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
  • A61K31/70—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
• • 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

Definitions

• the present invention relates to the use of an orally administrable DNMT inhibitor that has high stability to the hydrolytic metabolizing enzyme cytidine deaminase and can replace 5-aza-2'-deoxycytidine.
• CML chronic myelogenous leukemia
• Non-Patent Document 2 There was no curative treatment for CML except for allogeneic hematopoietic stem cell transplantation, but since the advent of imatinib, a ⁇ competitive ⁇ L tyrosine kinase inhibitor (Tyrosine Kinase Inhibitor, ⁇ ) in 2001. The use of this drug dramatically improved the prognosis of CML.
• second-generation ⁇ nolotinib, dasatinib and bosutinib
• third-generation ⁇ which are expected to be more effective than imatinib, can be used clinically, and the treatment results of CML have been further improved.
• Non-Patent Documents 3 to 4 some cases of ⁇ reaction refractory and ⁇ resistance acquisition cases due to point mutations in the ⁇ L tyrosine kinase domain have been reported (Non-Patent Documents 3 to 4), and effective treatments for them are Still limited. On the other hand, it has been reported that epigenetic changes are involved in the stage progression of CML and the acquisition of resistance to ⁇ , and the use of DNMTs inhibitors such as 5-azacitidine has been studied (Non-Patent Documents 5 to 5). 6).
• DNMTs is an abbreviation for DNA methyltransferases, methylation of the 6-position amino group of the adenine ring in the DNA strand (Adenine N 6 -specific DNA-methyltransferase: EC 2.1.1.72), cytosine. Catalyzes methylation of the ring 4-position amino group (Cytosine N 4- specific DNA-methyltransferase: EC 2.1.1.113) or methylation to the cytosine ring 5-position (Cytosine C 5- specific DNA-methyltransferase: EC 2.1.1.37) It is a group of enzymes.
• Non-Patent Documents 7-8 a group of enzymes that catalyze methylation to the 5-position of the cytosine ring in the sequence portion called ⁇ pG island, which is often found in the promoter region of the expressed gene (maintenance methyltransferase DNMT1 and de novo methyltransferase DNMT3 family). Is of particular physiological interest because it plays a vital role in regulating the normal development and differentiation of cells (Non-Patent Documents 7-8).
• DNMTs are also deeply involved in cancer development. That is, it is thought that 60 to 90% of all ⁇ pG have methylation at the 5-position of the cytosine ring, but abnormal levels of DNA methylation are closely related to silencing of expressed genes, and the promoter region. It has been clarified that the transcription / expression of a gene in which ( ⁇ pG island) is methylated at the 5-position of the cytosine ring at a high level is silenced (Non-Patent Documents 9 to 11).
• cells are equipped with a mechanism to introduce a methyl group to the 5-position of the cytosine ring at the same position in the newly created DNA strand, and it is also DNMTs that enable this "replication of DNA methylation". .. Therefore, in cancerous cells, most of the tumor suppressor genes are suppressed in transcription and expression, and are in a silencing state, so that they can easily proliferate.
• the SH group of the cysteine residue at the catalytically active center of DNMT attacks the cytosine ring 6 position in the DNA sequence, thereby activating the cytosine ring 5 position and methylating.
• a reaction mechanism has been proposed that promotes methyl group transfer from the group donor S-adenosyl-L-methionine.
• 5-azacitidine product name: "Vidaza (registered trademark)
• decitabine product name: " Dacogen (registered trademark)
• cytosine nucleosides DNA instead of 2'-deoxycytidine via the nucleic acid biosynthesis route.
• Drugs with such a mechanism of action can be used as a wide range of anticancer agents, but all compounds are easily hydrolyzed by the metabolic enzyme citidine deaminase present in blood and liver. Due to its drawback of being deaminated, it is only used clinically as a therapeutic agent for high-risk myelodysplastic syndrome and acute myelodysplastic syndrome, and because of its chemical instability, it can be used as an injection. The current situation is that it remains. Therefore, it is desired to develop an orally administrable drug that has high stability to cytidine deaminase and can replace 5-azacitidines.
• Patent Documents 1 and 2 SGI-110 (guadecitabin) (Patent Documents 1 and 2) has been found as a compound having high stability to the hydrolytic metabolizing enzyme cytidine deaminase, and a prodrug of 5-aza-2'-deoxycytidine has been found. Although clinical development is underway as a drug, this compound is extremely polar due to its dinucleotide structure, is not easily permeated through the membrane, and is not suitable as an oral administration agent (Non-Patent Documents 12 to 14). ..
• An object of the present invention is to create an orally administrable compound having high stability to the hydrolyzable metabolizing enzyme citidine deaminase and which can replace 5-aza-2'-deoxycytidine, and high-risk bone marrow. It is intended to be provided not only as a therapeutic agent for dysplasia syndrome and acute myelogenous leukemia, but also as a therapeutic agent or a preventive agent for CML ( ⁇ resistant CML) that has acquired ⁇ resistance.
• the present inventors provide a drug that is more useful than 5-aza-2'-deoxycytidine (product name: "Dacogen (registered trademark)" as a therapeutic drug for various myelodysplastic syndromes including high-risk myelodysplastic syndrome.
• a new compound having high stability to the hydrolyzable metabolizing enzyme cytidine deaminase and having excellent pharmacological action and physicochemical properties that can easily enter the nucleic acid biosynthesis route in vivo.
• various sugar-modified derivatives of 5-aza-2'-deoxycytidine were synthesized, and their chemical reactivity and biological activity were investigated.
• the R 3 , R 4 and R 5 are C 1 to C 8 alkyl groups or C 6 to C 10 aryl groups or C 7 to C 14 aryl alkyl groups, respectively, which may have a substituent [1]. ]
• a prophylactic / therapeutic agent for ⁇ -resistant CML which comprises combining the prophylactic / therapeutic agent for ⁇ -resistant CML according to any one of [1] to [9] with a concomitant agent.
• the prophylactic / therapeutic agent for ⁇ -resistant CML according to [10], wherein the concomitant agent is a p53 gene inhibitor or an enzyme inhibitor.
• the enzyme inhibitor is one or more selected from the group consisting of a tyrosine kinase inhibitor (TKI), a histone deacetylase inhibitor, a histone deacetylase inhibitor, a histone demethylase inhibitor, and the like.
• TKI tyrosine kinase inhibitor
• the preventive / therapeutic agent for ⁇ resistant CML is one or more selected from the group consisting of a tyrosine kinase inhibitor (TKI), a histone deacetylase inhibitor, a histone deacetylase inhibitor, a histone demethylase inhibitor, and the like.
• the p53 gene inhibitor or enzyme inhibitor is one or more selected from the group consisting of Pifithrin, Nutlin, DS3201, HBI-8000, Trichostatin A (TSA), Suramin, EPZ005687, Adox and the like.
• TSA Trichostatin A
• Equation (I): (In the formula, R 1 and R 2 are hydrogen atoms or formula (II): respectively.
• R 3 , R 4 and R 5 are alkyl groups or aryl groups or arylalkyl groups which may have substituents, respectively). However, this excludes cases where R 1 and R 2 are hydrogen atoms at the same time.
• a method for preventing or treating ⁇ -resistant CML which comprises administering an effective amount of the compound represented by) or a salt thereof.
• Equation (I): (In the formula, R 1 and R 2 are hydrogen atoms or formula (II): respectively.
• R 3 , R 4 and R 5 are alkyl groups or aryl groups or arylalkyl groups which may have substituents, respectively). However, this does not apply when R 1 and R 2 are hydrogen atoms at the same time.
• a method for preventing or treating ⁇ -resistant CML which comprises administering an effective amount of the compound represented by) or a salt thereof and a concomitant drug.
• R 3 , R 4 and R 5 are alkyl groups or aryl groups or arylalkyl groups which may have substituents, respectively). However, this does not apply when R 1 and R 2 are hydrogen atoms at the same time. ) Use of the compound represented by) or a salt thereof.
• the sugar moiety silyl ether derivative of 5-aza-2'-deoxycytidine is more lipophilic than the corresponding 5-aza-2'-deoxycytidine, allowing oral administration and intestinal tract. After being absorbed in the blood or in the liver, it is non-enzymatically hydrolyzed and activated in the cell membrane or intracellular of CML cells without being affected by the hydrolyzable metabolic enzyme cytidine deaminase, resulting in nucleic acid biosynthesis. Since it is presumed that it exhibits DNMT enzyme inhibitory activity by being incorporated into DNA via the route, it can be expected to function as a therapeutic or prophylactic agent for ⁇ -resistant CML whose expression is induced by DNMT. In addition, the sugar moiety silyl ether derivative of 5-aza-2'-deoxycytidine of the present invention is expected as an effective oral DNMT enzyme inhibitor against ⁇ resistant CML.
• the compound of the present invention or a salt thereof is a compound represented by the following formula (I).
• R 1 and R 2 are hydrogen atoms or formula (II): respectively.
• R 3 , R 4 and R 5 are alkyl groups or aryl groups or arylalkyl groups which may have substituents, respectively). However, this does not apply when R 1 and R 2 are hydrogen atoms at the same time.
• alkyl group refers to a saturated aliphatic hydrocarbon group, for example, a linear or branched or cyclic alkyl group having 1 to 8 carbon atoms, for example, a methyl group or an ethyl group.
• propyl group isopropyl group, butyl group, sec- butyl group, an isobutyl group, tert- butyl group, a pentyl group, C 1 ⁇ C 6 alkyl group such as hexyl, heptyl, 2-methylhexyl group, 5-methyl Hexyl group, 2,2-dimethylpentyl group, 4,4-dimethylpentyl group, 2-ethylpentyl group, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 1,3,3 -Trimethylbutyl group, 2,2,3-trimethylbutyl group, 2,3,3-trimethylbutyl group, 1-propylbutyl group, 1,1,2,2-tetramethylpropyl group, octyl group, 2-methyl Heptyl group, 3-methylheptyl group, 6-methylheptyl group, 2-ethylhexyl group, 5,5-dimethylhexyl group,
• C 1 to C 6 alkyl groups are methyl, ethyl and propyl groups.
• a more preferred example of the C 1 to C 6 alkyl groups is the ethyl group.
• preferred examples of the cyclic alkyl group are a cyclopentyl group and a cyclohexyl group.
• Aryl refers to monocyclic or bicyclic aromatic hydrocarbons. It is preferably a C 6 to C 10 aryl group such as a phenyl group and a naphthyl group, and more preferably a phenyl group.
• Arylalkyl refers to an alkyl group substituted with an aryl. Preferably, a C 7 ⁇ C 14 arylalkyl group. Examples of C 7 to C 14 arylalkyl groups include, but are not limited to, benzyl group, phenethyl group, naphthylmethyl group and the like.
• alkyl group which may have a substituent, the aryl group which may have a substituent, or the arylalkyl group which may have a substituent means that even if it has a substituent, It means that it may be non-replacement.
• the substituent may have 1 to 5, preferably 1 to 3, or more than 2 substituents at the substituents of the alkyl group, aryl group or arylalkyl group. In the case of, each substituent may be the same or different.
• substituent include an alkyl group, a halogen atom, a cyano group, a nitro group and the like, and an example of a preferable substituent is an alkyl group or a halogen atom.
• Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. Preferred examples are fluorine and chlorine atoms.
• the salt of the compound represented by the formula (I) of the present invention may be any salt as long as it is a pharmacologically acceptable salt.
• the salt include inorganic acid salts (for example, hydrochlorides, sulfates, hydrobromates and phosphates, etc.), organic acid salts (for example, acetates, trifluoroacetates, succinates, etc.).
• inorganic acid salts for example, hydrochlorides, sulfates, hydrobromates and phosphates, etc.
• organic acid salts for example, acetates, trifluoroacetates, succinates, etc.
• acid addition salts such as maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.). It is not limited to.
• the compound represented by the formula (I) of the present invention may be a crystal, a single crystal form, or a mixture of a plurality of crystal forms.
• the crystal can be produced by crystallization by applying a crystallization method known per se.
• the compound represented by the formula (I) of the present invention may be a solvate (for example, a hydrate), and a solvate and a non-solvate (for example, a non-hydrate). All of are included in the compound represented by the formula (I).
• the sugar moiety silyl ether derivative of 5-aza-2'-deoxycytidine of the present invention can be a prodrug of 5-aza-2'-deoxycytidine.
• sugar silyl ether derivatives of 5-aza-2'-deoxycytidine are very stable to cytidine deaminase, these derivatives absorbed from the gastrointestinal tract are in the blood. It is expected to have the property of being less susceptible to hydrolytic metabolism by the enzyme cytidine deaminase in the liver.
• the sugar moiety silyl ether derivative of 5-aza-2'-deoxycytidine (see formula (I)) according to the present invention which is expected to have high stability to the above hydrolyzable metabolizing enzymes, is induced to be expressed by DNMT. It can be a therapeutic or prophylactic agent for ⁇ resistant CML.
• Examples of the dehydrohalizing agent to be used include organic bases and inorganic bases, and the organic bases are not limited to these, but imidazole, 1-methylimidazole, morpholine, triethylamine, etc. Examples thereof include N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, n-butyllithium or potassium-tert-butoxide, and examples of the inorganic base include, but are not limited to, sodium hydride, sodium carbonate, and carbonic acid. Examples thereof include sodium hydrogen hydrogen, potassium carbonate, potassium hydrogen carbonate, cesium carbonate and the like.
• the amount of the base used is preferably equal to or more than the equivalent amount of the raw material compound. Further, although the range of usually 1.0 to 50.0 equivalents can be exemplified with respect to 1 mol of the raw material compound, the range of 1.0 to 10.0 equivalents is preferable, and more preferably 1.0 to 5. It is preferably in the range of 0 equivalents.
• the reaction of the present invention is preferably carried out in the presence of a solvent.
• the solvent in the reaction of the present invention may be any solvent as long as the reaction proceeds. Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide.
• the amount of the solvent used may be any amount as long as the reaction proceeds. The amount of solvent used in the reaction of the present invention can be appropriately adjusted by those skilled in the art.
• the reaction temperature of the present invention is not particularly limited.
• the temperature is ⁇ 20 ° C. to 50 ° C. (that is, ⁇ 20 ° C. to + 50 ° C.), preferably ⁇ 10 ° C. to 30 ° C. (Ie, -10 ° C to + 30 ° C), more preferably -10 ° C to 20 ° C (ie, -10 ° C to + 20 ° C), and even more preferably -5 ° C to 15 ° C (ie, -5 ° C to plus). 15 ° C.), particularly preferably in the range of ⁇ 5 ° C. to 10 ° C. (that is, -5 ° C. to + 10 ° C.).
• reaction time The reaction time of the present invention is not particularly limited. In one embodiment, from the viewpoint of improving the yield, suppressing by-products, economic efficiency, etc., 0.5 hours to 120 hours, preferably 1 hour to 72 hours, more preferably 1 hour to 48 hours, and further. Preferably, the range of 1 hour to 24 hours can be exemplified. However, the reaction time of the present invention can be appropriately adjusted by those skilled in the art.
• composition of the Present Invention The compound represented by the formula (I) of the present invention can be used as it is or mixed with a pharmacologically acceptable carrier by a method known per se to prepare a pharmaceutical composition for mammals.
• mammals For example, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.
• a pharmacologically acceptable carrier for example, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.
• the pharmacologically acceptable carrier various conventional organic or inorganic carrier substances are used as the preparation material, and examples thereof include excipients, lubricants, binders and disintegrants in solid preparations. Examples thereof include solvents, solubilizing agents and suspending agents, tensioning agents and buffering agents in liquid preparations. Further, if necessary, preparation additives such as preservatives, antioxidants, colorants and sweeteners can also be used.
• Examples of the dosage form of the pharmaceutical composition include tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, suspensions, oral preparations such as sustained-release agents, and the like. , These can be safely administered orally. However, this does not apply because liquid preparation is also possible.
• the pharmaceutical composition can be produced by a method commonly used in the field of formulation technology, for example, the method described in the Japanese Pharmacopoeia.
• the compound represented by the formula (I) of the present invention has many therapeutic and prophylactic uses.
• the compounds of the invention are used in the treatment of a wide variety of diseases that are sensitive to treatment with cytidines (eg, 5-aza-2'-deoxycytidine).
• Preferred indications that can be treated with the compounds of the invention include those with unwanted or uncontrolled cell division.
• Such indications include a variety of cancers, but preferably CML whose expression is evoked by the ⁇ CR- ⁇ L fusion gene, more preferably TKI-resistant CML.
• it can be expected to be effective against acute lymphocytic leukemia and acute myeloid leukemia.
• Examples of the concomitant agent of ⁇ -resistant CML of the present invention include, but are not limited to, ⁇ , a p53 gene inhibitor, an enzyme inhibitor, and the like.
• ⁇ are Imatinib, Gefitinib, Erlotinib, Sorafenib, Dasatinib, Sunitinib, Sunitinib, Lapatinib, Lapatinib, Lapatinib, Lapatinib (Crizotinib), Luxolitinib, Vandertinib, Vemurafenib, Axitinib, Bosutinib, Canonzantinib, Canonzantinib, (Afatinib), Dabrafenib, Ibrutinib, Trametinib, Ceritinib, Nintedanib, Lenvatinib, Lenvatinib, Parbotinib, Carbocitinib, Carbocitinib (B
• Non-Patent Document 2 The p53 gene inhibitor or enzyme inhibitor refers to Pifithrin, Nutlin, DS3201, HBI-8000, Trichostatin A (TSA), Suramin, EPZ005687, Adox and the like.
• TSA Trichostatin A
• the administration time of the prophylactic or therapeutic agent for ⁇ -resistant CML and the concomitant agent is not limited, and both of the concomitant agents are administered to the administration subject. They may be administered at the same time or at different times.
• the prophylactic or therapeutic agent for ⁇ -resistant CML and the concomitant drug may be formulated separately, or may be a mixture of both.
• the dose of the concomitant drug may be based on the clinically used dose, and can be appropriately selected depending on the administration target, administration route, disease, combination and the like.
• the dose of the concomitant drug may be, for example, one-third to three times the dose when the concomitant drug is used as a single agent.
• the administration form of the prophylactic or therapeutic agent for ⁇ -resistant CML and the concomitant agent of the present invention is not particularly limited, and it is sufficient that the prophylactic or therapeutic agent for ⁇ -resistant CML and the concomitant agent are combined at the time of administration.
• Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating a prophylactic or therapeutic agent for ⁇ -resistant CML and a concomitant drug, and (2) prevention or prevention of ⁇ -resistant CML. Simultaneous administration of two types of preparations obtained by separately formulating a therapeutic drug and a concomitant drug by the same route of administration, (3) Prevention of ⁇ -resistant CML or obtaining a therapeutic drug and a concomitant drug separately. Administration of the two preparations with a time lag in the same administration route, (4) Different administration routes of the two preparations obtained by separately formulating a prophylactic or therapeutic drug for ⁇ resistant CML and a concomitant drug.
• Prophylactic or therapeutic drug for ⁇ -resistant CML and concomitant drug separately formulated and administered at different routes of administration for example, ⁇ resistance
• Prophylactic or therapeutic agents for sex CML ⁇ administration in the order of concomitant agents, or administration in the reverse order are separately formulated and administered at different routes of administration (for example, ⁇ resistance)
• ⁇ resistance Prophylactic or therapeutic agents for sex CML ⁇ administration in the order of concomitant agents, or administration in the reverse order
• the prophylactic or therapeutic agent for ⁇ -resistant CML of the present invention the following excellent effects can be obtained.
• the dose of ⁇ -resistant CML can be reduced as compared with the case where a prophylactic or therapeutic drug and a concomitant drug are administered alone.
• the type of concomitant drug can be selected according to the patient's symptoms (mild, severe, etc.).
• the treatment period can be set longer by selecting a concomitant drug having a different mechanism of action from the prophylactic or therapeutic drug for ⁇ resistant CML.
• the therapeutic effect can be sustained by selecting a concomitant drug having a different mechanism of action from the prophylactic or therapeutic drug for ⁇ resistant CML.
• a synergistic effect can be obtained by using a prophylactic or therapeutic agent for ⁇ -resistant CML in combination with a concomitant agent.
• a DNMT inhibitor for example, a compound represented by the formula (I)
• a concomitant drug for example, a compound represented by the formula (I)
• the content ratio of the DNMT inhibitor (for example, the compound represented by the formula (I)) in the pharmaceutical preparation is usually 0.1 to 100% (w / w).
• the content ratio of the DNMT inhibitor (for example, the compound represented by the formula (I)) is usually 0.1 to 99.9% (w / w).
• Suitable pharmaceutical compositions used in the present invention include compositions in which the active ingredient is present in an effective amount, i.e., in an amount effective to achieve therapeutic and / or prophylactic objectives in the condition being treated. Things are included.
• the pharmaceutical composition used in the present invention is provided as a dosage form for oral administration.
• the pharmaceutical compositions provided herein may be provided in solid, semi-solid or liquid dosage form for oral administration.
• oral administration also includes buccal, tongue and sublingual administration.
• Suitable oral dosage forms include tablets, capsules, pills, troches, medicated candy, aromatics, cashiers, pellets, drug-added chewing gums, granules, powders, effervescent or non-foaming powders or granules.
• Solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs and syrups but not limited to these.
• the pharmaceutical composition comprises binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow promoters, colorants, pigment migration inhibitors, sweeteners and flavors. It may contain a carrier or excipient that is acceptable as one or more pharmaceuticals, not limited to these.
• the amount of the compound represented by the formula (I) of the present invention in the pharmaceutical composition or dosage form is, for example, about 1 mg to about 2,000 mg, about 10 mg to about 2,000 mg, about 20 mg to about 2,000 mg, and the like. It may be in the range of about 50 mg to about 1,000 mg, about 100 mg to about 500 mg, about 150 mg to about 500 mg or about 150 mg to about 250 mg.
• its effective dose is the nature of the cancer, the degree of progression of the cancer, the treatment policy, the degree of metastasis, the amount of the tumor, the weight, the age, the sex and the patient.
• the pharmaceutically effective amount is generally determined based on factors such as clinically observed symptoms and the degree of cancer metastasis.
• the daily dose is, for example, about 0.01 mg / kg to about 10 mg / kg (for an adult weighing 60 kg, about 0.5 mg to about 500 mg), preferably about 0.05 mg when administered to humans. It is from / kg to about 5 mg / kg, more preferably from about 0.1 mg / kg to about 2 mg / kg.
• the administration may be performed once or in multiple doses.
• the sugar moiety silyl of 5-aza-2'-deoxycytidine according to the present invention which has high stability to the above-mentioned hydrolytic metabolic enzyme and has appropriate hydrolytic reactivity under physiological conditions.
• the ether derivative (see formula (I)) can be a therapeutic or prophylactic agent for ⁇ resistant CML.
• the target 3'position silyloxy-5-aza-2'-deoxycytidine derivative (in the formula (I), R 1 is a hydrogen atom and R 2 is a silyl group) is white. It can be isolated as a powder.
• This synthesis method is hereinafter abbreviated as synthesis method A.
• Table 1 shows the analysis results in the case of 5'-O- (Triethylsilyl) -5-aza-2'-deoxycytidine (Compound F).
• Non-enzymatic hydrolysis of 5-aza-2'-deoxycytidine sugar silyl ether derivative 5-Aza-2'-deoxycytidine sugar silyl ether derivative (see formula (I)), eg 5'- About 1 mg of O- (Triethylsilyl) -5-aza-2'-deoxycytidine (Compound F) was dissolved in 1 mL of acetonitrile, 5 ⁇ L of it was added to 100 ⁇ L of 10 mM PBS solution, and the mixture was stirred at 37 ° C.
• Anti-CML and anti-T ⁇ resistant CML activity of 5-aza-2'-deoxycytidine sugar silyl ether derivative CML cell lines (BV173, MYL, Ba / F3 BCR-ABL WT ) and ⁇ resistant CML cell lines (MYL-R, Ba / F3 BCR-ABL T315I ) in the table below are used in culture medium (10% FBS and RPMI-). In 1640), seeds were seeded on a 96-well plate at 3,000 to 7,000 cells / 100 ⁇ L / well, and cultured at 37 ° C. for about 3 hours under a 5% carbon dioxide gas stream.
• each diluted with a culture solution to 50 ⁇ M to 0.05 ⁇ M (MYL, Ba / F3 BCR-ABL WT , MYL-R, Ba / F3 BCR-ABL T315I ) and 500 nM to 0.1 nM (BV173).
• IC 50 was calculated ratio of Ba / F3 BCR-ABL T315I lines to MYL-R strain and Ba / F3 BCR-ABL WT strain for MYL strain, respectively (see Table 3-2).
• Table 3-1) Table 3-2
• the MYL-R strain is a MYL strain that overexpresses Lyn
• the Ba / F3 BCR-ABL T315I strain is a strain in which the ABLT315I mutation is introduced into the Ba / F3 BCR-ABL WT strain, both of which have ⁇ resistance. Have won.
• the sugar moiety silyl ether derivative of 5-aza-2'-deoxycytidine (for example, compound F: 5'-O- (Triethylsilyl) -5-aza-2'- Deoxycytidine) was found to have very high anti-CML activity and anti- ⁇ resistant CML activity.
• the anti-CML activity of this compound F against the MYL-R strain is considerably higher than that of 5-azacitidine, and is similar to that of 5-aza-2'-deoxycytidine.
• DNA demethylation effect of 5-aza-2'-deoxycytidine sugar moiety silyl ether derivative The methylation ratio of the ⁇ pG island cytosine moiety of LINE-1 (Long interspersed nucleotide factor-1) was measured using the pyrosequencing method.
• a DNMT inhibitor having high stability against the metabolic enzyme cytidine deaminase can be provided to the medical field as a novel ⁇ resistant CML therapeutic agent or preventive agent.

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