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• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
• • 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
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/18—Sulfonamides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/10—Expectorants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• Myeloproliferative syndromes are disorders of the neoplastic type which have in common the fact that they originate from pluripotent stem cells from bone marrow, that is to say, cells which, by dividing, can form various types of blood cell.
• CML chronic myeloid leukaemia
• PV polycythemia vera
• ET essential thrombocythemia
• IM idiopathic myelofibrosis
• the molecular basis for chronic myeloid leukaemia has been known for some time and consists in the formation of the Philadelphia chromosome, or the 9; 22 translocation, and the generation of the BCR-ABL fusion gene; in these cases, called Philadelphia-positive myeloproliferative syndromes, the use of a specific ABL tyrosine kinase inhibitor (such as imitinib or desatinib) makes it possible to intervene selectively in the cells responsible for the pathology, limiting the possible consequences of a non-specific cytotoxicity to the detriment of the healthy cells.
• a specific ABL tyrosine kinase inhibitor such as imitinib or desatinib
• Histone deacetylases are enzymes capable of removing the acetyl group bound to the lysine residues in the N-terminal portion of histones or in other proteins.
• HDACs can be subdivided into four classes, on the basis of structural homologies.
• Class I HDACs HDAC 1, 2, 3 and 8 are similar to the RPD3 yeast protein and are located in the cell nucleus.
• Class II HDACs HDAC 4, 5, 6, 7, 9 and 10 are similar to the HDA1 yeast protein and are located both in the nucleus and in the cytoplasm.
• Class III HDACs are a structurally distinct form of NAD-dependent enzymes correlated with the SIR2 yeast protein.
• Class IV (HDAC 11) consists at the moment of a single enzyme having particular structural characteristics.
• HDACs of classes I, II and IV are zinc enzymes and can be inhibited by various classes of molecule: hydroxamic acid derivatives, cyclic tetrapeptides, short-chain fatty acids, aminobenzamides, derivatives of electrophilic ketones, and the like.
• Class III HDACs are not inhibited by hydroxamic acids, and their inhibitors have structural characteristics different from those of the other classes.
• histone deacetylase inhibitor in relation to the present invention is to be understood as meaning any molecule of natural, recombinant or synthetic origin capable of inhibiting the activity of at least one of the enzymes classified as histone deacetylases of class I, class II or class IV.
• Histone deacetylase inhibitors are a class of molecules provided with anti-neoplastic and anti-inflammatory activity.
• histone deacetylase inhibitors inhibit cell proliferation and induce cell death and differentiation [Gaofeng Bi and Guosheng Jiang in Cellular & Molecular Immunology 3, 285-290 (2006)].
• Histone deacetylase inhibitors are also capable of modulating the production of cytokines and other pro-inflammatory factors on the part of immuno-competent cells and have demonstrated, in vivo, anti-inflammatory properties [Frederic Blanchard and Céline Chipoy in Drug Discovery Today 10, 197-204 (2005); IM Adcock in British Journal of Pharmacology 150, 829-831 (2007)].
• a histone deacetylase inhibitor (Zolinza, vorinostat) has been approved for the treatment of cutaneous T-cell lymphoma.
• histone deacetylase inhibitors currently at the clinical study stage are described, with other analogues thereof, in the following patents: WO 2004/092115, WO 2005/019174, WO 2003/076422, WO 1997/043251, WO 2006/010750, WO 2006/003068, WO 2002/030879, WO 2002/022577, WO 1993/007148, WO 2008/033747, WO 2004/069823, EP 0847992 and WO 2004/071400, the contents of which are incorporated herein by reference in their entirety.
• ITF2357 reduced by 50% the release of tumor necrosis factor- ⁇ (TNF ⁇ ) at 10 to 22 nM, the release of intracellular interleukin (IL)-1 ⁇ at 12 nM, the secretion of IL-1 ⁇ at 12.5 to 25 nM, and the production of interferon- ⁇ (IFN ⁇ ) at 25 nM.
• Oral administration of 1.0 to 10 mg/kg ITF2357 to mice reduced LPS-induced serum TNF ⁇ and IFN ⁇ by more than 50% [Flavio Leoni et al. in Molecular Medicine 11, 1-15 (2005)].
• ITF2357 is capable of inhibiting the clonogenic activity of stem cells obtained from patients suffering from PV or ET [V. Guerini et al. Leukemia 22, 740-747 (2008)].
• concentrations at which inhibition of clonogenic activity is obtained are much lower than those necessary for obtaining a modification of the molecular markers (JAK2 V617F and STAT proteins) or a cytotoxic effect; the ambiguity of these results makes it difficult to provide for the transferability of these effects, obtained in vitro, to situations of treatment in vivo, especially for any therapeutic treatments in humans.
• the therapeutic dose of such an active principle, for the treatment of Philadelphia-negative myeloproliferative syndromes in humans is significantly lower than that normally used for the care of tumour syndromes and may be from 10 to 150 mg/day/patient, preferably from 30 to 120 mg/day/patient, and even more preferably from 50 to 100 mg/day/patient.
• the dose of ZolinzaTM (vorinostat) indicated for the treatment of cutaneous T-cell lymphoma is 400 mg/day.
• the present invention relates to the use of diethyl-[6-(4-hydroxycarbamoyl-phenylcarbamoyloxymethyl)-naphthalen-2-yl methyl]-ammonium chloride, preferably in monohydrate form, more preferably in monohydrate crystal form for the therapeutic treatment of Philadelphia-negative myeloproliferative syndromes (polycythemia vera, essential thrombocythemia or idiopathic myelofibrosis).
• Such an active principle may be used alone, i.e. not in combination with other active principles, or in combination with other cytostatic active principles such as, purely by way of example, hydroxyurea or pipobroman.
• the present invention relates also to the therapeutic use of such an active principle, for the treatment of Philadelphia-negative myeloproliferative syndromes, at daily doses lower than those used for the treatment of tumour pathologies (for example: cutaneous T-cell lymphoma), these doses being from 10 to 150 mg/day/patient, preferably from 30 to 120 mg/day/patient, and even more preferably from 50 to 100 mg/day/patient.
• tumour pathologies for example: cutaneous T-cell lymphoma
• treatment in relation to the present invention, is to be understood as meaning the action of caring for, relieving, mitigating, minimizing, eliminating or blocking the harmful effects resulting from the pathological state or the progression of the disease.
• the inhibitory activity of a particular compound, with respect to histone deacetylases may be measured in vitro using, for example, an enzyme test which demonstrates the inhibition of at least one of these enzymes. Tests of this type are known in the literature: see, for example, P. A. Marks et al. in J. Natl. Cancer Inst. 92 1210-1215 (2000); L. M. Butler et al. in Cancer Res. 60 5165-5170 (2000); V. M. Richon et al. in Proc. Natl. Acad. Sci. USA 95 3003-3007 (1998); M. Yoshida et al. in J. Biol. Chem. 265 17174-17179 (1990); kits for measuring the HDAC inhibition are also available commercially (e.g. Biomol International LP (USA); HDAC1 Fluorimetric Drug Discovery Kit, product number BML-AK511-0001).
• Duration of the treatment up to a maximum of 24 weeks of continual administration.
• the JAK2 V617F mutated, human cell line SET-2 (a megakaryoblastic cell line established from the peripheral blood of a patient with leukemic transformation of essential thrombocythemia) was obtained by the German cell bank DSMZ (catalogue number ACC 608) and grown in 24 well plates in culture medium (RPMI 1640+Hepes buffer 1M+Penicillin 10.000 IU/ml+Streptomycin 10.000 ⁇ g/ml+20% foetal calf serum). Previous experiments were carried out to determine the optimal number of cells giving a sufficient number of clones in each Petri dish to make a reproducible counting. In the case of the SET-2 line the number corresponded to 3 ⁇ 10 3 cells/Petri dish.
• the cells were harvested by centrifugation (10 min at 10 3 rpm) and then suspended in culture medium at the concentration of 90 ⁇ 10 3 cells/ml. 100 ⁇ l of the suspension were added to 3.0 ml of methyl-cellulose (MethocultTM, catalogue number H4230, Stemcell Technologies) prepared as described by manufacturer and, then, 50 ⁇ l of 63 fold concentrated solution of the HDAC inhibitor in 0.1% DMSO was added. For each compound 5 serial dilutions (1000-12 nM range) were tested. The methyl-cellulose solution containing the HDAC inhibitor was then carefully mixed using a sterile plastic Pasteur pipette avoiding the formation of bubbles.
• methyl-cellulose Metal-cellulose
• the EC 50 value (concentration required to reduce of 50% the number of clones) was calculated using GraphPad Prism 5.0 software and reported in the table below. Values for rhHDAC1 inhibition are also reported: the enzyme was obtained from BPS Biosciences (cat n. 50001) and the test was carried out using a BIOMOL kit, according to supplier instructions.

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