US20040072735A1 - Methods of inducing terminal differentiation - Google Patents

Methods of inducing terminal differentiation Download PDF

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Publication number
US20040072735A1
US20040072735A1 US10/379,149 US37914903A US2004072735A1 US 20040072735 A1 US20040072735 A1 US 20040072735A1 US 37914903 A US37914903 A US 37914903A US 2004072735 A1 US2004072735 A1 US 2004072735A1
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subject
composition
saha
hdac inhibitor
administered
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US10/379,149
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Inventor
Victoria Richon
Judy Chiao
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Sloan Kettering Institute for Cancer Research
Merck HDAC Research LLC
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Richon Victoria M.
Chiao Judy H.
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27805074&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20040072735(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Richon Victoria M., Chiao Judy H. filed Critical Richon Victoria M.
Priority to US10/379,149 priority Critical patent/US20040072735A1/en
Priority to NZ55018503A priority patent/NZ550185A/xx
Priority to US10/600,132 priority patent/US7456219B2/en
Priority to US10/616,649 priority patent/US7399787B2/en
Priority to US10/650,025 priority patent/US7148257B2/en
Priority to US10/665,079 priority patent/US20040127523A1/en
Priority to US10/692,523 priority patent/US20040132825A1/en
Publication of US20040072735A1 publication Critical patent/US20040072735A1/en
Priority to US10/567,952 priority patent/US20070060614A1/en
Priority to US11/391,971 priority patent/US7375137B2/en
Priority to US11/492,478 priority patent/US20060276547A1/en
Assigned to MERCK HDAC RESEARCH, LLC reassignment MERCK HDAC RESEARCH, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ATON PHARMA, INC.
Assigned to ATON PHARMA, INC. (A SUBSIDIARY OF MERCK & CO., INC.) reassignment ATON PHARMA, INC. (A SUBSIDIARY OF MERCK & CO., INC.) ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHIAO, JUDY H., MILLER, THOMAS A., RICHON, VICTORIA M.
Assigned to SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH reassignment SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KELLY, W. KEVIN, RICHON, VICTORIA M.
Priority to US11/853,700 priority patent/US7732490B2/en
Priority to US11/981,500 priority patent/US20080249179A1/en
Priority to US11/980,994 priority patent/US20080227862A1/en
Priority to US11/981,367 priority patent/US7652069B2/en
Priority to US11/983,469 priority patent/US20080114069A1/en
Priority to US12/077,415 priority patent/US7847122B2/en
Priority to US12/077,396 priority patent/US7851509B2/en
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: SLOAN-KETTERING INSTITUTE FOR CANCER RES
Priority to US12/653,073 priority patent/US8101663B2/en
Priority to US12/799,368 priority patent/US8067472B2/en
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: SLOAN-KETTERING INSTITUTE FOR CANCER RES
Priority to US13/276,710 priority patent/US20120041067A1/en
Abandoned legal-status Critical Current

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Definitions

  • the present invention provides methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or inhibiting histone deacetylases (HDAC) administration of pharmaceutical compositions comprising HDAC inhibitors.
  • HDAC histone deacetylases
  • 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.
  • Cancer is a disorder in which a population of cells has become, in varying degrees, unresponsive to the control mechanisms that normally govern proliferation and differentiation.
  • chemotherapeutic treatment of cancer a) blocking hormone-dependent tumor cell proliferation by interference with the production or peripheral action of sex hormones; and b) killing cancer cells directly by exposing them to cytotoxic substances, which injure both neoplastic and normal cell populations.
  • Cancer therapy is also being attempted by the induction of terminal differentiation of the neoplastic cells (1).
  • differentiation has been reported by exposure of cells to a variety of stimuli, including: cyclic AMP and retinoic acid (2,3), aclarubicin and other anthracyclines (4).
  • neoplastic transformation does not necessarily destroy the potential of cancer cells to differentiate (1,5,6).
  • tumor cells which do not respond to the normal regulators of proliferation and appear to be blocked in the expression of their differentiation program, and yet can be induced to differentiate and cease replicating.
  • agents including some relatively simple polar compounds (5,7-9), derivatives of vitamin D and retinoic acid (10-12), steroid 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 various transformed cell lines and primary human tumor explants to express more differentiated characteristics.
  • HMBA hybrid polar/apolar compound N,N′-hexamethylene bisacetamide
  • Commitment is defined as the capacity of cells to express terminal differentiation despite removal of inducer (25). Upon continued exposure to HMBA there is progressive recruitment of cells to differentiate. The present inventors have reported that MELC cell lines made 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 capable of inducing phenotypic changes consistent with differentiation in a broad variety of cells lines (5).
  • the characteristics of the drug-induced effect have been most extensively studied in the murine erythroleukemia cell system (MELC) (5,25,27,28).
  • MELC induction of differentiation is both time and concentration dependent.
  • the minimum concentration required to demonstrate an effect in vitro 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 drug exposure is about 36 hours.
  • HMBA protein kinase C is involved in the pathway of inducer-mediated differentiation (29).
  • the in vitro studies provided a basis for evaluating the potential of HMBA as a cytodifferentiation agent in the treatment of human cancers (30).
  • 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).
  • phase I clinical trials also have demonstrated that the potential efficacy of HMBA is limited, in part, by dose-related toxicity which prevents achieving optimal blood levels and by the need for intravenous administration of large quantities of the agent, over prolonged periods.
  • 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.
  • the polar end groups are different and only one is a large hydrophobic group.
  • Histone deacetylase inhibitors such as suberoylanilide hydroxamide acid (SAHA), belong to this class of agents that have the ability to induce tumor cell growth arrest, differentiation and/or apoptosis (39). These compounds are targeted towards mechanisms inherent to the ability of a neoplastic cell to become malignant, as they do not appear to have toxicity in doses effective for inhibition of tumor growth in animals (40).
  • SAHA suberoylanilide hydroxamide acid
  • H1, H2A, H2B, H3 and H4 There are five types of histones that have been identified in nucleosomes (designated H1, H2A, H2B, H3 and H4). Each nucleosome contains two of each histone type within its core, except for H1, which is present singly in the outer portion of the nucleosome structure. It is believed that when the histone proteins are hypoacetylated, there is a greater affinity of the histone to the DNA phosphate backbone This affinity causes DNA to be tightly bound to the histone and renders the DNA inaccessible to transcriptional regulatory elements and machinery. The regulation of acetylated states occurs through the balance of activity between two enzyme complexes, histone acetyl transferase (HAT) and histone deacetylase (HDAC).
  • HAT histone acetyl transferase
  • HDAC histone deacetylase
  • hypoacetylated state is thought to inhibit transcription of associated DNA. This hypoacetylated state is catalyzed by large multiprotein complexes that include HDAC enzymes. In particular, HDACs have been shown to catalyze the removal of acetyl groups from the chromatin core histones.
  • HDAC inhibition is thought occur through direct interaction with the catalytic site of the enzyme as demonstrated by X-ray crystallography studies (42).
  • the result of HDAC inhibition is not believed to have a generalized effect on the genome, but rather, only affects a small subset of the genome (43).
  • Evidence provided by DNA microarrays using malignant cell lines cultured with a HDAC inhibitor shows that there are a finite (1-2%) number of genes whose products are altered. For example, cells treated in culture with HDAC inhibitors show a consistent induction of the cyclin-dependent kinase inhibitor p21 (44). This protein plays an important role in cell cycle arrest.
  • HDAC inhibitors are thought to increase the rate of transcription of p21 by propagating the hyperacetylated state of histones in the region of the p21 gene, thereby making the gene accessible to transcriptional machinery. Genes whose expression is not affected by HDAC inhibitors do not display changes in the acetylation of regional associated histones (45).
  • HAT or HDAC activity is implicated in the development of a malignant phenotype.
  • the oncoprotein produced by the fusion of PML and RAR alpha appears to suppress specific gene transcription through the recruitment of HDACs (46). In this manner, the neoplastic cell is unable to complete differentiation and leads to excess proliferation of the leukemic cell line.
  • the aforementioned patents do not disclose specific oral formulations of the HDAC inhibitors or specific dosages and dosing schedules of the recited compounds. Importantly, the aforementioned patents do not disclose oral formulations that have favorable pharmacokinetic profiles such as high bioavailability which gives rise to high blood levels of the active compounds over an extended period of time.
  • the class of compounds of the present invention may be useful for selectively inducing terminal differentiation of neoplastic cells and therefore aid in treatment of tumors in patients.
  • suitable dosages and dosing schedules of these compounds and to develop formulations, preferably oral formulations, which give rise to steady, therapeutically effective blood levels of the active compounds over an extended period of time.
  • the present invention provides methods of producing a mean plasma concentration of a histone deacetylase (HDAC) inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration, which comprises administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • HDAC histone deacetylase
  • the present invention also provides methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells, and methods for inducing differentiation of tumor cells by producing a mean plasma concentration of a histone deacetylase (HDAC) inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration, by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • HDAC histone deacetylase
  • the present invention further provides methods of producing a mean plasma concentration of at least about 10 nM of suberoylanilide hydroxamic acid (SAHA) in vivo in a subject over a period of at least two hours following administration, which comprises administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • SAHA suberoylanilide hydroxamic acid
  • the present invention also provides methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells, and methods for inducing differentiation of tumor cells by producing a mean plasma concentration of at least 10 nM of SAHA in vivo in a subject over a period of at least two hours following administration, by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides pharmaceutical compositions suitable for oral administration, which comprise a compound useful for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or which is a potent inhibitor of histone deacetylase (HDAC).
  • the pharmaceutical compositions are further comprised of microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
  • the present invention also provides for pharmaceutical compositions for oral administration comprising SAHA, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
  • SAHA microcrystalline cellulose
  • the oral bioavailability of the active compounds in the formulations of the present invention is surprisingly high.
  • the formulations unexpectedly give rise to high, therapeutically effective blood levels of the active compounds over an extended period of time.
  • the present invention further provides a safe, daily dosing regimen of these formulations, which is easy to follow and to adhere to.
  • oral formulations comprising HDAC inhibitors, particularly suberoylanilide hydroxamic acid (SAHA), have very high overall oral bioavailability of the active compound in vivo. Furthermore, the formulations give rise to high blood levels of the active compound, which remain unexpectedly high over an extended period of time, for example, up to 10-12 hours.
  • SAHA suberoylanilide hydroxamic acid
  • the oral formulations of the present invention have many advantages, especially when compared to parenteral formulations, since on the one end they provide high, stable and prolonged therapeutically effective blood levels of HDAC inhibitors, and on the other hand are easy to administer to patients by any conventional mode of oral administration.
  • the present invention provides a pharmaceutical composition for oral administration comprising a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of the HDAC inhibitor effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the concentration of the HDAC inhibitor is effective to inhibit the HDAC for a period of at least 10 hours following administration.
  • the present invention provides a pharmaceutical composition for oral administration comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of SAHA effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the concentration of SAHA is effective to inhibit the HDAC for a period of at least 10 hours following administration.
  • the formulations of the present invention are useful for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells and therefore aid in treatment of tumors in patients.
  • the present invention also provides a method of selectively inducing terminal differentiation of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in the subject, comprising the step of orally administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of the HDAC inhibitor effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the present invention also provides a method of selectively inducing cell growth arrest of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in the subject, comprising the step of orally administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of the HDAC inhibitor effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the present invention also provides a method of selectively inducing apoptosis of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in the subject, comprising the step of orally administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of the HDAC inhibitor effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the present invention also provides a method of inducing differentiation of tumor cells in a subject having a tumor, comprising the step of orally administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of the HDAC inhibitor effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the present invention provides a method of inhibiting the activity of a histone deacetylase in a subject, comprising the step of orally administering to the subject an effective amount of a pharmaceutical composition comprising a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of the HDAC inhibitor effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the present invention also provides a method of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in the subject, comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof; wherein the composition provides a mean plasma concentration of SAHA effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the present invention also provides a method of inducing differentiation of tumor cells in a subject having a tumor comprising the step of administering to the subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof; wherein the composition provides a mean plasma concentration of SAHA effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof; wherein the composition provides a mean plasma concentration of SAHA effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the present invention provides a method of inhibiting the activity of a histone deacetylase in a subject, comprising the step of orally administering to the subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of SAHA effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • SAHA or any of the HDAC inhibitors are administered to the patient at a total daily dosage of between 25-4000 mg/m 2 . In another preferred embodiment, SAHA or any of the HDAC inhibitors are administered to the patient at a total daily dosage of 200 mg. SAHA or any of the HDAC inhibitors are administered to the patient at a total daily dosage of 400 mg.
  • the composition provides a mean plasma concentration of the HDAC inhibitor (e.g., SAHA) capable of inhibiting histone deacetylase over a period of at least 2 hours following administration, which is preferably at a concentration of at least about 10 nM.
  • the composition provides a mean plasma concentration of the HDAC inhibitor of at least about 10 nM over a period of at least 10 hours following administration.
  • the composition provides a mean plasma concentration of the HDAC inhibitor (e.g., SAHA) capable of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, or capable of inducing differentiation of tumor cells in a tumor, wherein the concentration is maintained over a period of at least 2 hours following administration, which is preferably at a concentration of at least about 2.5 ⁇ M.
  • the composition provides a mean plasma concentration of the HDAC inhibitor of at least about 2.5 ⁇ M over a period of at least 10 hours following administration.
  • compositions of the present invention may be formulated in any unit dosage form (liquid or solid) suited for oral administration, for example, in the form of a pellet, a tablet, a coated tablet, a capsule, a gelatin capsule, a solution, a suspension, or a dispersion.
  • the composition is in the form of a gelatin capsule.
  • any inert excipient that is commonly used as a carrier or diluent may 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.
  • compositions may further comprise a disintegrating agent (e.g., sodium croscarmellose) 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, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.
  • a disintegrating agent e.g., sodium croscarmellose
  • a lubricant e.g., magnesium stearate
  • additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.
  • HDAC inhibitors are suitable for use in the compositions of the present invention.
  • the HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA).
  • HDAC inhibitors that are suitable for use in the compositions of the present invention are:
  • R 3 and R 4 are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino group; and n is an integer from 5 to about 8.
  • R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from about 4 to about 8.
  • R 1 and R 2 are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl;
  • R 4 is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.
  • a pharmaceutical composition for oral administration comprising a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, microcrystalline cellulose as a carrier or diluent; croscarmellose sodium as a disintegrant; and magnesium stearate as a lubricant; wherein the composition provides a mean plasma concentration of the HDAC inhibitor effective to inhibit a histone deacetylase in vivo for a period of at least 2 hours following administration.
  • the HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA).
  • a pharmaceutical composition for oral administration comprising suberoylanilide hydroxamic acid (SAHA) or a pharmaceutically acceptable salt or hydrate thereof; microcrystalline cellulose as a carrier or diluent; croscarmellose sodium as a disintegrant; and magnesium stearate as a lubricant; wherein the composition provides a mean plasma concentration of the HDAC inhibitor effective to inhibit a histone deacetylase in vivo for a period of at least 2 hours following administration.
  • SAHA suberoylanilide hydroxamic acid
  • microcrystalline cellulose as a carrier or diluent
  • croscarmellose sodium as a disintegrant
  • magnesium stearate as a lubricant
  • the composition comprises 50-70% by weight of SAHA or a pharmaceutically acceptable salt or hydrate thereof; 20-40% by weight microcrystalline cellulose as a carrier or diluent; 5-15% by weight croscarmellose sodium as a disintegrant; and 0.1-5% by weight magnesium stearate as a lubricant.
  • the composition comprises about 50-200 mg of SAHA.
  • the composition is in the form of a gelatin capsule.
  • the present invention further provides a safe, daily dosing regimen of these formulations, which is easy to follow and to adhere to.
  • the formulations of the present invention are useful for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells and therefore aid in treatment of tumors in patients.
  • FIG. 1 is a picture of a Western blot (top panel) showing the quantities of acetylated histone-4 ( ⁇ -AcH4) in the blood plasma of patients following an oral or intravenous (IV) dose of SAHA.
  • IV SAHA was administered at 200 mg infused over two hours.
  • Oral SAHA was administered in a single capsule at 200 mg.
  • the amount of ⁇ -AcH4 is shown at the indicated time points.
  • Bottom panel Coomassie blue stain.
  • FIG. 2 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-4 ( ⁇ -AcH4) in the blood plasma of patients having a solid tumor, following an oral or intravenous (IV) dose of SAHA. IV and Oral SAHA were administered as in FIG. 1. The amount of ⁇ -AcH4 is shown at the indicated time points. The experiment is shown in duplicate (FIG. 2A and FIG. 2B). Bottom panels: Coomassie blue stain.
  • FIG. 3 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-4 ( ⁇ -AcH4) (FIG. 3A) and acetylated histone-3 ( ⁇ -AcH3) (FIGS. 3 B-E) in the blood plasma of patients following an oral or intravenous (IV) dose of SAHA, on Day 1 and Day 21. IV and Oral SAHA were administered as in FIG. 1. The amount of ⁇ -AcH4 or ⁇ -AcH3 is shown at the indicated time points. Bottom panels: Coomassie blue stain.
  • FIG. 4 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-3 ( ⁇ -AcH3) in the blood plasma of patients having a solid tumor, following an oral or intravenous (IV) dose of SAHA. IV and Oral SAHA were administered as in FIG. 1. The amount of ⁇ -AcH3 is shown at the indicated time points. Bottom panel: Coomassie blue stain.
  • FIG. 5 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-3 ( ⁇ -AcH3) in the blood plasma of patients following an oral or intravenous (IV) dose of SAHA.
  • IV SAHA was administered at 400 mg infused over two hours.
  • Oral SAHA was administered in a single capsule at 400 mg.
  • the amount of ⁇ -AcH4 is shown at the indicated time points.
  • the experiment is shown in triplicate (FIGS. 5A and B). Bottom panels: Coomassie blue stain.
  • FIG. 6 is a picture of a Western blot (top panel) showing the quantities of acetylated histone-3 ( ⁇ -AcH3) in the blood plasma of patients having a solid tumor, following an oral or intravenous (IV) dose of SAHA. IV and Oral SAHA were administered as in FIG. 5. The amount of ⁇ -AcH3 is shown at the indicated time points. Bottom panel: Coomassie blue stain.
  • FIG. 7 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-3 ( ⁇ -AcH3) in the blood plasma of patients having a solid tumor following an oral or intravenous (IV) dose of SAHA, on Day 1 and Day 21. IV and Oral SAHA were administered as in FIG. 4. The amount of ( ⁇ -AcH4 or ( ⁇ -AcH3 is shown at the indicated time points. The experiment is shown in triplicate (FIGS. 7 A-C). Bottom panels: Coomassie blue stain.
  • FIG. 8 is a picture of a Western blot (top panels) showing the quantities of acetylated histone-3 ( ⁇ -AcH3) in the blood plasma of patients following an oral or intravenous (IV) dose of SAHA. IV and Oral SAHA were administered as in FIG. 5. The amount of ⁇ -AcH3 is shown at the indicated time points. Bottom panels: Coomassie blue stain.
  • FIGS. 9 A-C is a graph showing the mean plasma concentration of SAHA (ng/ml) at the indicated time points following administration.
  • FIG. 9A Oral dose (200 mg and 400 mg) under fasting on Day 8.
  • FIG. 9B Oral dose with food on Day 9.
  • FIG. 9C IV dose on day 1.
  • FIG. 10 shows the apparent half-life of a SAHA 200 mg and 400 mg oral dose, on Days 8, 9 and 22.
  • FIG. 11 shows the AUC (ng/ml/hr) of a SAHA 200 mg and 400 mg oral dose, on Days 8, 9 and 22.
  • FIG. 12 shows the bioavailability of SAHA after a 200 mg and 400 mg oral dose, on Days 8, 9 and 22.
  • the present invention provides methods of producing a mean plasma concentration of a histone deacetylase (HDAC) inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration, which comprises administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • HDAC histone deacetylase
  • the present invention also provides methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting porliferation of such cells, and methods for inducing differentiation of tumor cells by producing a mean plasma concentration of a histone deacetylase (HDAC) inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration, by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • HDAC histone deacetylase
  • the present invention further provides methods of producing a mean plasma concentration of at least about 10 nM of suberoylanilide hydroxamic acid (SAHA) in vivo in a subject over a period of at least two hours following administration, which comprises administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • SAHA suberoylanilide hydroxamic acid
  • the present invention also provides methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells, and methods for inducing differentiation of tumor cells by producing a mean plasma concentration of at least 10 nM of SAHA in vivo in a subject over a period of at least two hours following administration, by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides pharmaceutical compositions suitable for oral administration, which comprise a compound useful for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or which is a potent inhibitor of histone deacetylase (HDAC).
  • the pharmaceutical compositions are further comprised of microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
  • the present invention also provides for pharmaceutical compositions for oral administration comprising SAHA, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
  • SAHA microcrystalline cellulose
  • the oral bioavailability of the active compounds in the formulations of the present invention is surprisingly high.
  • the formulations unexpectedly give rise to high, therapeutically effective blood levels of the active compounds over an extended period of time.
  • the present invention further provides a safe, daily dosing regimen of these formulations, which is easy to follow and to adhere to.
  • the oral bioavailability of the active compounds in the formulations of the present invention is surprisingly high. Moreover, the formulations unexpectedly give rise to high, therapeutically effective blood levels of the active compounds over an extended period of time.
  • the present invention further provides a safe, daily dosing regimen of these formulations, which is easy to follow, and which gives rise to a therapeutically effective amount of the recited compounds in vivo.
  • the formulations of the present invention are useful for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and therefore aid in treatment of tumors in patients.
  • the pharmaceutical compositions provided in the present invention give rise to an initial mean plasma concentration (i.e., the concentration that is obtained immediately after administration of the formulation), which remains unexpectedly high over an extended period of time.
  • an initial mean plasma concentration i.e., the concentration that is obtained immediately after administration of the formulation
  • parenteral formulations such as IV formulations
  • the oral compositions retain a high mean plasma concentration of the active compound over an extended period of time, for at least 2 hours, but more typically at least, 10 or 12 hours.
  • the mean plasma concentration of the oral dosage formulations does not drop below 50% of the initial mean plasma concentration for a period of time of up to 12 hours or even longer.
  • intravenous administration of the HDAC inhibitors described herein has proven to be the most effective.
  • the intravenous administration of the compound must be performed continuously, i.e., daily, for a prolonged period of time, such as for at least 3 days and preferably more than 5 days. This obviously provides a heavy burden on the patient receiving this treatment.
  • the unexpected and surprising findings of the present invention make it possible to formulate oral dosage forms that give rise to high and steady levels of the active compounds in-vivo, without the need to continuously administer the drugs, by IV infusions, which provides a tremendous advantage for the patient receiving the treatment.
  • the present invention provides a pharmaceutical composition for oral administration comprising a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of the HDAC inhibitor effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the concentration of the HDAC inhibitor is effective to inhibit the HDAC for a period of at least 8 hours following administration.
  • the concentration of the HDAC inhibitor is effective to inhibit the HDAC for a period of at least 10 hours following administration.
  • the concentration of the HDAC inhibitor is effective to inhibit the HDAC for a period of at least 12 hours following administration.
  • the present invention provides a pharmaceutical composition for oral administration comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent; wherein the composition provides a mean plasma concentration of SAHA effective to inhibit a histone deacetylase (HDAC) in vivo for a period of at least 2 hours following administration.
  • HDAC histone deacetylase
  • the concentration of SAHA is effective to inhibit the HDAC for a period of at least 8 hours following administration.
  • the concentration of SAHA is effective to inhibit the HDAC for a period of at least 10 hours following administration.
  • the concentration of SAHA is effective to inhibit the HDAC for a period of at least 12 hours following administration.
  • the formulations of the present invention are useful for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells and therefore aid in treatment of tumors in patients.
  • the present invention also provides a method of selectively inducing terminal differentiation of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in the subject, comprising producing a mean plasma concentration of a HDAC inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a method of selectively inducing cell growth arrest of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in the subject, comprising producing a mean plasma concentration of a HDAC inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a method of selectively inducing apoptosis of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in the subject, comprising producing a mean plasma concentration of a HDAC inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a method of inducing differentiation of tumor cells in a subject having a tumor, producing a mean plasma concentration of a HDAC inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a method of inhibiting the activity of a histone deacetylase in a subject, comprising producing a mean plasma concentration of a HDAC inhibitor capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a method of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in the subject, comprising producing a mean plasma concentration of SAHA capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a method of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells in a subject and thereby inhibiting proliferation of such cells in the subject, comprising producing a mean plasma concentration of at least 10 nM of SAHA in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a method of inducing differentiation of tumor cells in a subject having a tumor comprising producing a mean plasma concentration of SAHA capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a method of inducing differentiation of tumor cells in a subject having a tumor comprising producing a mean plasma concentration of at least 10 nM of SAHA in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a method of inhibiting the activity of a histone deacetylase in a subject, comprising producing a mean plasma concentration of SAHA capable of inhibiting a histone deacetylase in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides a method of inhibiting the activity of a histone deacetylase in a subject, comprising producing a mean plasma concentration of at least 10 nM of SAHA in vivo in a subject over a period of at least two hours following administration by administering to said subject an effective amount of a pharmaceutical composition comprising SAHA or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the composition provides a mean plasma concentration of the HDAC inhibitor (e.g., SAHA) capable of inhibiting histone deacetylase over a period of at least 2 hours following administration, which is preferably at a concentration of at least about 10 nM.
  • the composition provides a mean plasma concentration of the HDAC inhibitor of at least about 10 nM over a period of at least 8 hours following administration.
  • the composition provides a mean plasma concentration of the HDAC inhibitor of at least about 10 nM over a period of at least 10 hours following administration.
  • the composition provides a mean plasma concentration of the HDAC inhibitor of at least about 10 nM over a period of at least 12 hours following administration.
  • Non-limiting examples of mean plasma concentrations are about 10 nM, 25 nM, 40 nM, 45 nM, 50 nM, 100 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M, 5 ⁇ M 10 ⁇ M, 25, ⁇ M, 50 ⁇ M, 100 ⁇ M and the like. It should be apparent to a person skilled in the art that these doses are in no way limiting the scope of this invention, and that any mean plasma concentration which is capable of inhibiting a histone deacetylase is suitable.
  • the composition provides a mean plasma concentration of the HDAC inhibitor (e.g., SAHA) capable of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, or inducing differentiation of tumor cells in a tumor, wherein the concentration is maintained over a period of at least 2 hours following administration, which is preferably at a concentration of at least about 2.5 ⁇ M.
  • the composition provides a mean plasma concentration of the HDAC inhibitor of at least about 2.5 ⁇ M over a period of at least 8 hours following administration.
  • the composition provides a mean plasma concentration of the HDAC inhibitor of at least about 2.5 ⁇ M over a period of at least 10 hours following administration.
  • the composition provides a mean plasma concentration of the HDAC inhibitor of at least about 2.5 ⁇ M over a period of at least 12 hours following administration.
  • mean plasma concentrations are about 10 nM, 25 nM, 40 nM, 45 nM, 50 nM, 100 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M, 5 ⁇ M 10 ⁇ M, 25, ⁇ M, 50 ⁇ M, 100 ⁇ M and the like. It should be apparent to a person skilled in the art that these doses are in no way limiting the scope of this invention, and that any mean plasma concentration which is capable of inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells is suitable.
  • the composition provides a mean plasma concentration of the HDAC inhibitor (e.g., SAHA) effective to induce differentiation of tumor cells in a subject having a tumor, wherein the amount is maintained for a period of at least 2 hours following administration to the subject.
  • the composition provides a mean plasma concentration of the HDAC inhibitor effective to induce differentiation of tumor cells in a subject having a tumor, wherein the amount is maintained for a period of at least 8 hours following administration to the subject.
  • the composition provides a mean plasma concentration of the HDAC inhibitor effective to induce differentiation of tumor cells in a subject having a tumor, wherein the amount is maintained for a period of at least about 10 hours following administration to the subject.
  • Non-limiting examples of mean plasma concentrations are about 10 nM, 25 nM, 40 nM, 45 nM, 50 nM, 100 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M, 5 ⁇ M 10 ⁇ M, 25, ⁇ M, 50 ⁇ M, 100 ⁇ M and the like. It should be apparent to a person skilled in the art that these doses are in no way limiting the scope of this invention, and that any mean plasma concentration which is capable of inducing differentiation of tumor cells in a tumor is suitable.
  • the methods of the present invention are suitable for practice in vitro and in vivo. If the methods are practiced in vitro, contacting may be effected by incubating the cells with the compound.
  • the concentration of the compound in contact with the cells should be from about I about nM to about 25 mM, for example, from about 10 nM to about 1 mM, from about 40 nM to about 0.5 mM.
  • Non-limiting examples of specific doses are 10 nM, 25 nM, 40 nM, 45 nM, 50 nM, 100 nM, 1 ⁇ M, 2 ⁇ M, 2.5 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, 50 ⁇ M, 100 ⁇ M and the like.
  • the concentration depends upon the individual compound and the state of the neoplastic cells.
  • the methods of the present invention can be practiced in vitro, it is contemplated that the preferred embodiment for the methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells will comprise contacting the cells in vivo, i.e., by administering the compounds to a subject harboring neoplastic cells or tumor cells in need of treatment.
  • the methods of the present invention may also comprise initially administering to the subject an antitumor agent so as to render the neoplastic cells in the subject resistant to an antitumor agent and subsequently administering an effective amount of any of the compositions of the present invention, effective to selectively induce terminal differentiation, cell growth arrest and/or apoptosis of such cells.
  • the antitumor agent may be one of numerous chemotherapy agents such as an alkylating agent, an antimetabolite, a hormonal agent, an antibiotic, colchicine, a vinca alkaloid, L-asparaginase, procarbazine, hydroxyurea, mitotane, nitrosoureas or an imidazole carboxamide. Suitable agents are those agents that promote depolarization of tubulin.
  • the antitumor agent is colchicine or a vinca alkaloid; especially preferred are vinblastine and vincristine.
  • the cells preferably are treated so that they are resistant to vincristine at a concentration of about 5 mg/ml.
  • the treating of the cells to render them resistant to an antitumor agent may be effected by contacting the cells with the agent for a period of at least 3 to 5 days.
  • the contacting of the resulting cells with any of the compounds above is performed as described previously.
  • the compounds may also be administered together with radiation therapy.
  • the present invention also provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the patient an effective amount of any of the compositions of the present invention above, effective to selectively induce terminal differentiation of such neoplastic cells and thereby inhibit their proliferation.
  • the method of the present invention is intended for the treatment of human patients with tumors. However, it is also likely that the method would be effective in the treatment of tumors in other mammals.
  • the term tumor is intended to include any cancer caused by the proliferation of neoplastic cells, such as lung cancer, acute lymphoid myeloma, Hodgkins lymphoma, non-Hodgkins lymphoma, bladder melanoma, renal carcinoma, breast carcinoma, prostate carcinoma, ovarian carcinoma or colorectal carcinoma.
  • the administration of the pharmaceutical compositions can be carried out in unit dosages which may be administered orally once a day, twice a day, three times a day and the like.
  • Currently preferred embodiments are once-daily administration, twice-daily administration and three-times daily administration.
  • Histone deacetylases are enzymes that catalyze the removal of acetyl groups from lysine residues in the amino terminal tails of the nucleosomal core histones.
  • HDACs histone acetyl transferases
  • Histone acetylation affects gene expression and inhibitors of HDACs, such as the hydroxamic acid-based hybrid polar compound suberoylanilide hydroxamic acid (SAHA) induce growth arrest, differentiation and/or apoptosis of transformed cells in vitro and inhibit tumor growth in vivo.
  • SAHA hydroxamic acid-based hybrid polar compound suberoylanilide hydroxamic acid
  • HDACs can be divided into three classes based on structural homology.
  • Class I HDACs HDACs 1, 2, 3 and 8 bear similarity to the yeast RPD3 protein, are located in the nucleus and are found in complexes associated with transcriptional co-repressors.
  • Class II HDACs HDACs 4, 5, 6, 7 and 9 are similar to the yeast HDA1 protein, and have both nuclear and cytoplasmic subcellular localization. Both Class I and II HDACs are inhibited by hydroxamic acid-based HDAC inhibitors, such as SAHA.
  • Class III HDACs form a structurally distant class of NAD dependent enzymes that are related to the yeast SIR2 proteins and are not inhibited by hydroxamic acid-based HDAC inhibitors.
  • Histone deacetylase inhibitors or HDAC inhibitors are compounds that are capable of inhibiting the deacetylation of histones in vivo, in vitro or both.
  • HDAC inhibitors inhibit the activity of at least one histone deacetylase.
  • an increase in acetylated histone occurs and accumulation of acetylated histone is a suitable biological marker for assessing the activity of HDAC inhibitors. Therefore, procedures that can assay for the accumulation of acetylated histones can be used to determine the HDAC inhibitory activity of compounds of interest.
  • compounds that can inhibit histone deacetylase activity can also bind to other substrates and as such can inhibit other biologically active molecules such as enzymes. It is also to be understood that the compounds of the present invention are capable of inhibiting any of the histone deacetylases set forth above, or any other histone deacetylases.
  • the accumulation of acetylated histones in peripheral mononuclear cells as well as in tissue treated with HDAC inhibitors can be determined against a suitable control.
  • HDAC inhibitory activity of a particular compound can be determined in vitro using, for example, an enzymatic assays which shows inhibition of at least one histone deacetylase. Further, determination of the accumulation of acetylated histones in cells treated with a particular composition can be determinative of the HDAC inhibitory activity of a compound.
  • an enzymatic assay to determine the activity of a histone deacetylase inhibitor compound can be conducted as follows. Briefly, the effect of an HDAC inhibitor compound on affinity purified human epitope-tagged (Flag) HDAC1 can be assayed by incubating the enzyme preparation in the absence of substrate on ice for about 20 minutes with the indicated amount of inhibitor compound. Substrate ([ 3 H]acetyl-labelled murine erythroleukemia cell-derived histone) can be added and the sample can be incubated for 20 minutes at 37° C. in a total volume of 30 ⁇ L. The reaction can then be stopped and released acetate can be extracted and the amount of radioactivity release determined by scintillation counting.
  • An alternative assay useful for determining the activity of a histone deacetylase inhibitor compound is the “HDAC Fluorescent Activity Assay; Drug Discovery Kit-AK-500” available from BIOMOL® Research Laboratories, Inc., Plymouth Meeting, Pa.
  • mice can be injected intraperitoneally with an HDAC inhibitor compound.
  • Selected tissues for example, brain, spleen, liver etc, can be isolated at predetermined times, post 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 (about 1 ⁇ g) can be electrophoresed on 15% SDS-polyacrylamide gels and can be transferred to Hybond-P filters (available from Amersham).
  • Filters can be blocked with 3% milk and can be probed with a rabbit purified polyclonal anti-acetylated histone H4 antibody ( ⁇ Ac-H4) and anti-acetylated histone H3 antibody ( ⁇ Ac-H3) (Upstate Biotechnology, Inc.). Levels of acetylated histone can be visualized using a horseradish peroxidase-conjugated goat anti-rabbit antibody (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 (CB).
  • CB Coomassie Blue
  • hydroxamic acid-based HDAC inhibitors have been shown to up regulate the expression of the p21 WAF1 gene.
  • the p21 WAF1 protein is induced within 2 hours of culture with HDAC inhibitors in a variety of transformed cells using standard methods.
  • the induction of the p21 WAF1 gene is associated with accumulation of acetylated histones in the chromatin region of this gene. Induction of p21 WAF1 can therefore be recognized as involved in the G1 cell cycle arrest caused by HDAC inhibitors in transformed cells.
  • HDAC inhibitors fall into five general classes: 1) hydroxamic acid derivatives; 2) Short-Chain Fatty Acids (SCFAs); 3) cyclic tetrapeptides; 4) benzamides; and 5) electrophilic ketones.
  • the present invention includes within its broad scope compositions comprising HDAC inhibitors which are 1) hydroxamic acid derivatives; 2) Short-Chain Fatty Acids (SCFAs); 3) cyclic tetrapeptides; 4) benzamides; 5) electrophilic ketones; and/or any other class of compounds capable of inhibiting histone deacetylases, for use in inhibiting histone deacetylase, inducing terminal differentiation in neoplastic cells, and/or inducing differentiation of tumor cells in a tumor.
  • HDAC inhibitors which are 1) hydroxamic acid derivatives; 2) Short-Chain Fatty Acids (SCFAs); 3) cyclic tetrapeptides; 4) benzamides; 5) electrophilic ketones; and/or any other class of compounds capable of inhibiting histone deacetylases, for use in inhibiting histone deacetylase, inducing terminal differentiation in neoplastic cells, and/or inducing differentiation of tumor cells in a tumor.
  • HDAC inhibitors include, but are not limited to:
  • A. Hydroxamic Acid Derivatives such as suberoylanilide hydroxamic acid (SAHA) (Richon et al., Proc. Natl. Acad. Sci. USA 95,3003-3007 (1998)); m-carboxycinnamic acid bishydroxamide (CBHA) (Richon et al., supra); pyroxamide; trichostatin analogues such as trichostatin A (TSA) and trichostatin C (Koghe et al. 1998. Biochem. Pharmacol. 56: 1359-1364); salicylihydroxamic acid (SBHA) (Andrews et al., International J.
  • SAHA suberoylanilide hydroxamic acid
  • CBHA m-carboxycinnamic acid bishydroxamide
  • pyroxamide trichostatin analogues such as trichostatin A (TSA) and trichostatin C
  • SBHA suberoyl bishydroxamic acid
  • ABHA azelaic bishydroxamic acid
  • AAHA azelaic-1-hydroxamate-9-anilide
  • 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.
  • apicidin cyclic tetrapeptide [cyclo(N-O-methyl-L-tryptophanyl-L -isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)] (Darkin-Rattray et al., Proc. Natl. Acad. Sci. USA 93,1314313147 (1996)); apicidin Ia, apicidin Ib, apicidin Ic, apicidin Ia, and apicidin IIb (P.
  • SCFA Short chain fatty acid
  • valerate McBain et al., supra
  • 4-phenylbutyrate (4-PBA) (Lea and Tulsyan, Anticancer Research, 15,879-873 (1995)); phenylbutyrate (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); phenylacetate (Lea and Tulsyan, supra); 3-bromopropionate (Lea and Tulsyan, supra); tributyrin (Guan et al., Cancer Research, 60,749-755 (2000)); valproic acid and valproate.
  • Electrophilic ketone derivatives such as trifluoromethyl ketones (Frey et al, Bioorganic & Med. Chem. Lett. (2002), 12, 3443-3447; U.S. 6,511,990) and ⁇ -keto amides such as N-methyl- ⁇ -ketoamides
  • HDAC Inhibitors such as depudecin (Kwon et al. 1998. PNAS 95: 3356-3361.
  • Preferred hydroxamic acid based HDAC inhibitors are suberoylanilide hydroxamic acid (SAHA), m-carboxycinnamic acid bishydroxamate (CBHA) and pyroxamide.
  • SAHA has been shown to bind directly in the catalytic pocket of the histone deacetylase enzyme. SAHA induces cell cycle arrest, differentiation and/or apoptosis of transformed cells in culture and inhibits tumor growth in rodents. SAHA is effective at inducing these effects in both solid tumors and hematological cancers. It has been shown that SAHA is effective at inhibiting tumor growth in animals with no toxicity to the animal.
  • SAHA The SAHA-induced inhibition of tumor growth is associated with an accumulation of acetylated histones in the tumor.
  • SAHA is effective at inhibiting the development and continued growth of carcinogen-induced (N-methylnitrosourea) mammary tumors in rats.
  • SAHA was administered to the rats in their diet over the 130 days of the study.
  • SAHA is a nontoxic, orally active antitumor agent whose mechanism of action involves the inhibition of histone deacetylase activity.
  • HDAC inhibitors are those disclosed in U.S. Pat. Nos. 5,369,108, 5,932,616, 5,700,811, 6,087,367 and 6,511, 990, issued to some of the present inventors disclose compounds, the entire contents of which are incorporated herein by reference, non-limiting examples of which are set forth below:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 1, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • R 1 and R 2 can be the same or different; when R 1 and R 2 are the same, each is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine or thiazoleamino group; when R 1 and R 2 are different R 1 ⁇ R 3 —N—R 4, wherein each of R 3 and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl alkyloxy, aryloxy, arylalkyloxy or pyridine group, or R 3 and R 4 are bonded together to form a piperidine group, R 2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group and
  • R 1 and R 2 are the same and are a substituted or unsubstituted thiazoleamino group; and n is an integer from about 4 to about 8.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 2, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of R 3 and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, arylalkyloxy, aryloxy, arylalkyloxy or pyridine group, or R 3 and R 4 are bonded together to form a piperidine group, R 2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group and n is an integer from about 4 to about 8.
  • each of R 3 and R 4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group;
  • R 2 is a hydroxylamino, hydroxyl, amino, alkylamino, or alkyloxy group;
  • n is an integer from 5 to 7; and
  • R 3 —N—R 4 and R 2 are different.
  • n is 6.
  • R 4 is a hydrogen atom
  • R 3 is a substituted or unsubstituted phenyl and n is 6.
  • R 4 is a hydrogen atom
  • R 3 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, 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
  • n is 6, R 4 is a hydrogen atom and R 3 is a cyclohexyl 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 R 3 and R 4 bond together to form a piperidine group. In another embodiment of formula 2, n is 6, R 4 is a hydrogen atom and R 3 is a benzyloxy group. In another embodiment of formula 2, R 4 is a hydrogen atom and R 3 is a ⁇ -pyridine group. In another embodiment of formula 2, R 4 is a hydrogen atom and R 3 is a ⁇ -pyridine group.
  • R 4 is a hydrogen atom and R 3 is an ⁇ -pyridine group.
  • n is 6, and R 3 and R 4 are both methyl groups.
  • n is 6, R 4 is a methyl group and R 3 is a phenyl group.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 3, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • n is an integer from 5 to about 8.
  • n is 6.
  • the present invention provides a pharmaceutical composition comprising SAHA (4), or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • SAHA can be represented by the following structural formula.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 5, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 6 (pyroxamide), or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 7, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 8, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 9, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable earner or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 10, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • R 3 is hydrogen and R 4 cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group;
  • R 2 is a hydroxylamino group; and
  • n is an integer from 5 to about 8.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 11, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • R 3 and R 4 are independently a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, cycloalkyl, aryl, aryloxy, arylalkyloxy, or pyridine group, or R 3 and R 4 bond together to form a piperidine group; R 2 is a hydroxylamino group; and n is an integer from 5 to about 8.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 12, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group;
  • R is a hydrogen atom, a hydroxyl, group, a substituted or unsubstituted alkyl, arylalkyloxy, or aryloxy group; and each of m and n are independently the same as or different from each other and are each an integer from about 0 to about 8.
  • the HDAC inhibitor is a compound of Formula XI wherein X, Y and R are each hydroxyl and both m and n are 5.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 13, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of X and Y is a hydroxyl group and each of R 1 and R 2 is a methyl group.
  • each of X and Y is a hydroxyl group, each of R 1 and R 2 is a methyl group, each of n and o is 6, and m is2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 14, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 15, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino or aryloxyalkylamino group; and each of m and n are independently the same as or different from each other and are each an integer from about 0 to about 8.
  • each of X and Y is a hydroxyl group and each of m and n is 5.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 16, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of X and Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino or aryloxyalkylamino group;
  • R 1 and R 2 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted alkyl, arylalkyloxy or aryloxy group; and each of m and n are independently the same as or different from each other and are each an integer from about 0 to about 8.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 17, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of X an Y are independently the same as or different from each other and are a hydroxyl, amino or hydroxylamino group, a substituted or unsubstituted alkyloxy, alkylamino, dialkylamino, arylamino, alkylarylamino, or aryloxyalkylamino group; and n is an integer from about 0 to about 8.
  • each of X and Y is a hydroxylamino group; R 1 is a methyl group, R 2 is a hydrogen atom; and each of in and n is 2.
  • each of X and Y is a hydroxylamino group; R 1 is a carbonylhydroxylamino group, R 2 is a hydrogen atom; and each of in and n is 5.
  • each of X and Y is a hydroxylamino group; each of R 1 and R 2 is a fluoro group; and each of in and n is 2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 18, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 19, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of R 1 and R 2 are independently the same as or different from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group.
  • the HDAC inhibitor is a compound of structural Formula X wherein R 1 and R 2 are both hydroxylamino.
  • RI is a phenylamino group and R 2 is a hydroxylamino group.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 20, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of R 1 and R 2 are independently the same as or different from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group.
  • the HDAC inhibitor is a compound of structural Formula XI wherein R 1 and R 2 are both hydroxylamino.
  • R 1 is a hydroxylamino group.
  • R 2 is a hydroxylamino group.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 22, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of R 1 and R 2 are independently the same as or different from each other and are a hydroxyl, alkyloxy, amino, hydroxylamino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkyloxyamino, aryloxyamino, alkyloxyalkylamino, or aryloxyalkylamino group.
  • the HDAC inhibitor is a compound of structural Formula XII wherein R 1 and R 2 are both hydroxylamino.
  • R 1 is a phenylamino group and R 2 is a hydroxylamino group.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 24, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • 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-difluoro, 2,4-difluoro, 2,5-difluoro, 2,6-difuloro, 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 group; and n is an integer from 4 to 8.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 25 (CBHA), or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 26, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 27, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • R is a substituted or unsubstituted phenyl, piperidine, thiazole, 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from about 4 to about 8.
  • R is a substituted phenyl group.
  • R is a substituted phenyl group, where the substituent is selected from the group consisting of methyl, cyano, nitro, thio, trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro, bromo, iodo, 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, methyloxy, phenyloxy
  • R is a substituted or unsubstituted 2-pyridine, 3-pyridine or 4-pyridine and n is an integer from about 4 to about 8.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 28, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • 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.
  • R is a substituted phenyl group.
  • R is a substituted phenyl group, where the substituent is selected from the group consisting of methyl, cyano, nitro, thio, trifluoromethyl, amino, aminocarbonyl, methylcyano, chloro, fluoro, bromo, iodo, 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, methyloxy, phenyl
  • R is phenyl and n is 5. In another embodiment, n is 5 and R is 3-chlorophenyl.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 29, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of R 1 and R 2 is directly attached or through a linker and is substituted or unsubstituted, aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, cycloalkyl, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amino, thiazoleamino, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridyl, or quinolinyl or isoquinolinyl; n is an integer from about 3 to about 10 and R 3 is a hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino or alkyloxy group.
  • aryl e.g., phenyl
  • arylalkyl e.g., benzyl
  • the linker can be an amide moiety, e.g., O—, —S—, —NH—, NR 5 , —CH 2 —, —(CH 2 ) m —, —(CH ⁇ CH)—, phenylene, cycloalkylene, or any combination thereof, wherein R 5 is a substitute or unsubstituted C 1 -C 5 alkyl.
  • R 1 is —NH—R 4 wherein R 4 is substituted or unsubstituted, aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, cycloalkyl, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amino, thiazoleamino, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the structure of formula 30, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.
  • each of R 1 and R 2 is, substituted or unsubstituted, aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, cycloalkyl, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amino, thiazoleamino, hydroxyl, branched or unbranched alkyl, alkenyl, alkyloxy, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl;
  • R 3 is hydroxamic acid, hydroxylamino, hydroxyl, amino, alkylamino or alkyloxy group;
  • R 4 is hydrogen, halogen, phenyl or a cycloalkyl moiety; and A can be the same or different and represents an amide moiety, O—, —S—, —NH—,
  • R 1 and R 2 are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; and n is an integer from 3 to 10.
  • aryl e.g., phenyl
  • arylalkyl e.g., benzyl
  • naphthyl e.g., pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl
  • n is an integer from 3 to 10.
  • the compound of formula 30 can have the structure 31 or 32:
  • R 1 , R 2 and n have the meanings of Formula 30.
  • R 7 is selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl; n is an integer from 3 to 10 and Y is selected from:
  • n is an integer from 3 to 10
  • Y is selected from
  • R 7 ′ is selected from
  • aryl e.g., phenyl
  • arylalkyl e.g., benzyl
  • naphthyl pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl
  • n is an integer from 3 to 10 and R 7 ′ is selected from
  • R 1 and R 2 are each selected from substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl;
  • R 4 is hydrogen, a halogen, a phenyl or a cycloalkyl moiety and n is an integer from 3 to 10.
  • the compound of formula 36 can have the structure 37 or 38:
  • R 1 , R 2 , R 4 and n have the meanings of Formula 36.
  • L is a linker selected from the group consisting of an amide moiety, O—, —S—, —NH—, NR 5 , —CH 2 —, —(CH 2 ) m —, —(CH ⁇ CH)—, phenylene, cycloalkylene, or any combination thereof wherein R 5 is a substitute or unsubstituted C 1 -C 5 alkyl; and wherein each of R 7 and R 8 are independently a substituted or unsubstituted aryl (e.g., phenyl), arylalkyl (e.g., benzyl), naphthyl, pyridineamino, 9-purine-6-amino, thiazoleamino, aryloxy, arylalkyloxy, pyridyl, quinolinyl or isoquinolinyl;, n is an integer from 3 to 10 and m is an integer from 0-10.
  • a compound of Formula 39 can be:
  • HDAC inhibitors suitable for use in the invention include those shown in the following more specific formulas:
  • n is an integer from 3 to 10 or an enantiomer. In one particular embodiment of formula 43, n-5.
  • SAHA or any of the other HDACs can be synthesized according to the methods outlined in the Experimental Details Section, or according to the method set forth in U.S. Pat. Nos. 5,369,108, 5,700,811, 5,932,616 and 6,511,990, the contents of which are incorporated by reference in their entirety, or according to any other method known to a person skilled in the art.
  • homologs are molecules having substantial structural similarities to the above-described compounds and analogs are molecules having substantial biological similarities regardless of structural similarities.
  • compositions comprising pharmaceutically acceptable salts of the HDAC inhibitors with organic and inorganic acids, for example, acid addition salts which may, for example, be hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid and the like.
  • organic and inorganic acids for example, acid addition salts which may, for example, be hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid and the like.
  • compositions can also be prepared from by treatment with inorganic bases, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • inorganic bases for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • the invention also encompasses pharmaceutical compositions comprising hydrates of the HDAC inhibitors.
  • hydrate includes but is not limited to 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.
  • the HDAC inhibitors can be in a crystalline form, in amorphous form, and have any particle size.
  • the HDAC inhibitor particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.
  • compositions suitable for oral administration 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 compounds above, and a pharmaceutically acceptable carrier.
  • the effective amount is an amount effective to selectively induce terminal differentiation of suitable neoplastic cells and less than an amount which causes toxicity in a patient.
  • any inert excipient that is commonly used as a carrier or diluent may 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.
  • 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, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.
  • a disintegrating agent e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.
  • One embodiment is a pharmaceutical composition for oral administration comprising a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
  • Another embodiment has SAHA as the HDAC inhibitor.
  • Another embodiment comprises 50-70% by weight of a HDAC inhibitor or a pharmaceutically acceptable salt or hydrate thereof, 20-40% by weight microcrystalline cellulose, 5-15% by weight croscarmellose sodium and 0.1-5% by weight magnesium stearate.
  • Another embodiment comprises about 50-200 mg of a HDAC inhibitor.
  • the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e., as a solid or a 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.
  • the composition is formulated in a capsule.
  • the compositions of the present invention comprise in addition to the HDAC inhibitor active compound and the inert carrier or diluent, a hard gelatin capsule.
  • “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, 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 carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media 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.
  • 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., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • a gum 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., polymethylacrylate
  • calcium carbonate e.g., magnesium oxide, talc, or mixtures thereof.
  • pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils.
  • 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 saline and buffered media.
  • 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.
  • Solutions or suspensions can also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, 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 (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • compositions may further comprise binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers (e.g., tris-HCI., acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol), e.glyce
  • 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.
  • 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 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 (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used 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. Pat. No. 4,522,811.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of 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 are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the daily administration is then repeated continuously for a period of several days to several years. Oral treatment may continue for between one week and the life of the patient. Preferably the administration takes place for five consecutive days after which time the patient can be evaluated to determine if further administration is required.
  • the administration can be continuous or intermittent, i.e., treatment for a number of consecutive days followed by a rest period.
  • the compounds of the present invention may be administered intravenously on the first day of treatment, with oral administration on the second day and all consecutive days thereafter.
  • the compounds of the present invention may be administered for the purpose of preventing disease progression or stabilizing tumor growth.
  • compositions that contain an active component are well understood in the art, for example, by mixing, granulating, or tablet-forming processes.
  • the active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient.
  • the active agents are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions and the like as detailed above.
  • the compounds of the present invention may be administered at orally at a total daily dose of between 25 to 4000 mg/m 2 , for example, about 25 to 1000 mg, 50-1000 mg, 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 1000 mg and the like.
  • the compound is administered as a single dose when administering up to 400 mg to the patient.
  • the total is split into multiple dosages, for example, twice daily, three times daily or the like, preferably spread out over equal periods of time during the day.
  • two doses, e.g., 500 mg each can be administered 12 hours apart to achieve a total dosage of 1000 mg in a day.
  • SAHA or any of the HDAC inhibitors are administered to the patient at a total daily dosage of 200 mg. In another currently preferred embodiment, SAHA or any of the HDAC inhibitors are administered to the patient at a total daily dosage of 400 mg. In another currently preferred embodiment, SAHA or any of the HDAC inhibitors are administered to the patient at a total daily dosage of 600 mg.
  • the amount of the compound administered to the patient is less than an amount that would cause toxicity in the patient.
  • 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.
  • the concentration of the compound in the patient's plasma is maintained at about 10 nM.
  • the concentration of the compound in the patient's plasma is maintained at about 25 nM.
  • the concentration of the compound in the patient's plasma is maintained at about 50 nM.
  • the concentration of the compound in the patient's plasma is maintained at about 100 nM.
  • the concentration of the compound in the patient's plasma is maintained at about 500 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 1000 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 2500 nM. In another embodiment, the concentration of the compound in the patient's plasma is maintained at about 5000 nM. It has been found with HMBA that administration of the compound in an amount from about 5 gm/m 2 /day to about 30 gm/m 2 /day, particularly about 20 gm/m 2 /day, is effective without producing toxicity in the patient. The optimal amount of the compound that should 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.
  • the pharmaceutical composition comprises a histone deacetylase (HDAC) inhibitor; microcrystalline cellulose as a carrier or diluent; croscarmellose sodium as a disintegrant; and magnesium stearate as a lubricant.
  • HDAC histone deacetylase
  • the HDAC inhibitor is suberoylanilide hydroxamic acid (SAHA).
  • the percentage of the active ingredient and various excipients in the formulations may vary.
  • the composition may comprise between 20 and 90%, preferably between 50-70% by weight of the histone deacetylase (HDAC).
  • HDAC histone deacetylase
  • the composition may comprise between 10 and 70%, preferably between 20-40% by weight microcrystalline cellulose as a carrier or diluent.
  • the composition may comprise between 1 and 30%, preferably 5-15% by weight croscarmellose sodium as a disintegrant.
  • the composition may comprise between 0.1-5% by weight magnesium stearate as a lubricant.
  • the composition comprises about 50-200 mg of the HDAC inhibitor (e.g., 50 mg, 100 mg and 200 mg for the HDAC inhibitor, for example, SAHA).
  • the composition is in the form of a gelatin capsule.
  • a currently preferred embodiment of the invention is a solid formulation of SAHA with microcrystalline cellulose, NF (Avicel Ph 101), sodium croscarmellose, NF (AC-Di-Sol) and magnesium stearate, NF, contained in a gelatin capsule.
  • a further preferred embodiment is 200 mg of solid SAHA with 89.5 mg of microcrystalline cellulose, 9 mg of sodium croscarmellose and 1.5 mg of magnesium stearate contained in a gelatin capsule.
  • compositions of the present invention are not only useful for inhibiting the proliferation of neoplastic cells induction and treatment of cancer, and that these compositions are useful in treating a wide range of diseases for which HDAC inhibitors have been found useful.
  • HDAC inhibitors and in particular SAHA, have been found to be 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 and rheumatoid arthritis (RA) and psoriatic arthritis; inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciitis; cancers with leukocyte infiltration of the skin or organs, ischemic injury, including cerebral ischemia (e.g., brain injury as a result of trauma, epilepsy, hemorrhage or stroke, each of which may lead to neurodegeneration); HIV, heart failure, chronic, acute or mal
  • cytokine-induced toxicity e.g., septic shock, endotoxic shock
  • side effects from radiation therapy temporal mandibular joint disease, tumor metastasis; or an inflammatory condition resulting from strain, sprain, cartilage damage, trauma such as burn, orthopedic surgery, infection or other disease processes.
  • Allergic diseases and conditions include but are not limited to respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies, and the like.
  • respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.
  • HDAC inhibitors and in particular SAHA, have been found to be useful in the treatment of a variety of neurodegenerative diseases, a non-exhaustive list of which is:
  • A) syndromes appearing mainly in adults e.g., Huntington's disease, Multiple system atrophy combining dementia with ataxia and/ormanifestations of Parkinson's disease, Progressive supranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy body disease, and corticodentatonigral degeneration
  • B) syndromes appearing mainly in children or young adults e.g., Hallervorden-Spatz disease and progressive familial myoclonic epilepsy.
  • cerebellar degenerations e.g., cerebellar cortical degeneration and olivopontocerebellar atrophy (OPCA)
  • OPCA olivopontocerebellar atrophy
  • spinocerebellar degeneration Friedreich's atazia and related disorders
  • VI. Syndromes of muscular weakness and wasting without sensory changes motorneuron disease such as amyotrophic lateral sclerosis, spinal muscular atrophy (e.g., infantile spinal muscular atrophy (Werdnig-Hoffman), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander) and other forms of familial spinal muscular atrophy), primary lateral sclerosis, and hereditary spastic paraplegia.
  • motorneuron disease such as amyotrophic lateral sclerosis, spinal muscular atrophy (e.g., infantile spinal muscular atrophy (Werdnig-Hoffman), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander) and other forms of familial spinal muscular atrophy), primary lateral sclerosis, and hereditary spastic paraplegia.
  • VIII Syndromes of progressive visual loss such as pigmentary degeneration of the retina (retinitis pigmentosa), and hereditary optic atrophy (Leber's disease).
  • SAHA can be synthesized according to the method outlined below, or according to the method set forth in U.S. Pat. No. 5,369,108, the contents of which are incorporated by reference in their entirety, or according to any other method.
  • the mixture was then filtered through a pad of Celite (4,200 g) (the product was filtered to remove the neutral by-product (from attack by aniline on both ends of suberic acid).
  • the filtrate contained the salt of the product, and also the salt of unreacted 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 on the funnel with deionized water (4 ⁇ 5 L).
  • the wet filter cake was placed in a 72 L flask with 44 L of deionized water, the mixture heated to 50° C., and the solid isolated by a hot filtration (the desired product was contaminated with suberic acid which is has a much greater solubility in hot water. Several hot triturations were done to remove suberic acid. The product was checked by NMR [D 6 DMSO] to monitor the removal of suberic acid). The hot trituration 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.
  • the Nash pump is a liquid ring pump (water) and pulls a vacuum of about 29 inch of mercury.
  • An intermittent argon purge was used to help carry off water); 4,182.8 g of suberanilic acid was obtained.
  • the product still contained a small amount of suberic acid; therefore the hot trituration was done portionwise at 65° C., using about 300 g of product at a time. Each portion was filtered, and rinsed thoroughly with additional hot water (a total of about 6 L). This was repeated to purify the entire batch. This completely removed 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 week end. It was placed in trays and dried in a vacuum oven at 65° C. for 45 hours using the Nash pump and an argon bleed. The final product has a weight of 3,278.4 g (32.7% yield).
  • Flask 1 had a final pH of 8.98
  • Flask 2 had a final pH of 8.70.
  • the product from both flasks was isolated by filtration using a Buchner funnel and filter cloth. The filter cake was washed with 15 L of deionized water, and the funnel was covered and the product was partially dried on the funnel under vacuum for 15.5 hr. The product was removed and placed into five glass trays. The trays were placed in a vacuum oven and the product was dried to constant weight. The first drying period was for 22 hours at 60° C. using a Nash pump as the vacuum source with an argon bleed.
  • the trays were removed from the vacuum oven and weighed. The trays were returned to the oven and the product dried for an additional 4 hr and 10 minutes using an oil pump as the vacuum source and with no argon bleed. The material was packaged in double 4-mill polyethylene bags, and placed in a plastic outer container. The final weight after sampling was 2633.4 g (95.6%).
  • the crude SAHA was recrystallized from methanol/water.
  • a 50 L flask with a mechanical stirrer, thermocouple, condenser, and inlet for 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 give a solution.
  • 5,250 ml of deionized water was added to the reaction mixture. The heat was turned off, and the mixture was allowed to cool. When the mixture had cooled sufficiently so that the flask could be safely handled (28° C.), the flask was removed from the heating mantle, and placed in a tub for use as a cooling bath.
  • Ice/water was added to the tub to cool the mixture to ⁇ 5° C. The mixture was held below that temperature for 2 hours.
  • the product was isolated by filtration, and the filter cake washed with 1.5 L of cold methanol/water (2:1).
  • the funnel was covered, and the product was partially dried under vacuum for 1.75 hr.
  • 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 hr at 60° C. using a Nash pump as the vacuum source, and using an argon bleed.
  • the trays were removed for weighing, and then 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 a oil pump, and no argon bleed was used.
  • the material was packaged in double 4-mill polyethylene bags, and placed in a plastic outer container. The final weight after sampling was 2,540.9 g (92.5%).
  • SAHA Suberoylanilide Hydroxamic Acid
  • Patients Patients with histologically documented advanced stage, primary or metastatic adult solid tumors that are refractory to standard therapy or for which no curative standard therapy exists. Patients must have a Karnofsky Performance Status of ⁇ 70%, and adequate hematologic, hepatic and renal function. Patients must be at least four weeks from any prior chemotherapy, radiation therapy or other investigational anticancer drugs.
  • Dosing Schedule On the first day, patients were first treated with 200 mg of intravenously-administered SAHA. 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 800 mg doses of SAHA per day. Doses were administered to patients daily and continuously. Blood samples were taken on day one and on day 21 of oral treatment. Patients were taken off oral SAHA treatment due to disease progression, tumor regression, unacceptable side effects, or treatment with other therapies.
  • Results Comparison of serum plasma levels shows high bioavailability of SAHA administered orally, both when the patient fasted and when the patient did not fast, compared to SAHA administered intravenously (IV SAHA).
  • AUC is an estimate of the bioavailability of SAHA in (ng/ml)min, where 660 ng/ml is equal to 2.5 ⁇ M SAHA.
  • the AUC taken together with the half-life (t 1/2 ) shows that the overall bioavailability of oral SAHA is better than that of IV SAHA.
  • C max is the maximum concentration of SAHA observed after administration.
  • IV SAHA was administered at 200 mg infused over two hours.
  • the oral SAHA was administered in a single capsule at 200 mg.
  • Tables 2 and 3 summarize the results of an HPLC assay (LCMS using a deuterated standard) that quantitates the amount of SAHA in the blood plasma of the patients versus time, using acetylated histone-4 ( ⁇ -AcH4) as a marker.
  • LCMS LCMS using a deuterated standard
  • ⁇ -AcH4 acetylated histone-4
  • FIGS. 1 to 8 are HPLC slides showing the amount of ⁇ -AcH4 in patients in Cohorts I and II, measured at up to 10 hours after receiving the oral dose, compared with the ⁇ -AcH4 levels when SAHA was administered intravenously.
  • FIG. 9 shows the mean plasma concentration of SAHA (ng/ml) at the indicated time points following administration.
  • FIG. 9A Oral dose (200 mg and 400 mg) under fasting on Day 8.
  • FIG. 9B Oral dose with food on Day 9.
  • FIG. 9C IV dose on day 1.
  • FIG. 10 shows the apparent half-life of a SAHA 200 mg and 400 mg oral dose, on Days 8, 9 and 22.
  • FIG. 9 shows the apparent half-life of a SAHA 200 mg and 400 mg oral dose, on Days 8, 9 and 22.
  • FIG. 11 shows the AUC (ng/ml/hr) of a SAHA 200 mg and 400 mg oral dose, on Days 8, 9 and 22.
  • FIG. 12 shows the bioavailability of SAHA after a 200 mg and 400 mg oral dose, on Days 8, 9 and 22.
  • SAHA Suberoylanilide Hydroxyamic Acid
  • Dose Escalation Scheme and Number of Patients on Each Dose Level Dose Dosing #Patients Enrolled Cohort (mg/day) Schedule #Days of Dosing Rest Period (arm A/arm B/arm C)* I 200 Once a day Continuous None 6/0/0 II 400 Once a day Continuous None 5/4/2 III 400 q 12 hours Continuous None 6/3/0 IV 600 Once a day Continuous None 4/3/0 V 200 q 12 hours Continuous None 4/3/0 VI 300 q 12 hours Continuous None —/—/— Sub-totals: 25/13/2 Total 40
  • the 400 mg q12 hour dosing schedule was judged to have exceeded the maximally tolerated dose.
  • accrual was continued in cohort IV at a dose of 600 mg once a day.
  • two were inevaluable for the 28-day toxicity assessment because of early study termination due to rapid progression of disease.
  • the 600 mg dose was therefore judged to have exceeded the maximally tolerated dose and the 400 mg once a day dose was defined as the maximally tolerated dose for once daily oral administration.
  • the protocol was amended to evaluate additional dose levels of the twice a day dosing schedule at 200 mg BID and 300 mg BID administered continuously.
  • the interim pharmacokinetic analysis was based on 18 patients treated on the dose levels of 200 mg QD, 400 mg QD, and 400 mg BID.
  • the mean estimates of C max and AUC inf of SAHA administered orally under fasting condition or with food increased proportionally with dose in the 200 mg to 400 mg dose range.
  • the fraction of AUC inf due to extrapolation was 1% or less.
  • Mean estimates for apparent half-life were variable across dose groups under fasting condition or with food, ranging from 61 to 114 minutes.
  • the mean estimates of Cmax varies from 233 ng/ml (0.88 ⁇ M) to 570 ng/ml (2.3 ⁇ M).
  • the bioavailable fraction of SAHA, calculated from the AUC inf values after the IV infusion and oral routes, was found to be approximately 0.48.
  • Peripheral blood mononuclear cells were collected pre-therapy, immediately post-infusion and between 2-10 hours after oral ingestion of the SAHA capsules to assess the effect of SAHA on the extent of histone acetylation in a normal host cell.
  • Histones were isolated and probed with anti-acetylated histone (H3) antibody followed by HRP-secondary antibody.
  • H3 antibody anti-acetylated histone
  • HRP-secondary antibody anti-acetylated histone
  • Table 5 shows a dosing schedule for patients receiving SAHA intravenously. Patients begin in Cohort I, receiving 300 mg/m 2 of SAHA for five consecutive days in a week for one week, for a total dose of 1500 mg/m 2 . Patients were then observed for a period of two weeks and continued to Cohort II, then progressed through the Cohorts unless treatment was terminated due to disease progression, tumor regression, unacceptable side effects or the patient received other treatment.
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Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040018968A1 (en) * 2002-04-15 2004-01-29 George Sgouros Use of histone deacetylase inhibitors in combination with radiation for the treatment of cancer
US20040087631A1 (en) * 2002-03-04 2004-05-06 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20040122101A1 (en) * 2002-03-04 2004-06-24 Miller Thomas A. Polymorphs of suberoylanilide hydroxamic acid
US20040127523A1 (en) * 2002-03-04 2004-07-01 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20040132825A1 (en) * 2002-03-04 2004-07-08 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20040254220A1 (en) * 2003-03-17 2004-12-16 Syrrx, Inc. Histone deacetylase inhibitors
US20050048847A1 (en) * 2002-08-27 2005-03-03 Guang-Rung Hsieh Electrical power jack
US20050137234A1 (en) * 2003-12-19 2005-06-23 Syrrx, Inc. Histone deacetylase inhibitors
US20050159470A1 (en) * 2003-12-19 2005-07-21 Syrrx, Inc. Histone deacetylase inhibitors
US20060009527A1 (en) * 2002-02-15 2006-01-12 Richon Victoria M Method of treating TRX mediated diseases
US20060079551A1 (en) * 2001-10-16 2006-04-13 Richon Victoria M Treatment of neurodegenerative diseases and cancer of the brain using histone deacetylase inhibitors
US20060205941A1 (en) * 2004-12-16 2006-09-14 Bressi Jerome C Histone deacetylase inhibitors
US20060258694A1 (en) * 2005-05-11 2006-11-16 Bressi Jerome C Histone deacetylase inhibitors
US20060276547A1 (en) * 2002-03-04 2006-12-07 Bacopoulos Nicholas G Methods of treating cancer with HDAC inhibitors
US20070015809A1 (en) * 2005-07-14 2007-01-18 Bressi Jerome C Histone deacetylase inhibitors
US20070060614A1 (en) * 2002-03-04 2007-03-15 Bacopoulos Nicholas G Methods of treating cancer with hdac inhibitors
WO2007031853A2 (en) * 2005-09-14 2007-03-22 Nya Hamlet Pharma Ab Therapeutic combination of hamlet and a hdac inhibitor to treat cancer
WO2007056244A2 (en) * 2005-11-04 2007-05-18 Merck & Co., Inc. Methods of using saha and erlotinib for treating cancer
US20070129290A1 (en) * 2005-11-18 2007-06-07 Or Yat S Metabolite derivatives of the HDAC inhibitor FK228
US20070173527A1 (en) * 2006-01-13 2007-07-26 Bressi Jerome C Histone deacetylase inhibitors
US20070197473A1 (en) * 2005-11-04 2007-08-23 Frankel Stanley R Methods of using SAHA and Bortezomib for treating cancer
EP1833500A1 (en) * 2004-12-14 2007-09-19 Biorunx Co., Ltd Method to enhance the bone formation activity of bmp by runx2 acetylation
US20080124403A1 (en) * 2006-06-08 2008-05-29 Gloucester Pharmaceuticals Deacetylase inhibitor therapy
US20080132575A1 (en) * 2005-05-20 2008-06-05 Jeannie Chow Wong Formulations Of Suberoylanilide Hydroxamic Acid And Methods For Producing Same
US20080194690A1 (en) * 2005-05-13 2008-08-14 Topotarget Uk Limited Pharmaceutical Formulations Of Hdac Inhibitors
US20080202944A1 (en) * 2005-04-22 2008-08-28 Eduardo Santoli Method for Use of an Electrochemical Sensor and Electrodes Forming Said Sensor
US20080274120A1 (en) * 2005-11-10 2008-11-06 Topotarget Uk Limited Histone Deacetylase (Hdac) Inhibitors (Pxd101) for the Treatment of Cancer Alone or in Combination With Chemotherapeutic Agent
US20090012175A1 (en) * 2003-08-26 2009-01-08 Bacopoulos Nicholas G Methods of treating cancer with HDAC inhibitors
US20090186382A1 (en) * 2006-12-29 2009-07-23 Verdine Gregory L Preparation of Romidepsin
US20090215800A1 (en) * 2005-05-05 2009-08-27 Chroma Therapeutics Ltd Enzyme and Receptor Modulation
US20090305956A1 (en) * 2006-04-24 2009-12-10 Gloucester Pharmaceuticals, Inc. Treatment of Ras-Expressing Tumors
US20100093610A1 (en) * 2006-12-29 2010-04-15 Vrolijk Nicholas H Romidepsin-based treatments for cancer
US20100113602A1 (en) * 2007-02-27 2010-05-06 The United States Of America,As Represented By The Secretary,Department Of Health And Human Services Use of histone deacetylase inhibitors for the treatment of central nervous system metastases
US20100113392A1 (en) * 2006-11-03 2010-05-06 Badros Ashraf Z Methods of using saha and bortezomib for treating multiple myeloma
US20100190694A1 (en) * 2009-01-14 2010-07-29 Jan Fagerberg Methods for identifying patients who will respond well to cancer treatment
US20100286279A1 (en) * 2007-09-25 2010-11-11 Topotarget Uk Limited Methods of Synthesis of Certain Hydroxamic Acid Compounds
US20100317678A1 (en) * 2006-10-30 2010-12-16 Chroma Therapeutics Ltd. Hydroxamates as inhibitors of histone deacetylase
US20110003777A1 (en) * 2008-03-07 2011-01-06 Topotarget A/S Methods of Treatment Employing Prolonged Continuous Infusion of Belinostat
WO2012045804A1 (en) * 2010-10-08 2012-04-12 Vib Vzw Hdac inhibitors to treat charcot-marie-tooth disease
US8859502B2 (en) 2010-09-13 2014-10-14 Celgene Corporation Therapy for MLL-rearranged leukemia
US8980825B2 (en) 2010-07-12 2015-03-17 Celgene Corporation Romidepsin solid forms and uses thereof
US9101579B2 (en) 2012-11-14 2015-08-11 Celgene Corporation Inhibition of drug resistant cancer cells
US9134325B2 (en) 2012-09-07 2015-09-15 Celgene Corporation Resistance biomarkers for HDAC inhibitors
US9463215B2 (en) 2013-12-27 2016-10-11 Celgene Corporation Romidepsin formulations and uses thereof
US10285959B2 (en) 2005-02-03 2019-05-14 Topotarget Uk Limited Combination therapies using HDAC inhibitors
US11583521B2 (en) * 2020-07-01 2023-02-21 Jubilant Pharma Holdings Inc. Long-acting injection dosage form of beta 3 adrenoreceptor agonists

Families Citing this family (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6777217B1 (en) * 1996-03-26 2004-08-17 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US20030129724A1 (en) 2000-03-03 2003-07-10 Grozinger Christina M. Class II human histone deacetylases, and uses related thereto
US7244853B2 (en) 2001-05-09 2007-07-17 President And Fellows Of Harvard College Dioxanes and uses thereof
TWI319387B (en) 2002-04-05 2010-01-11 Astrazeneca Ab Benzamide derivatives
FR2847817B1 (fr) * 2002-11-28 2006-11-10 Centre Nat Rech Scient Utilisation d'un inhibiteur d'histone deacetylase pour le traitement des dystrophies musculaires
AU2004228011A1 (en) * 2003-04-01 2004-10-21 Memorial Sloan-Kettering Cancer Center Hydroxamic acid compounds and methods of use thereof
PL1651612T3 (pl) 2003-07-22 2012-09-28 Astex Therapeutics Ltd Związki 3,4-pochodne 1h-pirazolu i ich zastosowanie jako kinazy zależne od cyklin (cdk) i modulatory kinazy syntazy glikogenu-3 (gsk-3)
KR20050022216A (ko) * 2003-08-25 2005-03-07 윤덕구 동결건조 즉석소면 및 그 제조방법
WO2006016680A1 (en) * 2004-08-09 2006-02-16 Astellas Pharma Inc. Hydroxyamide compounds having activity as inhibitors of histone deacetylase (hdac)
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
AR054425A1 (es) 2005-01-21 2007-06-27 Astex Therapeutics Ltd Sales de adicion de piperidin 4-il- amida de acido 4-(2,6-dicloro-benzoilamino) 1h-pirazol-3-carboxilico.
MX2007008781A (es) * 2005-01-21 2007-09-11 Astex Therapeutics Ltd Compuestos farmaceuticos.
RU2007131101A (ru) * 2005-01-21 2009-02-27 Астекс Терапьютикс Лимитед (Gb) Комбинации пиразольных ингибиторов киназы и других средств против злокачественных новообразований
JP5475234B2 (ja) * 2005-01-21 2014-04-16 アステックス・セラピューティクス・リミテッド 医薬化合物
SG171690A1 (en) 2005-03-22 2011-06-29 Harvard College Treatment of protein degradation disorders
US20090182019A1 (en) * 2005-04-18 2009-07-16 The Johns Hopkins University Histone deacetylase inhibitors
EP2229941A1 (en) * 2005-05-20 2010-09-22 Merck Sharp & Dohme Corp. Formulations of suberoylanilide hydroxamic acid and methods for producing same
AU2006287378A1 (en) * 2005-09-07 2007-03-15 Braincells, Inc. Modulation of neurogenesis by HDac inhibition
WO2007117272A2 (en) * 2005-09-30 2007-10-18 The Henry M. Jackson Foundation For The Advancement Of Military Medicine Methods for treatment of hemorrhagic shock and related disorders
JP2009514879A (ja) * 2005-11-04 2009-04-09 メルク エンド カムパニー インコーポレーテッド Ｓａｈａ、カルボプラチン及びパクリタキセルを用いて癌を治療する方法及びその他の併用療法
AU2006323245B2 (en) * 2005-12-05 2011-03-03 Astrazeneca Ab New process for the preparation of esomeprazole non-salt form
US20070207950A1 (en) * 2005-12-21 2007-09-06 Duke University Methods and compositions for regulating HDAC6 activity
EP1991247B1 (en) 2006-02-14 2015-10-14 President and Fellows of Harvard College Bifunctional histone deacetylase inhibitors
DK2010168T3 (da) 2006-02-14 2014-07-21 Harvard College Histondeacetylase-inhibitore
EP2019674B1 (en) * 2006-05-03 2016-11-23 The President and Fellows of Harvard College Histone deacetylase and tubulin deacetylase inhibitors
EP2026805A1 (en) * 2006-05-08 2009-02-25 Astex Therapeutics Limited Pharmaceutical combinations of diazole derivatives for cancer treatment
WO2007131364A1 (en) * 2006-05-16 2007-11-22 Mcgill University Hybrid molecules having mixed vitamin d receptor agonism and histone deacetylase inhibitory properties
US20090239946A1 (en) * 2006-09-28 2009-09-24 Mckeown Arlene E Pharmaceutical compositions of HDAC inhibitors and chelatable metal compounds, and metal-HDAC inhibitors chelate complexes
RS52343B (en) * 2007-12-20 2012-12-31 Pharma Mar S.A. ANTITUMOR UNITS
EP2321264B1 (en) 2008-07-23 2016-05-04 President and Fellows of Harvard College Deacetylase inhibitors and uses thereof
WO2010043904A2 (en) 2008-10-15 2010-04-22 Generics [Uk] Limited Improved process
EP2362869A2 (en) 2008-11-26 2011-09-07 Generics [UK] Limited Polymorphs
ES2473792T3 (es) 2009-04-03 2014-07-07 Naturewise Biotech & Medicals Corporation Compuestos cin�micos y derivados de los mismos para la inhibición de la histona desacetilasa
US7994357B2 (en) * 2009-04-03 2011-08-09 Naturewise Biotech & Medicals Corporation Cinamic compounds and derivatives therefrom for the inhibition of histone deacetylase
EP2277387B1 (en) 2009-07-22 2016-10-19 NatureWise Biotech & Medicals Corporation New use of histone deacetylase inhibitors in changing mrjp3 protein in royal jelly
WO2011019393A2 (en) 2009-08-11 2011-02-17 President And Fellows Of Harvard College Class- and isoform-specific hdac inhibitors and uses thereof
JP2013508458A (ja) 2009-10-26 2013-03-07 ラモット・アット・テル−アヴィヴ・ユニヴァーシティ・リミテッド Ｆｔｓとｈｄａｃ阻害剤との組合せを用いたがん治療
WO2011084623A1 (en) 2009-12-16 2011-07-14 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Method of sensitizing cancer cells to the cytotoxic effects of death receptor ligands in cancer treatment
US20110195397A1 (en) * 2010-02-10 2011-08-11 Selinfreund Richard H Drink mixture for the stabilization of diagnostic biomarkers
WO2011127467A1 (en) * 2010-04-09 2011-10-13 Companion Diagnostics, Inc. Devices, systems, and methods for biomarker stabilization
EA201290972A1 (ru) 2010-05-05 2013-08-30 Тева Вимен'С Хелс, Инк. Способы уменьшения симптомов у субъектов с применением лекарственных форм для однократного введения с постепенно снижающимися скоростями высвобождения
US20120164674A1 (en) * 2010-10-28 2012-06-28 Selinfreund Richard H Devices and washes for biomarker stabilization
MX2014006479A (es) 2011-11-30 2015-01-22 Univ Emory Inhibidores antivirales de la janus cinasa utiles en el tratamiento o prevencion de infecciones retrovirales y otras infecciones virales.
CN102793693A (zh) * 2012-09-07 2012-11-28 天津医科大学 伏立诺他在制备治疗自身免疫及炎症性疾病药物方面的应用
KR20150127216A (ko) 2013-03-14 2015-11-16 제넨테크, 인크. 암의 치료 및 암 약물 내성의 예방 방법
CN103819364B (zh) * 2014-01-24 2015-12-02 中南大学 N-烃酰基环内酰胺衍生物的一锅合成方法
EP3247342A4 (en) 2015-01-23 2018-10-10 Temple University - Of The Commonwealth System of Higher Education Use of short chain fatty acids in cancer prevention
US10639349B2 (en) 2015-04-06 2020-05-05 The Johns Hopkins University H3T3A mutant protein efficiently reduces H3T3P and causes increased cell death of rapidly dividing cells
CN105055386A (zh) * 2015-08-12 2015-11-18 天津医科大学总医院 伏立诺他用于制备免疫调节药物的应用
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US11065217B2 (en) 2017-01-27 2021-07-20 Temple University—Of the Commonwealth System of Higher Education Use of short chain fatty acids for the treatment and prevention of diseases and disorders
BR112019021742A2 (pt) 2017-04-17 2020-05-05 Univ Chicago composição, sistema, composição farmacêutica, composição alimentícia ou nutracêutica, método e uso da composição
CA3156060A1 (en) 2019-09-27 2021-04-01 Takeda Pharmaceutical Company Limited 2-ISOINDOL-1,3,4-OXADIAZOLE DERIVATIVES USEFUL AS HDAC6 INHIBITORS

Citations (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4690918A (en) * 1985-01-30 1987-09-01 Teruhiko Beppu Use of trichostatin compounds for treating tumor cells
US5055608A (en) * 1988-11-14 1991-10-08 Sloan-Kettering Institute For Cancer Research Novel potent inducers of thermal differentiation and method of use thereof
US5175191A (en) * 1988-11-14 1992-12-29 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and methods of use thereof
US5369108A (en) * 1991-10-04 1994-11-29 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and methods of use thereof
US5608108A (en) * 1988-11-14 1997-03-04 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and method of use thereof
US5654333A (en) * 1991-10-21 1997-08-05 The United States Of America As Represented By The Department Of Health And Human Services Methods for prevention of cancer using phenylacetic acids and derivatives thereof
US5700811A (en) * 1991-10-04 1997-12-23 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and method of use thereof
US6231880B1 (en) * 1997-05-30 2001-05-15 Susan P. Perrine Compositions and administration of compositions for the treatment of blood disorders
US6239176B1 (en) * 1997-03-11 2001-05-29 Beacon Laboratories, Inc. Uses of hydroxy and ether-containing oxyalkylene esters for treating metabolic conditions
US6262116B1 (en) * 1998-01-23 2001-07-17 Sloan-Kettering Institute For Cancer Research Transcription therapy for cancers
US6495719B2 (en) * 2001-03-27 2002-12-17 Circagen Pharmaceutical Histone deacetylase inhibitors
US6511990B1 (en) * 1999-09-08 2003-01-28 Sloan-Kettering Institute For Cancer Research Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US20030082666A1 (en) * 2000-11-21 2003-05-01 Kammer Gary M. Method of treating autoimmune diseases
US20030161830A1 (en) * 2001-06-14 2003-08-28 Jackson Donald G. Novel human histone deacetylases
US20030235588A1 (en) * 2002-02-15 2003-12-25 Richon Victoria M. Method of treating TRX mediated diseases
USRE38506E1 (en) * 1991-10-04 2004-04-20 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and methods of use thereof
US20040087631A1 (en) * 2002-03-04 2004-05-06 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20040122101A1 (en) * 2002-03-04 2004-06-24 Miller Thomas A. Polymorphs of suberoylanilide hydroxamic acid
US20040127522A1 (en) * 2002-03-04 2004-07-01 Chiao Judy H. Methods of treating cancer with HDAC inhibitors
US20040132825A1 (en) * 2002-03-04 2004-07-08 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20040132643A1 (en) * 2002-01-09 2004-07-08 Fojo Antonio Tito Histone deacelylase inhibitors in diagnosis and treatment of thyroid neoplasms
US20040167184A1 (en) * 2001-03-27 2004-08-26 Wiech Norbert L. Treatment of lung cells with histone deacetylase inhibitors
US20040266818A1 (en) * 2003-04-01 2004-12-30 Ronald Breslow Hydroxamic acid compounds and methods of use thereof
US20050004007A1 (en) * 2000-09-12 2005-01-06 Steven Grant Promotion of adoptosis in cancer cells by co-administration of cyclin dependent kinase inhibitiors and cellular differentiation agents
US6905669B2 (en) * 2001-04-24 2005-06-14 Supergen, Inc. Compositions and methods for reestablishing gene transcription through inhibition of DNA methylation and histone deacetylase
US20060276547A1 (en) * 2002-03-04 2006-12-07 Bacopoulos Nicholas G Methods of treating cancer with HDAC inhibitors
US20070060614A1 (en) * 2002-03-04 2007-03-15 Bacopoulos Nicholas G Methods of treating cancer with hdac inhibitors

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA622801A (en) 1961-06-27 L. Clark Robert Substituted benzimidazolones
FR901228A (fr) 1943-01-16 1945-07-20 Deutsche Edelstahlwerke Ag Système d'aimant à entrefer annulaire
DE2460689C3 (de) * 1974-12-20 1980-06-26 Klinge Pharma Gmbh & Co, 8000 Muenchen 13-disubstituierte Propanol-(2)-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
JPS61251649A (ja) * 1985-04-05 1986-11-08 Mitsubishi Petrochem Co Ltd ジカルボン酸ジアニリドの製造法
HU9203780D0 (en) 1991-12-12 1993-03-29 Sandoz Ag Stabilized pharmaceutical products of hmg-coa reductase inhibitor and method for producing them
JPH11514857A (ja) 1995-09-20 1999-12-21 メルク エンド カンパニー インコーポレーテッド 抗原虫剤の標的としてのヒストンデアセチラーゼ
US6239178B1 (en) * 1996-05-17 2001-05-29 George Dimelow Alexander Lord Method of treating mammals
US6030961A (en) 1997-03-11 2000-02-29 Bar-Ilan Research & Development Co., Ltd. Oxyalkylene phosphate compounds and uses thereof
US6124495A (en) 1997-03-11 2000-09-26 Beacon Laboratories, Inc. Unsaturated oxyalkylene esters and uses thereof
JPH10262694A (ja) 1997-03-28 1998-10-06 Sumitomo Forestry Co Ltd Ｂ細胞性リンパ腫の骨髄転移検査法
US6387673B1 (en) 1997-05-01 2002-05-14 The Salk Institute For Biological Studies Compounds useful for the modulation of processes mediated by nuclear hormone receptors, methods for the identification and use of such compounds
AUPO721997A0 (en) 1997-06-06 1997-07-03 Queensland Institute Of Medical Research, The Anticancer compounds
PL203279B1 (pl) 1998-01-30 2009-09-30 Biogen Idec Inc Zastosowanie czynnika hamującego oddziaływanie pomiędzy LT-ß i jej receptorem
AUPP505798A0 (en) 1998-08-04 1998-08-27 Fujisawa Pharmaceutical Co., Ltd. Novel compound fr225497 substance
TR200100859T2 (tr) * 1998-09-25 2001-08-21 Warner-Lambert Company Asetildinalin ve gemsitabin, kapesitabin veya cisplatin kombinasyonu ile kanser kemoterapisi
IL142531A0 (en) 1998-10-13 2002-03-10 Fujisawa Pharmaceutical Co Cyclic peptide compound, processes for the preparation thereof and pharmaceutical compositions containing the same
JP2003500052A (ja) 1999-05-03 2003-01-07 メチルジーン インコーポレイテッド ヒストン脱アセチル酵素の抑制
US6450992B1 (en) 1999-07-02 2002-09-17 Smith & Nephew, Inc. Cannula interface
JP2001081031A (ja) 1999-08-30 2001-03-27 Schering Ag 溶解性および経口吸収性を改善したベンズアミド誘導体含有製剤
US6673564B2 (en) 1999-10-18 2004-01-06 Millennium Pharmaceuticals, Inc. Methods for using 22045, a human cyclic nucleotide phosphodiesterase
KR101026205B1 (ko) 1999-11-23 2011-03-31 메틸진 인코포레이티드 히스톤 디아세틸라제의 억제제
US7288567B2 (en) * 2000-03-24 2007-10-30 Methylgene Inc. Inhibitors of histone deacetylase
WO2002015921A2 (en) 2000-08-18 2002-02-28 The Governement Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Methods of treating cutaneous and peripheral t-cell lymphoma by a histone deacetylase inhibitor
PE20020354A1 (es) 2000-09-01 2002-06-12 Novartis Ag Compuestos de hidroxamato como inhibidores de histona-desacetilasa (hda)
NZ525439A (en) 2000-09-29 2004-11-26 Topotarget Uk Ltd Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors
GB0023983D0 (en) 2000-09-29 2000-11-15 Prolifix Ltd Therapeutic compounds
AR035659A1 (es) 2000-12-07 2004-06-23 Hoffmann La Roche Hidroxiamidas de acido (1-oxo-1,2,3,4-tetrahidro-naftalen-2-il)-alcanoico, proceso para la manufactura de estos compuestos, composiciones farmaceuticas que contienen dichos compuestos y los usos de los mismos
US6533803B2 (en) * 2000-12-22 2003-03-18 Advanced Medical Applications, Inc. Wound treatment method and device with combination of ultrasound and laser energy
WO2002060430A1 (en) * 2001-02-01 2002-08-08 Cornell Research Foundation, Inc. Use of retinoids plus histone deacetylase inhibitors to inhibit the growth of solid tumors
ITMI20011733A1 (it) 2001-08-07 2003-02-07 Italfarmaco Spa Derivati dell'acido idrossamico inibitori degli enzimi istone deacetilasi, quali nuovi farmaci antiinfiammatori inibenti la sintesi di citoc
EP2269609A3 (en) * 2001-10-16 2012-07-11 Sloan-Kettering Institute for Cancer Research Treatment of neurodegenerative diseases and cancer of the brain with SAHA
WO2003088954A1 (en) * 2002-04-15 2003-10-30 Sloan-Kettering Institute For Cancer Research Combination therapy for the treatment of cancer
JP4338734B2 (ja) * 2003-08-26 2009-10-07 メルク エイチディーエーシー リサーチ エルエルシー Ｈｄａｃ阻害剤による癌処置法
EP1667680A4 (en) * 2003-08-29 2008-10-08 Aton Pharma Inc COMBINED METHODS OF TREATING CANCER
JP2009504774A (ja) 2005-08-18 2009-02-05 メルク エンド カムパニー インコーポレーテッド 癌を治療するためにｓａｈａ及びターグレチンの併用方法
CN101325955A (zh) * 2005-11-04 2008-12-17 默克公司 用saha和培美曲塞治疗癌症的方法
JP2009514879A (ja) 2005-11-04 2009-04-09 メルク エンド カムパニー インコーポレーテッド Ｓａｈａ、カルボプラチン及びパクリタキセルを用いて癌を治療する方法及びその他の併用療法
JP2009514891A (ja) * 2005-11-04 2009-04-09 メルク エンド カムパニー インコーポレーテッド 癌を治療するためのｓａｈａ及びエルロチニブを用いる方法

Patent Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4690918A (en) * 1985-01-30 1987-09-01 Teruhiko Beppu Use of trichostatin compounds for treating tumor cells
US5773474A (en) * 1988-11-14 1998-06-30 The Trustees Of Columbia University In The City Of New York And Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and method of use thereof
US5055608A (en) * 1988-11-14 1991-10-08 Sloan-Kettering Institute For Cancer Research Novel potent inducers of thermal differentiation and method of use thereof
US5175191A (en) * 1988-11-14 1992-12-29 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and methods of use thereof
US5608108A (en) * 1988-11-14 1997-03-04 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and method of use thereof
US5932616A (en) * 1991-10-04 1999-08-03 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and methods of use thereof
US5700811A (en) * 1991-10-04 1997-12-23 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and method of use thereof
US6087367A (en) * 1991-10-04 2000-07-11 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and methods of use thereof
US5369108A (en) * 1991-10-04 1994-11-29 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and methods of use thereof
USRE38506E1 (en) * 1991-10-04 2004-04-20 Sloan-Kettering Institute For Cancer Research Potent inducers of terminal differentiation and methods of use thereof
US5654333A (en) * 1991-10-21 1997-08-05 The United States Of America As Represented By The Department Of Health And Human Services Methods for prevention of cancer using phenylacetic acids and derivatives thereof
US6239176B1 (en) * 1997-03-11 2001-05-29 Beacon Laboratories, Inc. Uses of hydroxy and ether-containing oxyalkylene esters for treating metabolic conditions
US6231880B1 (en) * 1997-05-30 2001-05-15 Susan P. Perrine Compositions and administration of compositions for the treatment of blood disorders
US6451334B2 (en) * 1997-05-30 2002-09-17 Susan P. Perrine Compositions and administration of compositions for the treatment of blood disorders
US6262116B1 (en) * 1998-01-23 2001-07-17 Sloan-Kettering Institute For Cancer Research Transcription therapy for cancers
US20040002506A1 (en) * 1999-09-08 2004-01-01 Sloan Kettering Institute For Cancer Research Novel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US6511990B1 (en) * 1999-09-08 2003-01-28 Sloan-Kettering Institute For Cancer Research Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US20050004007A1 (en) * 2000-09-12 2005-01-06 Steven Grant Promotion of adoptosis in cancer cells by co-administration of cyclin dependent kinase inhibitiors and cellular differentiation agents
US20030082666A1 (en) * 2000-11-21 2003-05-01 Kammer Gary M. Method of treating autoimmune diseases
US20030114525A1 (en) * 2000-11-21 2003-06-19 Kammer Gary M. Method of treating autoimmune diseases
US20040167184A1 (en) * 2001-03-27 2004-08-26 Wiech Norbert L. Treatment of lung cells with histone deacetylase inhibitors
US6495719B2 (en) * 2001-03-27 2002-12-17 Circagen Pharmaceutical Histone deacetylase inhibitors
US6905669B2 (en) * 2001-04-24 2005-06-14 Supergen, Inc. Compositions and methods for reestablishing gene transcription through inhibition of DNA methylation and histone deacetylase
US20030161830A1 (en) * 2001-06-14 2003-08-28 Jackson Donald G. Novel human histone deacetylases
US20040132643A1 (en) * 2002-01-09 2004-07-08 Fojo Antonio Tito Histone deacelylase inhibitors in diagnosis and treatment of thyroid neoplasms
US20030235588A1 (en) * 2002-02-15 2003-12-25 Richon Victoria M. Method of treating TRX mediated diseases
US20040127523A1 (en) * 2002-03-04 2004-07-01 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20040132825A1 (en) * 2002-03-04 2004-07-08 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20040127522A1 (en) * 2002-03-04 2004-07-01 Chiao Judy H. Methods of treating cancer with HDAC inhibitors
US20040122101A1 (en) * 2002-03-04 2004-06-24 Miller Thomas A. Polymorphs of suberoylanilide hydroxamic acid
US20040087631A1 (en) * 2002-03-04 2004-05-06 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20060167103A1 (en) * 2002-03-04 2006-07-27 Aton Pharma, Inc. Methods of treating cancer with HDAC inhibitors
US20060276547A1 (en) * 2002-03-04 2006-12-07 Bacopoulos Nicholas G Methods of treating cancer with HDAC inhibitors
US20070060614A1 (en) * 2002-03-04 2007-03-15 Bacopoulos Nicholas G Methods of treating cancer with hdac inhibitors
US20040266818A1 (en) * 2003-04-01 2004-12-30 Ronald Breslow Hydroxamic acid compounds and methods of use thereof

Cited By (105)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7879865B2 (en) 2001-10-16 2011-02-01 Sloan-Kettering Institute For Cancer Research Treatment of cancer of the brain using histone deacetylase inhibitors
US20110124731A1 (en) * 2001-10-16 2011-05-26 Sloan-Kettering Institute For Cancer Research Treatment Of Neurodegenerative Diseases And Cancer Of The Brain Using Histone Deacetylase Inhibitors
US20060079551A1 (en) * 2001-10-16 2006-04-13 Richon Victoria M Treatment of neurodegenerative diseases and cancer of the brain using histone deacetylase inhibitors
US20060009527A1 (en) * 2002-02-15 2006-01-12 Richon Victoria M Method of treating TRX mediated diseases
US20060009526A1 (en) * 2002-02-15 2006-01-12 Richon Victoria M Method of treating TRX mediated diseases
US7375137B2 (en) 2002-03-04 2008-05-20 Merck Hdac Research, Llc Methods of treating cancer with HDAC inhibitors
US20040122101A1 (en) * 2002-03-04 2004-06-24 Miller Thomas A. Polymorphs of suberoylanilide hydroxamic acid
US7652069B2 (en) 2002-03-04 2010-01-26 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US20040132825A1 (en) * 2002-03-04 2004-07-08 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US20080114069A1 (en) * 2002-03-04 2008-05-15 Richon Victoria M Methods of inducing terminal differentiation
US20100210729A1 (en) * 2002-03-04 2010-08-19 Richon Victoria M Methods of inducing terminal differentiation
US20100168242A1 (en) * 2002-03-04 2010-07-01 Miller Thomas A Polymorphs of suberoylanilide hydroxamic acid
US20040127522A1 (en) * 2002-03-04 2004-07-01 Chiao Judy H. Methods of treating cancer with HDAC inhibitors
US20040127523A1 (en) * 2002-03-04 2004-07-01 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US8101663B2 (en) 2002-03-04 2012-01-24 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US20080119562A1 (en) * 2002-03-04 2008-05-22 Richon Victoria M Methods of Inducing Terminal Differentiation
US20060276547A1 (en) * 2002-03-04 2006-12-07 Bacopoulos Nicholas G Methods of treating cancer with HDAC inhibitors
US7148257B2 (en) 2002-03-04 2006-12-12 Merck Hdac Research, Llc Methods of treating mesothelioma with suberoylanilide hydroxamic acid
US7732490B2 (en) 2002-03-04 2010-06-08 Merck Hdac Research, Llc Methods of treating cancer
US20070060614A1 (en) * 2002-03-04 2007-03-15 Bacopoulos Nicholas G Methods of treating cancer with hdac inhibitors
US7399787B2 (en) 2002-03-04 2008-07-15 Merck Hdac Research, Llc Methods of treating cancer with HDAC inhibitors
US7847122B2 (en) 2002-03-04 2010-12-07 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US20040087631A1 (en) * 2002-03-04 2004-05-06 Bacopoulos Nicholas G. Methods of treating cancer with HDAC inhibitors
US7456219B2 (en) 2002-03-04 2008-11-25 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US20080249179A1 (en) * 2002-03-04 2008-10-09 Bacopoulos Nicholas G Methods of treating cancer with HDAC inhibitors
US20080228005A1 (en) * 2002-03-04 2008-09-18 Miller Thomas A Polymorphs of suberoylanilide hydroxamic acid
US7851509B2 (en) 2002-03-04 2010-12-14 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US20080194692A1 (en) * 2002-03-04 2008-08-14 Miller Thomas A Polymorphs of suberoylanilide hydroxamic acid
US8067472B2 (en) 2002-03-04 2011-11-29 Merck Hdac Research, Llc Methods of treating Hodgkin's and non-Hodgkin's lymphoma
US20040018968A1 (en) * 2002-04-15 2004-01-29 George Sgouros Use of histone deacetylase inhibitors in combination with radiation for the treatment of cancer
US20050048847A1 (en) * 2002-08-27 2005-03-03 Guang-Rung Hsieh Electrical power jack
US20040254220A1 (en) * 2003-03-17 2004-12-16 Syrrx, Inc. Histone deacetylase inhibitors
US20050137232A1 (en) * 2003-03-17 2005-06-23 Syrrx, Inc. Histone deacetylase inhibitors
US20090012175A1 (en) * 2003-08-26 2009-01-08 Bacopoulos Nicholas G Methods of treating cancer with HDAC inhibitors
US20050159470A1 (en) * 2003-12-19 2005-07-21 Syrrx, Inc. Histone deacetylase inhibitors
US20050137234A1 (en) * 2003-12-19 2005-06-23 Syrrx, Inc. Histone deacetylase inhibitors
EP1833500A1 (en) * 2004-12-14 2007-09-19 Biorunx Co., Ltd Method to enhance the bone formation activity of bmp by runx2 acetylation
EP1833500A4 (en) * 2004-12-14 2009-08-12 Biorunx Co Ltd METHOD FOR REINFORCING BONE-MAKING ACTIVITY OF BMP BY RUNX2 ACETYLATION
US20060205941A1 (en) * 2004-12-16 2006-09-14 Bressi Jerome C Histone deacetylase inhibitors
US10285959B2 (en) 2005-02-03 2019-05-14 Topotarget Uk Limited Combination therapies using HDAC inhibitors
US10799469B2 (en) 2005-02-03 2020-10-13 Topotarget Uk Limited Combination therapies using HDAC inhibitors
US20080202944A1 (en) * 2005-04-22 2008-08-28 Eduardo Santoli Method for Use of an Electrochemical Sensor and Electrodes Forming Said Sensor
US20090215800A1 (en) * 2005-05-05 2009-08-27 Chroma Therapeutics Ltd Enzyme and Receptor Modulation
US20060258694A1 (en) * 2005-05-11 2006-11-16 Bressi Jerome C Histone deacetylase inhibitors
US9957227B2 (en) 2005-05-13 2018-05-01 Topotarget Uk Limited Pharmaceutical formulations of HDAC inhibitors
US8835501B2 (en) 2005-05-13 2014-09-16 Topotarget Uk Limited Pharmaceutical formulations of HDAC inhibitors
US20080194690A1 (en) * 2005-05-13 2008-08-14 Topotarget Uk Limited Pharmaceutical Formulations Of Hdac Inhibitors
US9856211B2 (en) 2005-05-13 2018-01-02 Topotarget Uk Limited Pharmaceutical formulations of HDAC inhibitors
US20080132575A1 (en) * 2005-05-20 2008-06-05 Jeannie Chow Wong Formulations Of Suberoylanilide Hydroxamic Acid And Methods For Producing Same
US8288440B2 (en) 2005-05-20 2012-10-16 Merck Sharp & Dohme Corp. Formulations of suberoylanilide hydroxamic acid and methods for producing same
US20100119596A1 (en) * 2005-05-20 2010-05-13 Jeannie Chow Wong Formulations of suberoylanilide hydroxamic acid and methods for producing same
US8450372B2 (en) 2005-05-20 2013-05-28 Merck Sharp & Dohme Corp. Formulations of suberoylanilide hydroxamic acid and methods for producing same
US8093295B2 (en) 2005-05-20 2012-01-10 Merck Sharp & Dohme Corp. Formulations of suberoylanilide hydroxamic acid and methods for producing the same
US20090111996A1 (en) * 2005-07-14 2009-04-30 Bressi Jerome C Histone deacetylase inhibitors
US20080114037A1 (en) * 2005-07-14 2008-05-15 Bressi Jerome C Histone deacetylase inhibitors
US20080119658A1 (en) * 2005-07-14 2008-05-22 Bressi Jerome C Histone deacetylase inhibitors
US20080108829A1 (en) * 2005-07-14 2008-05-08 Bressi Jerome C Histone deacetylase inhibitors
US20070015809A1 (en) * 2005-07-14 2007-01-18 Bressi Jerome C Histone deacetylase inhibitors
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7741494B2 (en) 2005-07-14 2010-06-22 Takeda San Diego, Inc. Histone deacetylase inhibitors
US20080119648A1 (en) * 2005-07-14 2008-05-22 Bressi Jerome C Histone deacetylase inhibitors
US20090036368A1 (en) * 2005-09-14 2009-02-05 Hamlet Pharma Ab Therapeutic Combination
WO2007031853A3 (en) * 2005-09-14 2007-05-18 Hamlet Pharma Ab Therapeutic combination of hamlet and a hdac inhibitor to treat cancer
WO2007031853A2 (en) * 2005-09-14 2007-03-22 Nya Hamlet Pharma Ab Therapeutic combination of hamlet and a hdac inhibitor to treat cancer
US20070197473A1 (en) * 2005-11-04 2007-08-23 Frankel Stanley R Methods of using SAHA and Bortezomib for treating cancer
WO2007056244A2 (en) * 2005-11-04 2007-05-18 Merck & Co., Inc. Methods of using saha and erlotinib for treating cancer
US20070197568A1 (en) * 2005-11-04 2007-08-23 Paul Bunn Methods of using SAHA and Erlotinib for treating cancer
US20090247549A1 (en) * 2005-11-04 2009-10-01 Frankel Stanley R Methods of using saha and bortezomib for treating cancer
WO2007056244A3 (en) * 2005-11-04 2007-09-07 Merck & Co Inc Methods of using saha and erlotinib for treating cancer
US20080274120A1 (en) * 2005-11-10 2008-11-06 Topotarget Uk Limited Histone Deacetylase (Hdac) Inhibitors (Pxd101) for the Treatment of Cancer Alone or in Combination With Chemotherapeutic Agent
US9603926B2 (en) 2005-11-10 2017-03-28 Topotarget Uk Limited Histone deacetylase (HDAC) inhibitors for the treatment of cancer
US8828392B2 (en) 2005-11-10 2014-09-09 Topotarget Uk Limited Histone deacetylase (HDAC) inhibitors (PXD101) for the treatment of cancer alone or in combination with chemotherapeutic agent
US20070129290A1 (en) * 2005-11-18 2007-06-07 Or Yat S Metabolite derivatives of the HDAC inhibitor FK228
US20070173527A1 (en) * 2006-01-13 2007-07-26 Bressi Jerome C Histone deacetylase inhibitors
US9539303B2 (en) 2006-04-24 2017-01-10 Celgene Corporation Treatment of Ras-expressing tumors
US20090305956A1 (en) * 2006-04-24 2009-12-10 Gloucester Pharmaceuticals, Inc. Treatment of Ras-Expressing Tumors
US8957027B2 (en) 2006-06-08 2015-02-17 Celgene Corporation Deacetylase inhibitor therapy
US20080124403A1 (en) * 2006-06-08 2008-05-29 Gloucester Pharmaceuticals Deacetylase inhibitor therapy
US9259452B2 (en) 2006-06-08 2016-02-16 Gelgene Corporation Deacetylase inhibitor therapy
US8962825B2 (en) 2006-10-30 2015-02-24 Glaxosmithkline Intellectual Property Development Limited Hydroxamates as inhibitors of histone deacetylase
US20100317678A1 (en) * 2006-10-30 2010-12-16 Chroma Therapeutics Ltd. Hydroxamates as inhibitors of histone deacetylase
US20100113392A1 (en) * 2006-11-03 2010-05-06 Badros Ashraf Z Methods of using saha and bortezomib for treating multiple myeloma
US8691534B2 (en) 2006-12-29 2014-04-08 Celgene Corporation Preparation of romidepsin
US20090186382A1 (en) * 2006-12-29 2009-07-23 Verdine Gregory L Preparation of Romidepsin
US20090209616A1 (en) * 2006-12-29 2009-08-20 Verdine Gregory L Preparation of romidepsin
US20100093610A1 (en) * 2006-12-29 2010-04-15 Vrolijk Nicholas H Romidepsin-based treatments for cancer
US20100113602A1 (en) * 2007-02-27 2010-05-06 The United States Of America,As Represented By The Secretary,Department Of Health And Human Services Use of histone deacetylase inhibitors for the treatment of central nervous system metastases
US20100286279A1 (en) * 2007-09-25 2010-11-11 Topotarget Uk Limited Methods of Synthesis of Certain Hydroxamic Acid Compounds
US8642809B2 (en) 2007-09-25 2014-02-04 Topotarget Uk Ltd. Methods of synthesis of certain hydroxamic acid compounds
US20110003777A1 (en) * 2008-03-07 2011-01-06 Topotarget A/S Methods of Treatment Employing Prolonged Continuous Infusion of Belinostat
US20100190694A1 (en) * 2009-01-14 2010-07-29 Jan Fagerberg Methods for identifying patients who will respond well to cancer treatment
US8980825B2 (en) 2010-07-12 2015-03-17 Celgene Corporation Romidepsin solid forms and uses thereof
US9624271B2 (en) 2010-07-12 2017-04-18 Celgene Corporation Romidepsin solid forms and uses thereof
US9518094B2 (en) 2010-07-12 2016-12-13 Celgene Corporation Romidepsin solid forms and uses thereof
US8859502B2 (en) 2010-09-13 2014-10-14 Celgene Corporation Therapy for MLL-rearranged leukemia
AU2011311531B2 (en) * 2010-10-08 2014-11-20 Life Sciences Research Partners Vzw HDAC inhibitors to treat Charcot-Marie-Tooth disease
US9238028B2 (en) * 2010-10-08 2016-01-19 Vib Vzw HDAC inhibitors to treat charcot-marie-tooth disease
WO2012045804A1 (en) * 2010-10-08 2012-04-12 Vib Vzw Hdac inhibitors to treat charcot-marie-tooth disease
US9134325B2 (en) 2012-09-07 2015-09-15 Celgene Corporation Resistance biomarkers for HDAC inhibitors
US9101579B2 (en) 2012-11-14 2015-08-11 Celgene Corporation Inhibition of drug resistant cancer cells
US9468664B2 (en) 2013-12-27 2016-10-18 Celgene Corporation Romidepsin formulations and uses thereof
US9463215B2 (en) 2013-12-27 2016-10-11 Celgene Corporation Romidepsin formulations and uses thereof
US9782451B2 (en) 2013-12-27 2017-10-10 Celgene Corporation Romidepsin formulations and uses thereof
US9795650B2 (en) 2013-12-27 2017-10-24 Celgene Corporation Romidepsin formulations and uses thereof
US11583521B2 (en) * 2020-07-01 2023-02-21 Jubilant Pharma Holdings Inc. Long-acting injection dosage form of beta 3 adrenoreceptor agonists

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US20120041067A1 (en) 2012-02-16
RU2394022C2 (ru) 2010-07-10
EP2322160A1 (en) 2011-05-18
US20040127523A1 (en) 2004-07-01
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CN1720034A (zh) 2006-01-11
EP1487426A2 (en) 2004-12-22
RU2010108448A (ru) 2011-09-20
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US7732490B2 (en) 2010-06-08
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AU2003213684A1 (en) 2003-09-22
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CA2671976A1 (en) 2003-09-18
CN101259120A (zh) 2008-09-10
NO332749B1 (no) 2013-01-07
KR100892016B1 (ko) 2009-04-07
KR20070057794A (ko) 2007-06-07
WO2003075839A2 (en) 2003-09-18
ZA200407942B (en) 2006-05-31
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JP2010001302A (ja) 2010-01-07
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US20080119562A1 (en) 2008-05-22
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US20040127522A1 (en) 2004-07-01
US20080114069A1 (en) 2008-05-15
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NO329984B1 (no) 2011-01-31
JP4732693B2 (ja) 2011-07-27
PL372239A1 (en) 2005-07-11
KR100868813B1 (ko) 2008-11-14
ES2532607T3 (es) 2015-03-30
AU2003213684B2 (en) 2007-04-26
NZ567758A (en) 2009-07-31
EP2266552A3 (en) 2011-03-02
ZA200601757B (en) 2007-11-28
IL163909A (en) 2010-12-30
EP2082737B1 (en) 2014-12-31
JP5675071B2 (ja) 2015-02-25
EP2082737A2 (en) 2009-07-29
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AU2003213684C1 (en) 2008-10-23
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