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WO2016195353A1 - Utilisation de 1'-cyano-cytarabine permettant le traitement du cancer - Google Patents

Utilisation de 1'-cyano-cytarabine permettant le traitement du cancer Download PDF

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Publication number
WO2016195353A1
WO2016195353A1 PCT/KR2016/005715 KR2016005715W WO2016195353A1 WO 2016195353 A1 WO2016195353 A1 WO 2016195353A1 KR 2016005715 W KR2016005715 W KR 2016005715W WO 2016195353 A1 WO2016195353 A1 WO 2016195353A1
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WO
WIPO (PCT)
Prior art keywords
cancer
ara
cyano
compound
cda
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Ceased
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PCT/KR2016/005715
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English (en)
Inventor
Su-Sung OH
Hyangmi KIM
Seongrim BYEON
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Kainos Medicine Inc
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Kainos Medicine Inc
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Publication date
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Publication of WO2016195353A1 publication Critical patent/WO2016195353A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

Definitions

  • the present invention relates to a cytidine deaminase (CDA)-resistant compound selected from the group consisting of ⁇ -cyano-cytarabine (l'-CN- Ara-C), ⁇ -cyano-gemcitabine, l'-cyano-5-azacytidine and l'-cyano-5-aza-2'- deoxycytidine, a prodrug or an acceptable salt thereof; a pharmaceutical composition comprising the same; and a method for preventing or treating a cancer using the compound.
  • CDA cytidine deaminase
  • Nucleoside analogs as a class of therapeutic agents are prevalent in the clinical treatment of cancer and viral disease (X. Liu, et al. , Expert Opin. Investig. Drugs, 2012, 21 : 541-555).
  • anti-cancer nucleosides are grouped as antimetabolites, hypomethylating agents or others depending on their mechanism of action. They differ greatly in the means by which they cause cell death after they are incorporated into DNA.
  • the key biochemical pathway responsible for the cytotoxic action of nucleoside analogs is mediated mainly by the incorporation of the drug into DNA which subsequently results in interfere with DNA replication or termination of DNA synthesis (A. J. Townsend, et al , Molecular Pharmacology, 1987, 32: 330-339; P. Huang et al., J. Bio. Chem., 1990, 265 : 16617- 16625)
  • Anti-cancer nucleosides are typically analogs of natural nucleosides of cytidine, adenosine, guanosine and thymidine (B. Ewald, et al. , Oncogene, 2008, 27: 6522-6537).
  • CDA cytidine deaminase
  • CDA is an intracellular enzyme of the pyrimidine salvage pathways that catalyzes the deamination of cytidine and deoxycytidine to uridine and deoxyuridine, respectively (S. Costanzi et al, Chem. Med. Chem., 2012, 6: 1452-1458).
  • human CDA recognizes as substrates a number of cytidine-based anti-cancer drugs such as Ara-C, gemcitabine, decitabine and azacytidine for the degradation of cytosine to uracil.
  • Ara-C is a nucleoside cytotoxic anti-cancer agent useful for the chemotherapy of cancers, especially, hematological malignancies. It has been used as a standard treatment agent for acute myeloid leukemia since 1969. However, Ara-C rapidly undergoes deamination by CDA present in blood and tissues such as liver to become inactive metabolite, uracil- Ara-C. We excrete uracil-Ara-C through urine and Ara-C has no anti-cancer activity. Oral plasma exposure of Ara-C is very low, less than 20%, and clearance rate is high (O. Schiavon, et al, European Journal of Medicinal Chemistry, 2004, 39: 123-133).
  • Ara-C has no anti-cancer effect against solid tumors.
  • formation of uracil-Ara-C by CDA deamination is increased, active metabolite, triphosphate-Ara-C that plays a role in inhibiting DNA synthesis is diminished.
  • very low plasma exposure of Ara-C brings out poor distribution into solid tumor tissues (J. P. Godefridus, Deoxynucleoside Analogs in Cancer Therapy, 2006, 139; W. A. Bleyer, Clinical Cancer Research, 1999, 5 : 3349-3351)
  • cytidine-based nucleoside anti-cancer drugs do not meet the stability requirement against CDA deamination.
  • this modified structure was aimed at achieving improved oral pharmacokinetic properties including high oral absorption via oral administration, high in vivo efficacy with a low dose and expanding indication area to solid tumors, as well as hematological malignancies.
  • a cytidine deaminase (CDA)-resistant compound selected from the group consisting of ⁇ - cyano-cytarabine represented by formula (II), ⁇ -cyano-gemcitabine represented by formula (III), l'-cyano-5-azacytidine represented by formula (IV) and - cyano-5-aza-2'-deoxycytidine represented by formula (V), a prodrug or an acceptable salt thereof:
  • Fig. 1 View of the complex between human CDA (PDB ID: 1MQ0) and
  • Ara-C (a) as resulting from molecular docking -CN-Ara-C (b);
  • Fig. 2 Relative susceptibility of cytidine, Ara-C and -CN- Ara-C to CDA of Test Example 2;
  • Fig. 3 Pharmacokinetics of the Ara-C (mouse) and -CN-Ara-C (mouse, rat and dog) of Test Example 4 through IV and PO administration routes;
  • Fig. 4 The tumor volume of IP and PO Ara-C and ⁇ -CN- Ara-C administered mice in HL-60 human leukemia xenograft of Test Example 5; and Fig. 5: ⁇ -CN- Ara-C concentration in plasma and tumor tissues in HL-60 human leukemia xenograft of Test Example 6.
  • the present invention provides a cytidine deaminase (CDA)-resistant compound selected from the group consisting of -cyano-cytarabine represented by formula (II), ⁇ -cyano-gemcitabine represented by formula (III), l'-cyano-5- azacytidine represented by formula (IV) and l'-cyano-5-aza-2'-deoxy cytidine represented by formula (V), a prodrug or an acceptable salt thereof:
  • CDA cytidine deaminase
  • the compound of the present invention is highly resistant to deamination by CDA and highly stable against CDA.
  • the high level of CDA resistance of the compound of the present invention affords animals such as mouse, rat and dog excellent pharmacokinetic properties and in vivo efficacy by PO or IV administration.
  • the present invention provides a pharmaceutical composition for preventing or treating a cancer, comprising the compound of the present invention as an active ingredient, and a pharmaceutically acceptable carrier or an excipient.
  • the cancer may be selected from the group consisting of hematological malignancies, epithelial tumors, melanoma, leukemia, acute promyelocyte leukemia, lymphoma, osteogenic sarcoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, ovarian cancer, lung cancer and a combination thereof.
  • the compound may be formulated in a pharmaceutical composition, comprising one or more of the compound and a pharmaceutically acceptable carrier or an excipient.
  • the compound can be mixed with a pharmaceutically acceptable carrier or an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable carrier or an excipient which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the compound.
  • the pharmaceutical compositions can be in the form of tablets, pills, powers, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, and other orally ingestible formulations.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, magnesium carbonate, water, ethanol, propylene glycol, syrup, and methyl cellulose.
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propyl-hydroxybenzoates, sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl- and propyl-hydroxybenzoates, sweetening agents
  • preserving agents such as methyl- and propyl-hydroxybenzoates, sweetening agents
  • sweetening agents such as methyl- and propyl-hydroxybenzoates, sweetening agents
  • flavoring agents such as talc, magnesium stearate, and mineral oil
  • the compositions of the present invention can also be formulated so as to provide quick, sustained or delayed release of the novel compound after administration to the patient by employing procedures known in the art.
  • the term "pharmaceutically acceptable carrier” refers to those components in the particular dosage form employed which are considered inert and are typically employed in the pharmaceutical fields to formulate a dosage form containing a particular active compound. This may include without limitation solids, liquids and gases, used to formulate the particular pharmaceutical product.
  • carriers include diluents, flavoring agents, solubilizers, suspending agents, binders or tablet disintegrating agents, encapsulating materials, penetration enhancers, solvents, emollients, thickeners, and dispersants, sustained release forms, such as matrices, transdermal delivery components, buffers, stabilizers, and the like.
  • composition of the present invention may be formulated in the absence or presence of carriers or excipients that provide a sustained released effect.
  • the pharmaceutical composition of the present invention may be prepared according to methods known in the art. It is contemplated that administration of such compositions may be via oral, injectable and/or parenteral routes depending upon the needs of the subject.
  • the pharmaceutical composition of the present invention can also be administered by nasal or oral inhalation, oral ingestion, intramuscular injection, intravenous injection, intraperitoneal injection, transdermally, or other forms of administration.
  • Aerosol formulations for use in this invention typically include propellants, such as a fluorinated alkane, surfactants and co-solvents and may be filled into aluminum or other conventional aerosol containers which are then closed by a suitable metering valve and pressurized with propellant, producing a metered dose inhaler. Aerosol preparations are typically suitable for nasal or oral inhalation, and may be in powder or solution form, in combination with a compressed gas, typically compressed air. Additionally, aerosols may be useful topically. Topical preparations useful herein include creams, ointments, solutions, suspensions and the like. These may be formulated to enable one to apply the appropriate dosage topically to the affected area once daily, up to 3-4 times daily as appropriate. Topical sprays may be included herein as well.
  • propellants such as a fluorinated alkane, surfactants and co-solvents
  • Aerosol preparations are typically suitable for nasal or oral inhalation, and may be in powder or solution form, in combination with a compressed gas, typically
  • transdermal delivery may be an option, which can provide a relatively steady state delivery of the medication.
  • Transdermal delivery typically involves the use of a compound in solution, with an alcoholic vehicle, optionally a penetration enhancer, such as a surfactant and other optional ingredients.
  • Transdermal delivery systems of matrix and reservoir type are examples of suitable transdermal systems.
  • Transdermal delivery differs from conventional topical treatment in that the dosage form delivers a systemic dose of medication to the patient.
  • the present invention includes a method for inhibiting the growth of a cell using a compound of the present invention.
  • the present invention provides a method for inhibiting the growth of a cancer cell in a subject, which comprises administering a therapeutically effective amount of the compound to the subject in need thereof.
  • the present invention provides a method for preventing or treating a cancer in a subject, which comprises administering a therapeutically effective amount of the compound to the subject in need thereof.
  • Combination therapy includes combining the method of preventing or treating cancer as described in the invention and one or more cancer therapeutic methods.
  • the cancer therapeutic methods include surgical therapy, radiation therapy, administering an anticancer agent (including, for example, antineoplastics, novantrone, bicalutamide, esterified estrogens, goserelin, histrelin, leuprolide, nilandron, triptorelin pamoate, docetaxel, taxotere, carboplatin, and cisplatin angiogenesis inhibitors), immunotherapy, antineoplastons, investigational drugs, vaccines, and less conventional therapies (sometimes referred to as novel or innovative therapies, which include, for example, chemoembolization, hormone therapy, local hyperthermia, photodynamic therapy, radiofrequency ablation, stem cell transplantation, and gene therapy).
  • an anticancer agent including, for example, antineoplastics, novantrone, bicalutamide, esterified estrogens, goserelin, histrelin
  • the compound may be administered in combination with other active agents.
  • the compound used in the methods of prevention or treatment is administered in an amount which effectively achieves the desired therapeutic result in a subject.
  • the compound may be administered as a pharmaceutical composition, or in the absence of a carrier or diluent.
  • the dosages of the compound will vary somewhat depending upon the components of the compound, the rate of in vivo hydrolysis, etc. Those skilled in the art can determine the optimal dose of the compound based on clinical experience and the treatment indication.
  • the amount of compound administered to a subject is about 0.1 to about 100 mg/kg of body weight, more preferably, about 5 to about 40 mg/kg.
  • Other preferred dosages include about 0.1 to about 10 mg/kg of body weight, about 1 to about 100 mg/kg of body weight, about 1 to about 60 mg/kg of body weight, about 1 to about 10 mg/kg of body weight, about 10 to about 100 mg/kg of body weight, about 10 to about 60 mg/kg of body weight, about 20 to about 60 mg/kg of body weight and about 30 to about 50 mg/kg of body weight.
  • the compound can also be converted into a pharmaceutically acceptable salt or pharmaceutically acceptable solvate or other physical forms (e.g., polymorphs) by methods known in the art field.
  • the subjects that may be treated using the compounds of the present invention may be mammals including humans.
  • the present invention also includes a use of the compound of the present invention for the manufacture of a medicament for preventing or treating a cancer.
  • the present invention also includes a kit comprising one or more of the compound of the present invention and instructions for its use.
  • Ara-C favorably interacts with the E67 through the H-bonds and with the hydrophobic V38 and C65 with preserved goldscore 51.9 compared to reference goldscore 52.6. However, this interaction is disrupted by the presence of CN in 1 '-position of Ara-C. As shown in Fig.l (b), ⁇ -CN group causes crash in binding pocket with reduced goldscore 45.8.
  • -CN- Ara-C was not a substrate of CD A, and completely resistant to deamination by CDA in vitro.
  • CellTiter-Glo ® Luminescent Cell Viability Assay (Promega #G7572) was used to measure the 50% inhibition concentration (IC 50 ) of the Ara-C and l '-CN- Ara-C against ML-2 (human acute myeloma leukemia), MOLT-4 (human acute lymphoblastic leukemia), MV-4- 1 1 (human biphenotypic B myelomonocytic leukemia), HL-60 (human acute promyelocyte leukemia), Hep G2 (human hepatocellular carcinoma), HCT 1 16 (human colorectal carcinoma) cell lines. Six hundred cells in 90 ⁇ media were plated per well in duplicates in a 96-well plate.
  • l '-CN- Ara-C exhibited the proliferative activities on hematological cancer, liver cancer and colon cancer cells.
  • LC-MS liquid chromatography-mass spectrometry
  • TEST EXAMPLE 5 Tumor growth inhibition efficacy of l'-CN-Ara- C in HL-60 human leukemia xenograft
  • Tumor growth inhibition (TGI) activities of IP-administered Ara-C, and IP/PO-administered l'-CN- Ara-C were compared in HL-60 human leukemia xenografts.
  • Tumor growth inhibitions were observed in in vivo subcutaneous mouse xenograft model (HL-60 cell line, Corning #3603).
  • NOD/SCID female mice of 6-8 week age and weighing approximately 18-22 g, were used for tumor inoculation.
  • the amounts of treated compounds are represented in milligram (mg) of compound per kilogram (kg) of animal body weight (mg/kg, mpk).
  • Administration route of the test compound was either intraperitoneal (IP) injection or peros (PO, oral) injection.
  • mice Three groups, i.e., vehicle group (Control group), Ara-C group (treatment at 40 mpk of cytarabine through IP injection; Comparative group) and ⁇ -CN- Ara-C group (treatment at 40 mpk through IP and 60 mpk through PO injection) of mice were used.
  • the overall administration schedule was 2 cycles of treatment for 5 days (5d ON), followed by 2 days of non-treatment (2d OFF). Tumor sizes were measured using a caliper, once every 4 days, and the tumor volume was expressed in mm using Equation 1 :
  • V 0.5 a x b 2
  • a and b are the long and short diameters of the tumor, respectively.
  • the tumor volume (mm ) and body weight (g) results of the three groups are shown in Fig. 4.
  • tumor growth inhibition (% TGI) and body weight change (% BW change) compared to that of Ara-C were shown in Table 4.
  • oral (PO) dosing of ⁇ -CN- Ara-C shows a good potency.
  • IP dosing of ⁇ -CN- Ara-C exhibited superior efficacy (73% TGI) to IP dosing of Ara-C at the same dose (40 mpk).
  • the concentration of Ara-C and -CN- Ara-C in plasma/tumor tissue were evaluated in Test Example 5 in HL-60 human leukemia xenografts.
  • ⁇ -CN- Ara-C retained high intracellular drug concentration in plasma/tumor tissue from leukemia HL-60 cell derived xenograft model.

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Abstract

La présente invention concerne un composé résistant à la cytidine désaminase (CDA) choisi parmi le groupe constitué de la 1'-cyano-cytarabine, la 1'-cyano-gemcitabine, la 1'-cyano-5-azacytidine et la 1'-cyano-5-aza-2'-désoxycytidine, un promédicament ou un de ses sels pharmaceutiquement acceptables ; une composition pharmaceutique comprenant ledit composé ; et un procédé de prévention ou de traitement d'un cancer à l'aide du composé. En outre, le composé de la présente invention peut être utilisé en tant qu'agent thérapeutique pour la prévention ou le traitement d'un cancer.
PCT/KR2016/005715 2015-06-01 2016-05-30 Utilisation de 1'-cyano-cytarabine permettant le traitement du cancer Ceased WO2016195353A1 (fr)

Applications Claiming Priority (2)

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US201562169030P 2015-06-01 2015-06-01
US62/169,030 2015-06-01

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WO2016195353A1 true WO2016195353A1 (fr) 2016-12-08

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023230A1 (fr) * 1995-12-22 1997-07-03 East Carolina University Procede de traitement des troubles caracterises par une surexpression de la cytidine-desaminase ou de la desoxycytidine-desaminase
US20130196941A1 (en) * 2010-07-13 2013-08-01 Clavis Pharma Asa Parenteral formulations of elacytarabine derivatives
WO2015072784A1 (fr) * 2013-11-14 2015-05-21 Kainos Medicine, Inc. Promédicament réciproque comportant des acides gras à chaîne courte et de la zébularine ou de la 1'-cyano-cytarabine pour un traitement de cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023230A1 (fr) * 1995-12-22 1997-07-03 East Carolina University Procede de traitement des troubles caracterises par une surexpression de la cytidine-desaminase ou de la desoxycytidine-desaminase
US6136791A (en) * 1995-12-22 2000-10-24 East Carolina University Agent and method for treating disorders associated with cytidine deaminase or deoxycytidine deaminase overexpression
US20130196941A1 (en) * 2010-07-13 2013-08-01 Clavis Pharma Asa Parenteral formulations of elacytarabine derivatives
WO2015072784A1 (fr) * 2013-11-14 2015-05-21 Kainos Medicine, Inc. Promédicament réciproque comportant des acides gras à chaîne courte et de la zébularine ou de la 1'-cyano-cytarabine pour un traitement de cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YOSHIDA, TAKAHIRO ET AL.: "Influence of cytidine deaminase on antitumor activity of 2'-deoxycytidine analogs in vitro and in vivo", DRUG METABOLISM & DISPOSITION, vol. 38, no. 10, 2010, pages 1814 - 1819, XP055332831 *

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