WO2008042146A1 - Amine base salts of saha and polymorphs thereof - Google Patents
Amine base salts of saha and polymorphs thereof Download PDFInfo
- Publication number
- WO2008042146A1 WO2008042146A1 PCT/US2007/020610 US2007020610W WO2008042146A1 WO 2008042146 A1 WO2008042146 A1 WO 2008042146A1 US 2007020610 W US2007020610 W US 2007020610W WO 2008042146 A1 WO2008042146 A1 WO 2008042146A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- saha
- salt
- composition
- amine base
- lysine
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims abstract description 36
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
Definitions
- the present invention provides amine base salts of SAHA, polymorphs and pharmaceutical compositions thereof.
- the invention provides a method of treating cancer by administering the pharmaceutical composition.
- the invention also provides a crystalline composition comprising the amine base and SAHA.
- the invention also provides methods of obtaining the amine base salt and crystalline composition.
- 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).
- cyclic AMP and retinoic acid (2,3) aclarubicin and other anthracyclines (4).
- retinoic acid 2,3
- aclarubicin aclarubicin
- anthracyclines Despite many advances in the field of oncology, the majority of solid tumors remain incurable in the advanced stages. Cytotoxic therapy is used in most cases, however, it often causes significant morbidity to the patient without significant clinical benefit. Less toxic and more specific agents to treat and control advanced malignancies are being explored.
- 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.
- Histone deacetylase inhibitors such as suberoylanilide hydroxamide acid
- SAHA tumor cell growth arrest, differentiation and/or apoptosis
- 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 (26).
- histone acetylation and deacetylation are mechanisms by which transcriptional regulation in a cell is achieved (27). These effects are thought to occur through changes in the structure of chromatin by altering the affinity of histone proteins for coiled DNA in the nucleosome.
- Hl histones that have been identified in nucleosomes (designated Hl, H2A, H2B, H3 and H4).
- Each nucleosome contains two of each histone type within its core, except for Hl, 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). The hypoacetylated state is thought to inhibit transcription of associated DNA.
- HDAC histone deacetyl
- SAHA ZOLINZA TM (vorinostat)
- SAHA has been shown to be useful for treating cancer, selectively inducing terminal differentiation of neoplastic cells, inducing cell growth arrest and/or inducing apoptosis.
- the inhibition of HDAC by SAHA is thought occur through direct interaction with the catalytic site of the enzyme as demonstrated by X-ray crystallography studies (28).
- HDAC inhibition is not believed to have a generalized effect on the genome, but rather, only affects a small subset of the genome (29).
- 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.
- cells treated in culture with HDAC inhibitors show a consistent induction of the cyclin-dependent kinase inhibitor p21 (30). 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 (31).
- the present invention provides amine base salts of SAHA, polymorphs and pharmaceutical compositions thereof.
- the invention provides SAHA salts from an amine base selected from: Benethamine, Betaine, Choline, Deanol, 2-
- the salt is a Lysine salt of SAHA.
- the invention also provides a crystalline composition comprising the amine base and SAHA.
- the invention provides a method of treating cancer by administering the pharmaceutical composition.
- the invention also provides methods of obtaining the amine base salt and crystalline composition.
- FIG. 1 Figure 1 shows the x-ray diffractogram for the crystalline composition comprising L-Lysine and SAHA.
- FIG. 2 Figure 2 shows the differential scanning calorimetry results of the crystalline composition comprising L-Lysine and SAHA.
- compositions are 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. 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. 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 Compositions of this invention, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
- peaks at 2 ⁇ can shift up to ⁇ 0.3 degrees (error) in one direction, for example, all peaks in X-ray powder powder diffraction pattern shift up to +0.3 degrees, or up to -0.3 degrees.
- An X-ray powder powder diffraction pattern or peaks within that error is considered the same or substantially similar.
- SAHA can form pharmaceutically acceptable salts with a base such as a) an inorganic base, for example, to form an alkali metal salt (e.g. lithium salt, sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), or an ammonium salt; b) an organic base, for example, to form an organic amine salt (e.g.
- the invention provides base amine SAHA salts from Benethamine, Betaine, Choline, Deanol, 2-(Diethylamino)ethanol, Diethanolamine, Ethylenediamine, Hydrabamine, lH-Imidazole, 4-(2-Hydroxyethyl)morpholine, morpholine, Piperidine, Piperazine, Tromethamine or Lysine.
- the invention provides base amine SAHA salts from Benethamine, Betaine, Choline, Deanol, Ethylenediamine, Hydrabamine, 1H-Imidazole, 4-(2-Hydroxyethyl)morpholine, morpholine, Piperidine, Piperazine, Tromethamine or Lysine.
- the invention provides base amine SAHA salts from Betaine, Hydrabamine, Tromethamine or Lysine.
- the invention provides a Lysine salt of SAHA.
- the invention provides an L-Lysine salt of SAHA.
- the invention also provides a pharmaceutical composition comprising a Lysine salt of SAHA and a pharmaceutically acceptable carrier.
- the Lysine to SAHA ratio is 1 :2 or 1:1. In one embodiment, the Lysine to SAHA ratio is 1 :1.
- the salt of SAHA can be in amorphous form.
- the salt of SAHA may be crystalline, micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid.
- the salt of SAHA can be in any crystalline form.
- the invention provides a crystalline composition comprising Lysine and SAHA, and is characterized by an X-ray powder diffraction pattern with copper Ka radiation substantially similar to that set forth in Figure 1.
- the crystalline composition is characterized by an X-ray powder diffraction pattern with copper Ka radiation, including characteristic peaks at 6.8, 20.1 and 23.2 degrees 20.
- the crystalline composition is characterized by an X-ray powder diffraction pattern with copper Ka radiation, including characteristic peaks at 6.8, 12.6, 18.7, 20.1, 23.2, 24.0 degrees 20.
- the crystalline composition is characterized by an X-ray powder diffraction pattern with copper Ka radiation, including characteristic peaks at 6.8, 12.0, 12.6, 16.4, 18.7, 20.1, 23.2, 24.0 and 29.3 degrees 20.
- the endotherm of the crystalline composition exhibits an extrapolated onset temperature of approximately 182°C by differential scanning calorimetry.
- the crystalline composition comprising SAHA and Lysine may have Lysine in the solvent channels of the crystal lattice of SAHA. The interaction between the SAHA and Lysine may be through hydrogen bonding.
- the crystalline composition comprises a Lysine salt of SAHA, wherein the interaction between SAHA and Lysine is electrostatic.
- the invention provides a crystalline composition comprising an amine base and SAHA.
- the crystalline composition comprising SAHA and amine base has the amine base in the solvent channels of the crystal lattice of SAHA.
- the interaction between the SAHA and amine base may be through hydrogen bonding.
- the crystalline composition comprises an amine base salt of SAHA, wherein the interaction between SAHA and amine base is electrostatic.
- compositions comprising hydrates or solvates of the amine base salt of SAHA.
- hydrate includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like.
- the pharmaceutically accetaptable carrier in the pharmaceutical compositions can be in solid particle form.
- 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.
- the 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.
- the pharmaceutical composition described herein may further be comprised of microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
- the percentage of the Compositions of this invention and various excipients in the formulations may vary.
- the pharmaceutical composition may comprise between about 20 and 90%, between about 50-80% or between about 60-70% by weight of the Compositions of this invention.
- the pharmaceutical composition may comprise between about 10 and 70%, between about 20-40%, between about 25-35% by weight microcrystalline cellulose as a carrier or diluent.
- the pharmaceutical composition may comprise between about 1 and 30%, between about 1-10%, between about 2-5% by weight croscarmellose sodium as a disintegrant.
- the pharmaceutical composition may comprise between about 0.1-5% or about 0.5-1.5% by weight magnesium stearate as a lubricant.
- the pharmaceutical composition of the invention is about 50-
- compositions of this invention 80% by weight of compositions of this invention; about 20-40% by weight microcrystalline cellulose; about 1-10% by weight croscarmellose sodium; and about 0.1-5% by weight magnesium stearate.
- the pharmaceutical composition of the invention is about 60-70% by weight of compositions of this invention; about 25-35% by weight microcrystalline cellulose; about 2-5% by weight croscarmellose sodium; and about 0.5-1.5% by weight magnesium stearate.
- the pharmaceutical composition described comprises about 50-200 mg or 50-600 mg of the compositions of this invention.
- a particular embodiment of the invention is a solid formulation of the compositions of this invention with microcrystalline cellulose, NF (Avicel Ph 101), sodium croscarmellose, NF (AC-Di-SoI) and magnesium stearate, NF, contained in a gelatin capsule.
- a further embodiment is a pharmaceutical composition comprising about 100 mg compositions of this invention, about 44.3 mg of microcrystalline cellulose, about 4.5 mg of croscarmellose sodium, about 1.2 mg of magnesium stearate.
- the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e., as a solid or liquid form.
- Suitable solid oral formulations include for example, tablets, capsules, pills, granules, pellets and the like.
- Suitable liquid oral formulations include for example, emulsions, oils and the like.
- the composition is formulated in a capsule.
- the pharmaceutical compositions of the present invention comprise a hard gelatin capsule in addition to the compositions of this invention and the inert carrier or diluent.
- 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 non-aqueous solutions, suspensions, emulsions or oils.
- non-aqueous solvents examples include propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
- 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.
- Suspensions can also include the following components: 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).
- EDTA ethylenediaminetetraacetic acid
- 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), 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, polyethylene glycerol), a glidant (e.g., colloidal silicon dioxide), antioxidants (e.g., ascorbic acid, sodium metabisulfite, butylated binders (e
- the compositions of this invention is prepared with carriers that will protect the compositions 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. Patent No. 4,522,811.
- compositions that contain an active component are well understood in the art, for example, by mixing, granulating, or tablet- forming processes.
- 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 oral compositions are formulated in dosage unit form for ease of administration and uniformity of dosage.
- 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 compositions of this invention 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 Compositions of this invention 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.
- the dosage unit contains about 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 110 mg, 105 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, or 40 mg of compositions of this invention.
- the amount of SAHA in the compositions of this invention is about 100 mg.
- the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
- the pharmaceutical composition is a single capsule, wherein the amount of SAHA in the compositions of this invention is about 100 mg. In one embodiment, the pharmaceutical composition is two capsules, wherein the amount of SAHA in each capsule is about 50 mg.
- the invention also provides a method of obtaining an amine base salt of SAHA comprising the step of adding SAHA and an amine base in a reaction medium.
- the amine base is Lysine.
- the amine base is Benethamine, Betaine, Choline, Deanol, 2-(Diethylamino)ethanol, Diethanolamine, Ethylenediamine, Hydrabamine, lH-Imidazole, 4-(2-Hydroxyethyl)morpholine, morpholine, Piperidine,
- the reaction medium is an organic solvent or mixture of organic solvent and water.
- the organic solvent is ethanol.
- the invention also provides a method of obtaining a crystalline composition comprising SAHA and an amine base comprising the step of crystallizing the amine base salt in an organic solvent or in a mixture of organic solvent and water.
- the amine base is Lysine.
- the amine base is Benethamine, Betaine, Choline, Deanol, 2-(Diethylamino)ethanol, Diethanolamine, Ethylenediamine, Hydrabamine, IH- Imidazole, 4-(2-Hydroxyethyl)morpholine, morpholine, Piperidine, Piperazine, Tromethamine or Lysine.
- the crystalline amine base salt of SAHA is crystallized from an organic solvent.
- the organic solvent may be an alcohol such as methanol, ethanol or isopropanol.
- the organic solvent is one or more of methanol, ethanol, acetonitrile and isopropanol.
- the organic solvent is ethanol.
- the organic solvent used in the reaction medium is the same as that in the crystallization.
- the mixture of organic solvent and water comprises about 1-99% organic solvent and about 99-1% of water. In another embodiment, the mixture comprises 40-99% ethanol and 60%- 1% of water. In one embodiment, the mixture comprises about 15-85% organic solvent and about 1-15% water. In a particular embodiment, the mixture comprises about 85% organic solvent and about 15% water. In another particular embodiment, the mixture comprises 1 : 1 ethanol and water. In yet another particular embodiment, the mixture comprises 9: 1 ethanol and water.
- the ratios or percentages of organic solvent to water described here are by volume.
- the organic solvent is an alcohol (e.g. methanol, ethanol, isopropanol and the like).
- suitable organic solvents as used herein may include, by way of example and without limitation, chlorinated solvents, hydrocarbon solvents, ether solvents, polar protic solvents and polar aprotic solvents.
- Suitable halogenated solvents include, but are not limited to carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 1,2- dichloroethane, 2-chloropropane, hexafluorobenzene, 1 ,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane, chlorotrifluoromethane, bromotrifiuoromethane, carbon tetrafluoride, dichlorofluoromethane, chlorodifluoromethane, trifluorome
- Suitable hydrocarbon solvents include, but are not limited to benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane.
- Suitable ether solvents include, but are not limited to dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, Methylene glycol diisopropyl ether, anisole, or t-butyl methyl ether.
- Suitable polar protic solvents include, but are not limited to methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2- methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, and glycerol.
- Suitable polar aprotic solvents include, but are not limited to dimethylformamide (DMF), dimethylacetamide (DMAC), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), l,3-dimethyl-2-imidazolidinone (DMI), N- methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile (ACN), dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, isopropyl acetate, t-butyl acetate, sulfolane, N,N-dimethylpropionamide, nitromethane, nitrobenzene, hexamethylphosphoramide.
- DMF dimethylformamide
- the invention further provides a method of treating cancer comprising the step of administering to a patient a therapeutically effective amount of an amine base salt of SAHA or crystalline composition comprising an amine base and SAHA.
- the invention also provides the use of an amine base salt of SAHA or crystalline composition comprising an amine base and SAHA in the manufacture of a medicament for the treatment of cancer.
- the amine base is Lysine.
- the amine base is Benethamine, Betaine, Choline, Deanol, 2-(Diethylamino)ethanol, Diethanolamine, Ethylenediamine, Hydrabamine, IH- Imidazole, 4-(2-Hydroxyethyl)morpholine, morpholine, Piperidine, Piperazine, Tromethamine or Lysine.
- 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 an amine base salt of SAHA or crystalline composition comprising an amine base and SAHA, 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 cancer. However, it is also likely that the method would be effective in the treatment of cancer in other mammals.
- Cancer includes but is not limited to 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 pharmaceutical compositions can be used in the treatment of a wide variety of cancers, including but not limited to solid tumors (e.g., tumors of the head and neck, lung, breast, colon, prostate, bladder, rectum, brain, gastric tissue, bone, ovary, thyroid, or endometrium), hematological malignancies (e.g., leukemias, lymphomas, myelomas), carcinomas (e.g. bladder carcinoma, renal carcinoma, breast carcinoma, colorectal carcinoma), neuroblastoma, or melanoma.
- solid tumors e.g., tumors of the head and neck, lung, breast, colon, prostate, bladder, rectum, brain, gastric tissue, bone, ovary, thyroid, or endometrium
- hematological malignancies e.g., leukemias, lymphomas, myelomas
- carcinomas e.g. bladder carcinoma, renal carcinoma, breast carcinoma, colorectal carcinoma
- neuroblastoma e.g.
- Non-limiting examples of these cancers include diffuse large B-cell lymphoma (DLBCL), T-cell lymphomas or leukemias, e.g., cutaneous T-cell lymphoma (CTCL), noncutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotrophic virus (HTLV), adult T-cell leukemia/lymphoma (ATLL), as well as acute lymphocytic leukemia, acute nonlymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, multiple myeloma, mesothelioma, childhood solid tumors, brain neuroblastoma, retinoblastoma, glioma, Wilms' tumor, bone cancer and soft-tissue sarcomas, common solid tumors of adults such as head and
- the pharmaceutical composition may be administered orally in a gelatin capsule.
- the composition may be administered in unit dosages according to the methods described herein once-daily, twice-daily or three times-daily.
- 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.
- 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 pharmaceutical compositions of the present invention may be administered 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, or 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.
- the amine base salt of SAHA is administered to the patient at a total daily dosage of 200 mg. In another embodiment, the amine base salt of SAHA is administered to the patient at a total daily dosage of 400 mg. In another embodiment, the amine base salt of SAHA is administered to the patient at a total daily dosage of 600 mg.
- the amount of the amine base salt of SAHA administered to the patient is less than an amount that would cause unmanageable toxicity in the patient. In certain embodiments, the amount of the amine base salt of SAHA 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. In one embodiment, the concentration of the amine base salt of SAHA in the patient's plasma is maintained at between about 10 nM to about 5000 nM. The optimal amount of the amine base salt of SAHA 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 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,
- Suitable agents are those agents that promote depolarization of tubulin.
- the antitumor agent is colchicine or a vinca alkaloid; vinblastine or 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.
- Alkylating agents react with nucleophilic residues, such as the chemical entities on the nucleotide precursors for DNA production. They affect the process of cell division by alkylating these nucleotides and preventing their assembly into DNA.
- alkylating agents include, but are not limited to, bischloroethylamines (nitrogen mustards, e.g., chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard), aziridines (e.g., thiotepa), alkyl alkone sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, streptozocin), nonclassic alkylating agents (altretamine, dacarbazine, and procarbazine), platinum compounds (carboplastin and cisplatin). These compounds react with phosphate, amino, hydroxyl, sulfihydryl, carboxyl, and imidazole groups.
- nitrogen mustards e.g., chlorambucil, cyclophosphamide, ifosfamide, mechlor
- the alkylating agents are cell cycle phase nonspecific agents because they exert their activity independently of the specific phase of the cell cycle.
- the nitrogen mustards and alkyl alkone sulfonates are most effective against cells in the Gl or M phase. Nitrosoureas, nitrogen mustards, and aziridines impair progression from the Gl and S phases to the M phases. Chabner and Collins eds. (1990) "Cancer Chemotherapy: Principles and Practice", Philadelphia: JB Lippincott.
- the alkylating agents are active against wide variety of neoplastic diseases, with significant activity in the treatment of leukemias and lymphomas as well as solid tumors.
- this group of drugs is routinely used in the treatment of acute and chronic leukemias; Hodgkin's disease; non-Hodgkin's lymphoma; multiple myeloma; primary brain tumors; carcinomas of the breast, ovaries, testes, lungs, bladder, cervix, head and neck, and malignant melanoma.
- the major toxicity common to all of the alkylating agents is myelosuppression. Additionally, Gastrointestinal adverse effects of variable severity occur commonly and various organ toxicities are associated with specific compounds. Black and Livingston (1990) Drugs 39: 489-501; and 39: 652-673.
- Antibiotics act by directly inhibiting DNA or RNA synthesis and are effective throughout the cell cycle.
- antibiotic agents include anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione), mitomycin C, bleomycin, dactinomycin, plicatomycin.
- anthracyclines e.g., doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione
- mitomycin C e.g., doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione
- mitomycin C e.g., doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione
- mitomycin C e.g., doxorubicin, daunorubicin
- Bleomycin is generally believed to chelate iron and forms an activated complex, which then binds to bases of DNA, causing strand scissions and cell death.
- the antibiotic agents have been used as therapeutics across a range of neoplastic diseases, including carcinomas of the breast, lung, stomach and thyroids, lymphomas, myelogenous leukemias, myelomas, and sarcomas.
- the primary toxicity of the anthracyclines within this group is myelosuppression, especially granulocytopenia. Mucositis often accompanies the granulocytopenia and the severity correlates with the degree of myelosuppression.
- cardiac toxicity associated with high dosage administration of the anthracyclines.
- Antimetabolic agents are a group of drugs that interfere with metabolic processes vital to the physiology and proliferation of cancer cells. Actively proliferating cancer cells require continuous synthesis of large quantities of nucleic acids, proteins, lipids, and other vital cellular constituents.
- antimetabolites inhibit the synthesis of purine or pyrimidine nucleosides or inhibit the enzymes of DNA replication. Some antimetabolites also interfere with the synthesis of ribonucleosides and RNA and/or amino acid metabolism and protein synthesis as well. By interfering with the synthesis of vital cellular constituents, antimetabolites can delay or arrest the growth of cancer cells.
- antimetabolic agents include, but are not limited to, fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, and gemcitabine.
- Antimetabolic agents have been widely used to treat several common forms of cancer including carcinomas of colon, rectum, breast, liver, stomach and pancreas, malignant melanoma, acute and chronic leukemia and hair cell leukemia. Many of the adverse effects of antimetabolite treatment result from suppression of cellular proliferation in mitotically active tissues, such as the bone marrow or gastrointestinal mucosa. Patients treated with these agents commonly experience bone marrow suppression, stomatitis, diarrhea, and hair loss. Chen and Grem (1992) Curr. Opin. Oncol. 4: 1089-1098.
- the hormonal agents are a group of drug that regulate the growth and development of their target organs. Most of the hormonal agents are sex steroids and their derivatives and analogs thereof, such as estrogens, progestogens, anti-estrogens, androgens, anti- androgens and progestins. These hormonal agents may serve as antagonists of receptors for the sex steroids to down regulate receptor expression and transcription of vital genes.
- hormonal agents examples include synthetic estrogens (e.g., diethylstibestrol), antiestrogens (e.g., tamoxifen, toremifene, fiuoxymesterol and raloxifene), antiandrogens (bicalutamide, nilutamide, flutamide), aromatase inhibitors (e.g., aminoglutethimide, anastrozole and tetrazole), luteinizing hormone release hormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate and mifepristone.
- synthetic estrogens e.g., diethylstibestrol
- antiestrogens e.g., tamoxifen, toremifene, fiuoxymesterol and raloxifene
- antiandrogens e.g., antiandrogens (bicalutamide, nilut
- Hormonal agents are used to treat breast cancer, prostate cancer, melanoma and meningioma. Because the major action of hormones is mediated through steroid receptors, 60% receptor-positive breast cancer responded to first-line hormonal therapy; and less than 10% of receptor-negative tumors responded. The main side effect associated with hormonal agents is flare. The frequent manifestations are an abrupt increase of bony pain, erythema around skin lesions, and induced hypercalcemia.
- progestogens are used to treat endometrial cancers, since these cancers occur in women that are exposed to high levels of oestrogen unopposed by progestogen.
- Antiandrogens are used primarily for the treatment of prostate cancer, which is hormone dependent. They are used to decrease levels of testosterone, and thereby inhibit growth of the tumor. Hormonal treatment of breast cancer involves reducing the level of oestrogen- dependent activation of oestrogen receptors in neoplastic breast cells. Anti-oestrogens act by binding to oestrogen receptors and prevent the recruitment of coactivators, thus inhibiting the oestrogen signal. LHRH analogues are used in the treatment of prostate cancer to decrease levels of testosterone and so decrease the growth of the tumor.
- Aromatase inhibitors act by inhibiting the enzyme required for hormone synthesis. In post-menopausal women, the main source of oestrogen is through the conversion of androstenedione by aromatase.
- Plant-derived agents are a group of drugs that are derived from plants or modified based on the molecular structure of the agents. They inhibit cell replication by preventing the assembly of the cell's components that are essential to cell division.
- plant derived agents include vinca alkaloids (e.g., vincristine, vinblastine, vindesine, vinzolidine and vinorelbine), podophyllotoxins (e.g., etoposide (VP-16) and teniposide (VM-26)), taxanes (e.g., paclitaxel and docetaxel).
- vinca alkaloids e.g., vincristine, vinblastine, vindesine, vinzolidine and vinorelbine
- podophyllotoxins e.g., etoposide (VP-16) and teniposide (VM-26)
- taxanes e.g., paclitaxel and docetaxel.
- Plant-derived agents are used to treat many forms of cancer.
- vincristine is used in the treatment of the leukemias, Hodgkin's and non-Hodgkin's lymphoma, and the childhood tumors neuroblastoma, rhabdomyosarcoma, and Wilms' tumor.
- Vinblastine is used against the lymphomas, testicular cancer, renal cell carcinoma, mycosis fungoides, and Kaposi's sarcoma.
- Doxetaxel has shown promising activity against advanced breast cancer, non- small cell lung cancer (NSCLC), and ovarian cancer.
- Etoposide is active against a wide range of neoplasms, of which small cell lung cancer, testicular cancer, and NSCLC are most responsive.
- the plant-derived agents cause significant side effects on patients being treated.
- the vinca alkaloids display different spectrum of clinical toxicity. Side effects of vinca alkaloids include neurotoxicity, altered platelet function, myelosuppression, and leukopenia.
- Paclitaxel causes dose-limiting neutropenia with relative sparing of the other hematopoietic cell lines.
- the major toxicity of the epipophyllotoxins is hematologic (neutropenia and thrombocytopenia).
- Other side effects include transient hepatic enzyme abnormalities, alopecia, allergic reactions, and peripheral neuropathy.
- Biologic agents are a group of biomolecules that elicit cancer/tumor regression when used alone or in combination with chemotherapy and/or radiotherapy.
- biologic agents include immuno-modulating proteins such as cytokines, monoclonal antibodies against tumor antigens, tumor suppressor genes, and cancer vaccines.
- IL-2 is a T-cell growth factor that is central to T-cell-mediated immune responses. The selective antitumor effects of IL-2 on some patients are believed to be the result of a cell-mediated immune response that discriminate between self and nonself.
- IFN- ⁇ has demonstrated activity against many solid and hematologic malignancies, the latter appearing to be particularly sensitive.
- interferons include, interferon- ⁇ , interferon-/? (fibroblast interferon) and interferon- ⁇ (fibroblast interferon).
- cytokines include erythropoietin (epoietin- ⁇ ), granulocyte-CSF (filgrastin), and granulocyte, macrophage-CSF (sargramostim).
- Other immuno-modulating agents other than cytokines include bacillus Calmette-Guerin, levamisole, and octreotide, a long-acting octapeptide that mimics the effects of the naturally occuring hormone somatostatin.
- the anti-cancer treatment can comprise treatment by immunotherapy with antibodies and reagents used in tumor vaccination approaches.
- the primary drugs in this therapy class are antibodies, alone or carrying e.g. toxins or chemostherapeutics/cytotoxics to cancer cells.
- Monoclonal antibodies against tumor antigens are antibodies elicited against antigens expressed by tumors, preferably tumor-specific antigens.
- monoclonal antibody HERCEPTIN® (trastuzumab) is raised against human epidermal growth factor receptor2 (HER2) that is overexpressed in some breast tumors including metastatic breast cancer. Overexpression of HER2 protein is associated with more aggressive disease and poorer prognosis in the clinic.
- HERCEPTIN® is used as a single agent for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein.
- Another example of monoclonal antibodies against tumor antigens is
- RITUXAN® rituximab
- RITUXAN is used as single agent for the treatment of patients with relapsed or refractory low-grade or follicular, CD20+, B cell non-Hodgkin's lymphoma.
- MYELOT ARG® (gemtuzumab ozogamicin)
- CAMPATH® (alemtuzumab) are further examples of monoclonal antibodies against tumor antigens that may be used.
- Tumor suppressor genes are genes that function to inhibit the cell growth and division cycles, thus preventing the development of neoplasia. Mutations in tumor suppressor genes cause the cell to ignore one or more of the components of the network of inhibitory signals, overcoming the cell cycle checkpoints and resulting in a higher rate of controlled cell growth-cancer. Examples of the tumor suppressor genes include Duc-4, NF-I, NF-2, RB, p53, WTl, BRCAl and BRCA2.
- DPC4 is involved in pancreatic cancer and participates in a cytoplasmic pathway that inhibits cell division.
- NF-I codes for a protein that inhibits Ras, a cytoplasmic inhibitory protein.
- NF-I is involved in neurofibroma and pheochromocytomas of the nervous system and myeloid leukemia.
- NF-2 encodes a nuclear protein that is involved in meningioma, schwanoma, and ependymoma of the nervous system.
- RB codes for the pRB protein, a nuclear protein that is a major inhibitor of cell cycle. RB is involved in retinoblastoma as well as bone, bladder, small cell lung and breast cancer.
- TAAs tumor-associated antigens
- GM2 prostate specific antigen
- PSA prostate specific antigen
- AFP ⁇ -fetoprotein
- CEA carcinoembryonic antigen
- MART-I gap 100, MAGE 1,3 tyrosinase
- papillomavirus E6 and E7 fragments whole cells or portions/lysates of autologous tumor cells and allogeneic tumor cells.
- Suitable differentiation agents include the compounds disclosed in any one or more of the following references. a) Polar compounds (Marks et al (1987); Friend, C, Scher, W., Holland, J. W., and Sato, T. (1971) Proc. Natl. Acad. Sci. (USA) 68: 378-382; Tanaka, M., Levy, J., Terada, M., Breslow, R., Rifkind, R.
- Lysine (3.78 mL of a 0.1 M solution in water, 0.38 mmol) were added to a 20.0 mL vial.
- SAHA can be synthesized according to the procedure disclosed in U.S. patent publication 2004/0072735.
- the resultant mixture was stirred at 40 °C for 4 h, and cooled to ambient temperature with further stirring for 12 h. After this time, all solvent was removed under reduced pressure and the residue was taken up in ethanol (3.0 mL). The slurry was stirred at ambient temperature for 24 h and the solid was then collected via filtration and dried in a vacuum oven.
- the X-ray powder powder diffraction pattern ( Figure 1) of the crystalline composition was generated on a PANanalytical X'Pert Pro X-ray powder diffractometer using a continuous scan from 2 to 40 degrees 20. Copper K- Alpha 1 (K ⁇ l) and K- Alpha 2 (Ko2) radiation was used as the source. The experiment was run under ambient conditions.
- the crystalline composition is characterized by an X-ray powder diffraction (XRPD) pattern with peaks at 6.8, 20.1 and 23.2 degrees (2 ⁇ ).
- the crystalline composition is further characterized by peaks at 12.6, 18.7 and 24.0 degrees (2 ⁇ ). Additional peaks attributed to the crystalline composition are observed at 12.0, 16.4 and 29.3 degrees (20).
- the DSC curve ( Figure 2) was generated by a TA Instruments QlOOO differential scanning calorimeter at a heating rate of 10°C/min from room temperature to 300 0 C in a crimped aluminum pan with a nitrogen atmosphere. The endotherm exhibits an extrapolated onset temperature of approximately 182°C.
- EXAMPLE 4 Patient Studies Patients are administered an oral pharmaceutical composition comprising an amine base SAHA salt or crystalline composition comprising an amine base and SAHA. Patients with either Cutaneous T-cell Lymphoma or Peripheral T-cell Lymphoma are administered the pharmaceutical composition once daily continuously, wherein the amount of SAHA administered is 400 mg. Patients with either Cutaneous T-cell Lymphoma or Peripheral T-cell Lymphoma are administered the pharmaceutical composition twice daily three to five days per week, wherein the amount of SAHA administered for each dose is 300 mg.
- Patients with advanced leukemias and myelodysplatic syndrome are administered the pharmaceutical composition orally (po) three times (tid) a day for 14 days followed by 1 week of rest, for a 3- week course, wherein the amount of SAHA administered for each dose is at 100 mg, 150 mg, 200 mg or 250 mg.
Abstract
Description
Claims
Priority Applications (5)
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CA002663614A CA2663614A1 (en) | 2006-09-28 | 2007-09-24 | Amine base salts of saha and polymorphs thereof |
EP07838753A EP2079304A4 (en) | 2006-09-28 | 2007-09-24 | Amine base salts of saha and polymorphs thereof |
AU2007302670A AU2007302670A1 (en) | 2006-09-28 | 2007-09-24 | Amine base salts of SAHA and polymorphs thereof |
US12/311,403 US20100035991A1 (en) | 2006-09-28 | 2007-09-24 | Amide base salts of saha and polymorphis thereof |
JP2009530389A JP2010504969A (en) | 2006-09-28 | 2007-09-24 | SAHA amine base salts and polymorphs thereof |
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US84830106P | 2006-09-28 | 2006-09-28 | |
US60/848,301 | 2006-09-28 |
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WO2008042146A1 true WO2008042146A1 (en) | 2008-04-10 |
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PCT/US2007/020610 WO2008042146A1 (en) | 2006-09-28 | 2007-09-24 | Amine base salts of saha and polymorphs thereof |
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US (1) | US20100035991A1 (en) |
EP (1) | EP2079304A4 (en) |
JP (1) | JP2010504969A (en) |
CN (1) | CN101516191A (en) |
AU (1) | AU2007302670A1 (en) |
CA (1) | CA2663614A1 (en) |
WO (1) | WO2008042146A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2012509929A (en) * | 2008-11-26 | 2012-04-26 | ジェネリクス・(ユーケー)・リミテッド | Polymorphism |
WO2012103165A2 (en) | 2011-01-26 | 2012-08-02 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies and uses thereof |
WO2014018625A1 (en) | 2012-07-25 | 2014-01-30 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies and uses thereof |
US9162974B2 (en) | 2008-10-15 | 2015-10-20 | Generics (Uk) Limited | Process for the preparation of vorinostat |
Families Citing this family (1)
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US20090076154A1 (en) * | 2007-09-17 | 2009-03-19 | Protia, Llc | Deuterium-enriched vorinostat |
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US5804601A (en) * | 1995-04-10 | 1998-09-08 | Takeda Chemical Industries, Ltd. | Aromatic hydroxamic acid compounds, their production and use |
US20040122101A1 (en) * | 2002-03-04 | 2004-06-24 | Miller Thomas A. | Polymorphs of suberoylanilide hydroxamic acid |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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IT1252708B (en) * | 1991-12-23 | 1995-06-26 | Guidotti & C Spa Labor | STABLE SALTS OF (+) - (1R, 2S) -2 ((N- (2-HYDROXYLAMINE-2-OSSOETHL) -N-METHYLAMINE) CARBONYL) CYCLOHEXAN-1-CARBOXYL, ACE INHIBITIVE ACTIVITY, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
PE20020354A1 (en) * | 2000-09-01 | 2002-06-12 | Novartis Ag | HYDROXAMATE COMPOUNDS AS HISTONE-DESACETILASE (HDA) INHIBITORS |
-
2007
- 2007-09-24 JP JP2009530389A patent/JP2010504969A/en not_active Withdrawn
- 2007-09-24 EP EP07838753A patent/EP2079304A4/en not_active Withdrawn
- 2007-09-24 CN CNA2007800351059A patent/CN101516191A/en active Pending
- 2007-09-24 US US12/311,403 patent/US20100035991A1/en not_active Abandoned
- 2007-09-24 WO PCT/US2007/020610 patent/WO2008042146A1/en active Application Filing
- 2007-09-24 CA CA002663614A patent/CA2663614A1/en not_active Abandoned
- 2007-09-24 AU AU2007302670A patent/AU2007302670A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5804601A (en) * | 1995-04-10 | 1998-09-08 | Takeda Chemical Industries, Ltd. | Aromatic hydroxamic acid compounds, their production and use |
US20040122101A1 (en) * | 2002-03-04 | 2004-06-24 | Miller Thomas A. | Polymorphs of suberoylanilide hydroxamic acid |
Non-Patent Citations (1)
Title |
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See also references of EP2079304A4 * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9162974B2 (en) | 2008-10-15 | 2015-10-20 | Generics (Uk) Limited | Process for the preparation of vorinostat |
JP2012509929A (en) * | 2008-11-26 | 2012-04-26 | ジェネリクス・(ユーケー)・リミテッド | Polymorphism |
WO2012103165A2 (en) | 2011-01-26 | 2012-08-02 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies and uses thereof |
EP3763740A1 (en) | 2011-01-26 | 2021-01-13 | Celldex Therapeutics, Inc. | Anti-kit antibodies and uses thereof |
WO2014018625A1 (en) | 2012-07-25 | 2014-01-30 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies and uses thereof |
EP3381943A1 (en) | 2012-07-25 | 2018-10-03 | Celldex Therapeutics, Inc. | Anti-kit antibodies and uses thereof |
EP4063391A1 (en) | 2012-07-25 | 2022-09-28 | Celldex Therapeutics, Inc. | Anti-kit antibodies and uses thereof |
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US20100035991A1 (en) | 2010-02-11 |
EP2079304A4 (en) | 2010-01-06 |
CA2663614A1 (en) | 2008-04-10 |
AU2007302670A1 (en) | 2008-04-10 |
EP2079304A1 (en) | 2009-07-22 |
CN101516191A (en) | 2009-08-26 |
JP2010504969A (en) | 2010-02-18 |
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