continuous programming.
16. 16. A pharmaceutical composition comprising suberoylanilide hydroxamic acid (SAHA) which is represented by the following structural formula: or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of cutaneous lymphomas of T-lymphocytes, which is administered orally in a continuous schedule of 400 mg / day.
17. 17. A kit comprising at least one pharmaceutically effective unit dosage of SAHA or a pharmaceutically effective salt or hydrate thereof, wherein the pharmaceutically effective unit dosage is approximately 400 mg, and instructions for the treatment against cutaneous lymphomas of T lymphocytes. by oral administration according to a continuous schedule of 400 mg / day.