WO2004011481A1 - Derive de phosmidosine et procede de production associe - Google Patents

Derive de phosmidosine et procede de production associe Download PDF

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WO2004011481A1
WO2004011481A1 PCT/JP2003/000985 JP0300985W WO2004011481A1 WO 2004011481 A1 WO2004011481 A1 WO 2004011481A1 JP 0300985 W JP0300985 W JP 0300985W WO 2004011481 A1 WO2004011481 A1 WO 2004011481A1
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Prior art keywords
compound
salt
general formula
hydrogen atom
group
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PCT/JP2003/000985
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English (en)
Japanese (ja)
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Mitsuo Sekine
Kohji Seio
Kazuhisa Okada
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Sankyo Co
Mitsuo Sekine
Kohji Seio
Kazuhisa Okada
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Priority to AU2003208084A priority Critical patent/AU2003208084A1/en
Publication of WO2004011481A1 publication Critical patent/WO2004011481A1/fr

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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
    • A61K31/70—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
    • A61K31/7076—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 containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—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 containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • 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
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a nucleotide antibiotic phosmidosine derivative and a method for producing the same.
  • Phosmidosine is an antibiotic produced by Streptomyces actinomycete strain RK-16, which specifically inhibits spore formation by Botrytis cinerea, the causative agent of gray rot of various vegetables and fruits. (Uramoto, M. et al., J. Antibiot., 44, 375, 1991). Later, it was revealed that fosmidosine is a nucleotide antibiotic having the following structure (Phillips, D.R. et al., J. Org. Chem., 58, 854. 1993). The structural features of fosmidosine are that it contains 8-oxoadenosine-5'-monophosphate as a nucleotide component, and that it contains proline as an amino acid component. It is connected by a mid bond.
  • phosmidosine has a morphological reversion activity in rat kidney cells transformed by the temperature-sensitive oncogene v-src and changed in morphology by temperature change. G1 for the progress of the cycle Phosmidosine has been reported to have anticancer activity (Matsuura, N. et al., J. Antibiot., 49, 361, 1996).
  • fosmidosine was also achieved by Moriguchi et al., And it was shown that fosmidosine is about 10 times more active than fosmidosine A (Sekine, M. et al., J. Org. Synth. Chem. Jpn., 59, 1109, 2000).
  • this synthesis method had a problem that the yield was low and phosmidosine could not be supplied stably in large quantities.
  • the methyl ester of the phosphoric acid moiety of phosmidosine has poor chemical stability and has a problem that the methyl ester is easily decomposed in an aqueous solution, so that a phosmidosine derivative having high activity and excellent stability is provided. It was desired to provide Disclosure of the invention
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, reacted an 8-oxoadenosine derivative with an amidite reagent synthesized from N-phosphitylation of proline amide, followed by oxidation of the product. It has been found that by carrying out the above, a condensation product useful as an intermediate for producing phosmidosine or a derivative thereof can be produced extremely efficiently. It has also been found that by performing sulfidation instead of oxidation in the above reaction, a phosphorothioate compound useful as an intermediate for producing a fosmidosine derivative can be obtained.
  • the present inventors produced an alkyl-substituted form of fosmidosine and a phosphorothioate derivative from these production intermediates, and examined their cell growth inhibitory effect and physicochemical properties. It has been found that these compounds have a biological activity equivalent to that of fosmidosine, have no degradation of the alkyl ester, and have extremely desirable properties as pharmaceuticals.
  • the present invention has been completed based on the above findings. That is, the present invention provides the following general formula (I):
  • R 1 represents (8 alkyl group; R 2 represents a hydrogen atom or a nitrogen atom protecting group; R 3 and R 4 each independently represent a hydrogen atom or a hydroxyl protecting group; and R 4 may combine with each other to form a ring together with the two oxygen atoms to which they are attached; R 5 represents a hydrogen or nitrogen protecting group; X represents 0 or S. Except when R 1 is a methyl group and X is 0.) or a salt thereof.
  • R 1 is C 2 _ 8 alkyl group
  • R 2 is a hydrogen atom
  • R 3 and R 4 are both hydrogen atom
  • R 5 is a hydrogen atom
  • X is 0 der Ru said compound or a salt thereof
  • a and R 1 _ 8 alkyl group, Ri Oh R 2 is a hydrogen atom
  • R 3 ⁇ Pi R 4 are both hydrogen atom
  • R 5 is a hydrogen atom
  • X is S.
  • the present invention in the compounds represented by compound IA (the general formula (I), R 1 is C 2 _ 8 alkyl group, R 2 is a hydrogen atom, R 3 and R 4 is a hydrogen atom, R 5 is a hydrogen atom and X is 0, or is a _ 8 alkyl group, R 2 is a hydrogen atom, and R 3 and R 4 are both a hydrogen atom Or a compound in which R 5 is a hydrogen atom and X is S) or a physiologically acceptable salt thereof as an active ingredient.
  • This medicament can be used as an antitumor agent for the treatment of various solid or non-solid cancers.
  • the present invention provides a method for treating a cancer, which comprises using the compound IA or a physiologically acceptable salt thereof for the manufacture of the above-mentioned medicament, and treating the cancer.
  • a method is provided that comprises administering to a mammal, including a human, a therapeutically effective amount of a physiologically acceptable salt thereof.
  • a cancer cell growth inhibitor comprising the compound IA or a physiologically acceptable salt thereof; a G1-phase cell cycle arresting agent comprising the compound IA or a physiologically acceptable salt thereof;
  • a phosphorylation inhibitor of RB protein comprising Compound IA or a physiologically acceptable salt thereof is provided.
  • compound IB in the compound represented by the above general formula (I), RR 2 , R 3 , R 4 , R 5, and X are as defined above, provided that R 1 is C 2 one 8 alkyl group, R 2 is a hydrogen atom, R 3 and R 4 are both hydrogen atom, R 5 is a hydrogen atom If it, and X is 0 in, ⁇ Pi R 1 is - 8 alkyl group, R 2 is a hydrogen atom, an R 3 and are both hydrogen atoms, but a hydrogen atom, and X is Or a salt thereof, except when it is S) or a salt thereof. Further, according to the present invention, there is provided a method for producing the compound IB,
  • R 12 represents a protecting group for a nitrogen atom
  • R 13 and R 14 each independently represent a protecting group for a hydroxyl group, but R 13 and R 14 are bonded to each other to form two oxygens to which they are bonded. Which may form a ring together with an atom
  • R 11 represents an _ 8 alkyl group
  • R 15 represents a protecting group for a nitrogen atom
  • R 16 and R 17 each independently represent an _ 8 alkyl group.
  • the present invention provides a method comprising oxidizing or sulfurizing the obtained reactant.
  • the reaction between the compound represented by the above general formula (II) and the compound represented by the above general formula (III) is carried out in the presence of 5-mercapto-1-methyltetrazone. Can be done below.
  • a method for producing fosmidosine or the above compound IA or a salt thereof which comprises a step of deprotecting the above compound IB or a salt thereof; and a method for producing fosmidosine or the above compound IA or a salt thereof.
  • the reaction is carried out by reacting the compound represented by the general formula (II) with the compound represented by the general formula (III).
  • a method comprising the steps of: oxidizing or sulfurizing to obtain a compound IB; and (b) deprotecting the compound IB obtained in the step (a).
  • the compound represented by the general formula (III) is a novel compound provided for the first time according to the present invention, and is useful as an intermediate for producing fosmidosine, the compound IA, or a salt thereof.
  • the compound IB or a salt thereof which is an intermediate for producing phosmidosine or the compound IA or a salt thereof; an intermediate for the production of phosmidosine or the compound IA or a salt thereof.
  • a compound represented by the above general formula (II); a compound represented by the above general formula (II), which is an intermediate for producing phosmidosine or the above compound IA or a salt thereof; a production of the above compound IB or a salt thereof The present invention provides a compound represented by the above general formula (II), which is an intermediate for use; and a compound represented by the above general formula (III), which is an intermediate for producing the above compound IB or a salt thereof.
  • the alkyl group means a linear, branched, cyclic, or a combination thereof.
  • Alkyl groups represented by R 1 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group , 2-methylbutyl, 1-methylbutyl, neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methynolepentyl, 3-methylpentynole, 2-methylpentyl , 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- Dimethylbutyl group, 2-ethylbutyl group, 1-ethylbutyl group, 1-ethyl-1-methylpropyl
  • the type of the protecting group for the nitrogen atom represented by R 2 is not particularly limited, and is inert in the reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III). Any protecting group may be used as long as it can be deprotected without affecting other functional groups after the reaction.
  • Any protecting group may be used as long as it can be deprotected without affecting other functional groups after the reaction.
  • the protecting group for the nitrogen atom see, for example, "Protective Groups in Organic Syntheses, TW Green and PGM Wuts, 3rd Ed., 1999, John Wiley &Sons". Those skilled in the art can appropriately select from the described protecting groups.
  • protecting group for the nitrogen atom represented by R 2 for example, it is preferable to select a protecting group that is stable under basic conditions and can be easily deprotected under acidic conditions, and more specifically, tert- A protecting group such as butoxycarponyl (B0C) can be selected.
  • tert- A protecting group such as butoxycarponyl (B0C) can be selected.
  • B0C butoxycarponyl
  • the type of the hydroxyl-protecting group represented by R 3 and is not particularly limited, and is inactive in the reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III); After the reaction, any protecting group may be used as long as it can be deprotected without affecting other functional groups.
  • the protecting group for the hydroxyl group can be appropriately selected by those skilled in the art from, for example, the protecting groups described in the above-mentioned “Protective 'groups' organic-synthesis”.
  • As the protecting group for the hydroxyl group represented by R 3 and R 4 for example, it is preferable to select a protecting group that is stable under basic conditions and can be easily deprotected under acidic conditions.
  • An isopropylidene group in which 3 and R 4 are mutually bonded can be mentioned. The same applies to the protecting groups represented by R 13 and R 14 .
  • the type of the protecting group for the nitrogen atom represented by R 5 is not particularly limited, and is inert in the reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III). Any protecting group may be used as long as it can be deprotected without affecting other functional groups after the reaction. For example, those skilled in the art can use the protecting group for a nitrogen atom described in “Protective 'Groups' in” Organic. Can be appropriately selected.
  • As the protecting group for the nitrogen atom represented by R 5 for example, it is preferable to select a protecting group that is stable under basic conditions and can be easily deprotected under acidic conditions. And a protecting group such as trityl (Tr). The same applies to the protective group R 15 represents.
  • X represents 0 or S.
  • the compound in which R 1 is a methyl group and X is 0 is a novel compound represented by the general formula (I) Is not included in the scope of the present invention.
  • the compound represented by the above general formula (I) or a salt thereof may exist as a hydrate or a solvate, but these substances are also included in the scope of the present invention.
  • the compound represented by the above general formula (I) has a plurality of asymmetric carbons, but may further have one or more asymmetric carbons depending on the type of the substituent.
  • stereoisomers such as optically active diastereomers based on the presence of a plurality of asymmetric carbons, or mixtures or racemates of arbitrary stereoisomers are all included in the scope of the present invention. You.
  • the three-dimensional display in the chemical formula shown in this specification indicates an absolute configuration.
  • R 1 is C 2 _ 8 alkyl group
  • R 2 is a hydrogen atom
  • R 3 and R 4 are both hydrogen atoms
  • R 5 is a hydrogen atom and X is 0 or R 1 is an alkyl group
  • R 2 is a hydrogen atom
  • R 3 and R 4 are both hydrogen atoms
  • R 5 is a hydrogen atom
  • X is S, which is included in the above general formula (I).
  • This compound IA or a physiologically acceptable salt thereof is useful as an active ingredient of a medicament.
  • the compound IA has a cancer cell growth inhibitory effect and has an effect of arresting the cell cycle in the G1 phase, and thus is useful as an active ingredient of a medicament for treating cancer.
  • compound IA has the effect of suppressing the expression level of cyclin D1, and consequently inhibiting the phosphorylation of RB protein, a cell cycle regulator. Can inhibit the cell cycle in the GI phase.
  • the medicament provided by the present invention is effective for one or more compounds selected from the group consisting of compound IA and physiologically acceptable salts thereof, and hydrates and solvates thereof. It can be used as an antitumor agent for the treatment of solid tumors or non-solid cancers.
  • the medicament of the present invention can be orally or parenterally administered to mammals including humans.
  • the above-mentioned substances may be administered as they are, but generally, one or more of the above substances and one or more pharmaceutical additives are used. It is desirable to prepare and administer a pharmaceutical composition containing the same.
  • compositions suitable for oral administration include, for example, granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, and liquids.
  • Pharmaceutical compositions suitable for administration include, for example, injections for intravenous administration, intramuscular administration, or subcutaneous administration, drops, suppositories, transdermal absorbents, transmucosal absorbents, nasal drops, eardrops Preparations, eye drops, inhalants and the like.
  • a preparation prepared as a pharmaceutical composition in the form of a powder may be dissolved at the time of use and used as an injection or infusion.
  • the form of the pharmaceutical composition is not limited to these.
  • solid or liquid pharmaceutical additives can be used.
  • the pharmaceutical additives may be either organic or inorganic.
  • excipients for the preparation of a solid pharmaceutical composition for oral use, for example, excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents and the like can be used.
  • excipient include lactose, sucrose, sucrose, glucose, corn starch, starch, talc, sorbitol, crystalline cellulose, dextrin, kaolin, calcium carbonate, and silicon dioxide.
  • binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropinolose cellulose, and hydroxypropane. Mouth pill methylcellulose, calcium citrate, dextrin, or pectin can be mentioned.
  • the lubricant include magnesium stearate, talc, polyethylene glycol, silica, and hardened spot oil. Any coloring agent can be used as long as it is normally permitted to be added to a medicine.
  • cocoa powder, heart-shaped brain, aromatic acid, heart-shaped oil, dragon brain, cinnamon powder, or the like can be used.
  • appropriate coating such as sugar coating or gelatin coating can be applied, and if necessary, a preservative and an antioxidant can be added.
  • a commonly used inert diluent such as water or vegetable oil can be used.
  • examples thereof include a wetting agent, a suspending aid, a sweetener, A fragrance, a coloring agent, a preservative, or the like can be added.
  • the liquid pharmaceutical composition After preparing the liquid pharmaceutical composition, it may be filled into capsules of an absorbent material such as gelatin.
  • the solvent or suspending agent used for preparing a liquid pharmaceutical composition include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin.
  • the base used in the production of suppositories for example, cocoa butter, emulsified cocoa butter, laurin fat, witebsol, and the like can be given.
  • water, ethyl alcohol, macrogol, or propylene glycol, or a mixture thereof, or the like can be used as a carrier.
  • PH regulators such as citrate, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid, or sodium hydroxide; buffers such as sodium citrate, sodium acetate, or sodium phosphate; sodium bisulfite, ethylenediamine A stabilizer such as acetic acid, thioglycolic acid, or thiolactic acid, or an isotonic agent such as sodium chloride, glucose, mannitol, or glycerin may be added.
  • solubilizers, soothing agents, or local anesthetics Can also be used.
  • a base When preparing a pharmaceutical composition for external use in the form of an ointment or a cream, a base, a stabilizer, a wetting agent, a preservative, and the like can be used. Can be mixed to prepare a pharmaceutical composition.
  • a base for example, white petrolatum, polyethylene, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicon, bentonite, or the like can be used.
  • a preservative methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, or the like can be used.
  • the above-mentioned ointment, cream, gel, paste, or the like can be applied to a usual support in a conventional manner.
  • a woven or non-woven fabric made of cotton, staple, or synthetic fiber, a film made of soft vinyl chloride, polyethylene, polyurethane, or the like, or a foam sheet can be suitably used.
  • the dose of the medicament of the present invention is not particularly limited.
  • the mass of the compound IA as an active ingredient per adult day is usually about 10 to 1,000 mg per day. It is preferable to increase or decrease this dose appropriately according to the age, disease state and symptoms of the patient.
  • the daily dose may be administered once a day or divided into two or three times a day at appropriate intervals, or may be administered intermittently every few days.
  • the mass of compound IA as an active ingredient per adult day is about 5 to 50 Omg.
  • R ⁇ R 2 , R ⁇ R 5 , and X have the same meanings as described above, provided that R 1 is C 2 _ an 8 alkyl group, R 2 is a hydrogen atom, R 3 ⁇ Pi is both a hydrogen atom, R 5 is a hydrogen atom, and when X is 0, and R 1 - 8 alkyl group R 2 is a hydrogen atom, R 3 and R 4 are both hydrogen atoms, R 5 is a hydrogen atom, and a compound excluding the case where X is S; (I) is included.
  • This compound IB or a salt thereof is phosmidosine (in the above general formula (I), R 1 is a methyl group, R 2 is a hydrogen atom, R 3 and R 4 are both hydrogen atoms, and R 5 is a hydrogen atom And a compound corresponding to the case where X is 0) or an intermediate for the production of the compound IA.
  • Compound IB can be produced by the first step shown in the following scheme according to the production method provided by the present invention. Phosmidosine and the above compound IA can be produced by a second step of deprotection from compound IB.
  • the first step includes a step of reacting the compound represented by the general formula (II) with the compound represented by the general formula (II), and oxidizing or sulfurizing the obtained reaction product.
  • a compound in which X is 0 can be produced
  • a compound in which X is S can be produced.
  • the reaction between the compound represented by the general formula (II) and the compound represented by the general formula (III) can be performed, for example, in the presence of 5-mercapto-1-methyltetrazole ( Filippov, D. et al., Tetrahedron Lett., 39, 4891, 1998).
  • the oxidation step for example, tert- Buchiruhai Doropaokisai de oxidizing agent can be suitably used, such as, the sulfide ⁇ , ⁇ , ⁇ ', ⁇ ' - can be used tetra E chill thiuram disulfinate Doya S 8 .
  • the reagents for oxidation and sulfidation are not limited to these, and it is needless to say that those skilled in the art can appropriately select from oxidizing agents commonly used.
  • oxidizing agents and oxidants described in books such as "Reagents for Organic Synthesis, Vol. 1, 1967 to Vol. 16, 1992, John Wiley &Sons".
  • the reaction between the compound represented by the above general formula (II) and the compound represented by the above general formula (III) can be usually performed in the presence of a solvent in an anhydrous environment. To the reflux temperature, preferably room temperature.
  • the solvent used for the reaction is not particularly limited as long as it has sufficient solubility for the reactive species and is inert in the reaction.
  • nitrile solvents such as acetonitrile, chlorine solvents such as methylene chloride and chloroform, aromatic solvents such as benzene, toluene and xylene, ether solvents such as getyl ether, tetrahydrofuran, and dioxane.
  • nitrile solvents such as acetonitrile, chlorine solvents such as methylene chloride and chloroform, aromatic solvents such as benzene, toluene and xylene, ether solvents such as getyl ether, tetrahydrofuran, and dioxane.
  • nitrile solvents such as acetonitrile, chlorine solvents such as methylene chloride and chloroform
  • aromatic solvents such as benzene, toluene and xylene
  • ether solvents such as getyl ether, tetrahydrofuran, and dioxane.
  • the reaction is desirably performed under
  • an oxidizing agent is added to the reaction system and the solvent is refluxed from o ° c. It can be carried out at a temperature in the range up to the temperature, preferably at room temperature.
  • tert-butyl hydroperoxide is used as the oxidizing agent, about 5 to 20 mol, preferably about 10 mol, of the compound represented by the general formula (II) is used.
  • An oxidizing agent can be used.
  • a sulfurizing agent is added to the reaction system, and the solvent is removed from 0 ° C at 0 ° C.
  • the reaction can be carried out at a temperature in the range up to the reflux temperature, preferably at room temperature.
  • ⁇ , ⁇ , ⁇ ′, ⁇ ′-tetraethylthiuram disulfide or the like is used as the sulfurizing agent, it is preferably about 1 to 10 mol, preferably about 1 to 10 mol, based on the compound represented by the above general formula (II). Can use about 2 to 5 mol of a sulfurizing agent.
  • phosmidosine or compound I ⁇ ⁇ ⁇ can be produced by subjecting the obtained compound I ⁇ to a deprotection reaction, but the deprotection reaction depends on the type of protecting group used.
  • the reaction is carried out by selecting appropriate reaction conditions. Conditions for deprotection can be found in, for example, written books such as "Protective Groups in Organic Syntheses," TW Green and PGM Wuts, 3rd Ed., 1999, John Wiley & Sons. By referring to this, a person skilled in the art can select appropriate conditions.
  • R 12 is a protecting group other than a tert-butoxycarbonyl group
  • R 12 is a protecting group other than a tert-butoxycarbonyl group
  • the reaction conditions in the first step in the above scheme include, for example, ⁇ Protective Groups in Organic Syntheses, TW Green and PGM Wuts, 3rd Ed., 1999, John Wiley & Sons), the reaction conditions in the first step in the above scheme
  • an appropriate protecting group can be selected, and the protecting group can be introduced onto a nitrogen atom according to the method described in the above publication.
  • the compound represented by the general formula (III) includes a proline amide in which a ring-forming nitrogen atom is protected by a trityl group or the like and a general formula (IV): R 210 -P [N (R 24 ) (R 25 )] [N (R 26 ) (R 27 )] (wherein R 21 , R 24 , R 25 , R 26 and R 27 each independently represent a compound represented by the formula ( 8 alkyl group)) It can be easily produced by reacting in the presence of an acid catalyst such as a suitable activator, for example, 1H-tetrazole, N, N-diisopropylammonium 1H-tetrazolidate, and performing selective N-phosphitylation.
  • an acid catalyst such as a suitable activator
  • R 24 , R 25 , R 26 , and R 27 are preferably all the same alkyl group, and more preferably, these groups are all isopropyl groups.
  • the compound IB having the alkyl group selected as R 21 and the compounds IA and Fosmidosine can be produced (R 1 in these compounds corresponds to R 21 )-Reaction of proline amide having a protected ring nitrogen atom with a compound represented by the general formula (IV)
  • R 1 in these compounds corresponds to R 21
  • a compound represented by the general formula (IV) can be carried out in an anhydrous environment usually in the presence of a solvent, and can be carried out at a temperature in the range of 0 ° C. to the reflux temperature of the solvent, and preferably at room temperature.
  • a chlorinated solvent such as methylene chloride or chloroform, benzene.
  • Aromatic solvents such as toluene and xylene, ether solvents such as getyl ether, tetrahydrofuran, and dioxane, and nitrile solvents such as acetonitrile can be used.
  • the reaction is preferably performed under an inert gas such as argon or nitrogen.
  • the production intermediates and target compounds produced by the above production methods are separated and purified by methods commonly used in the field of synthetic organic chemistry, such as neutralization, filtration, extraction, drying, concentration, recrystallization, and various types of chromatography. Isolation and purification can be performed by any means, but the intermediate for production can be subjected to the next reaction without particular purification.
  • compound IB can be obtained as a diastereomer because of its chirality on the phosphorus atom.
  • a phosmidosine derivative which is an oxidation product, can be obtained by performing isomer fractionation by reverse-phase HPLC. These diastereomers can also be separated purely. This method is specifically shown in Examples.
  • the compound When it is desired to obtain an intermediate for production and a salt of the target compound, if the compound is obtained in the form of a salt from the reaction system, it may be purified as it is. If the compound is obtained in a free form, an appropriate The salt may be formed by dissolving or suspending in an organic solvent and adding an acid or a base. It is also possible to convert a compound obtained in the form of a salt into a compound in a free form and then to a suitable salt.
  • the desired compound can be easily produced by appropriately selecting reaction conditions, starting materials, reaction reagents and the like while referring to the above, and appropriately modifying or modifying these methods as necessary.
  • Example 1 The compound of the present invention was synthesized according to the following scheme. Hereinafter, the compound numbers correspond to the compound numbers in the scheme.
  • 8-Oxoadenosine (1) (5.66 g, 20 mmol) was suspended in acetone (200 raL), and acetone-dimethyl acetal (49.2 ml, 400 mmol) and p-toluenesulfonic acid monohydrate (7.61 g, 40 mmol) was added and the mixture was stirred at room temperature for 4 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (200 ml) was added to neutralize the system, and the solvent was distilled off under reduced pressure.
  • the solution was extracted with chloroform-isopropyl alcohol (3: 1, v / v) and saturated aqueous sodium hydrogen carbonate, the collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in a mixed solvent of methanol-triethylamine (9: 1 v / v, 200 mL), di-tert-butyl dicarbonate (5.97 mL, 26 mmol) was added, and the mixture was stirred at room temperature for 2 hours. . Thereafter, the reaction system was diluted with chloroform, and the organic layer was washed three times with a saturated aqueous solution of sodium hydrogen carbonate.
  • N-Tritylproline amide (3) (2.14 g, 6 mmol) and ⁇ , ⁇ -diisopropylpropylammonium tetrazolide (616 mg, 3.6 mmol) were added three times with anhydrous pyridine and three times with anhydrous toluene. It was azeotropically dehydrated and dissolved in anhydrous methylene chloride (60 mL). Ethyl ( ⁇ , ⁇ , ⁇ ', ⁇ , -tetraisopropyl) phosphorodiamidite (2.46 mL, 9 carbonyl)
  • the 8-oxoadenosine derivative (2) (805 mg, 1.9 mmol) and the amidite reagent (4a) (2.09 g, 3.6 mmol) were azeotropically dehydrated with anhydrous acetonitrile four times, and then anhydrous acetonitrile (30 mL) And 5-mercapto-1-methyltetrazole (552 mg, 4.75 mmol) was added thereto, followed by stirring at room temperature for 1 hour under an argon atmosphere. Thereafter, a 6M tert-butylhydroxide-decane solution (3.17 mL, 19 mmol) was added, and the mixture was further stirred at room temperature for 10 minutes.
  • the above product (5a) (1.57 g, 1.81 phenol) was dissolved in an 80% formic acid aqueous solution (20 mL), and the mixture was stirred at room temperature for 12 hours.
  • alkyl esters (6b, 6c, fast or slow) were similarly synthesized and separated.
  • the compound IA included in the general formula (I) provided by the present invention has an antitumor activity equivalent to that of phosmidosine and is extremely chemically stable. Is useful as an active ingredient of a medicament.
  • the present invention provides
  • the compound IB included in the general formula (I) provided is useful as a production intermediate for the production of fosmidosine or compound IA.

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Abstract

L'invention concerne un dérivé de phosmidosine, de très bonne stabilité, représenté par la formule générale suivante (I) : (dans laquelle R1 représente un groupe C1-8 alkyle, R3 et R4 représentent, chacun de manière indépendante, un atome d'hydrogène ou un groupe de protection d'un groupe hydroxy, sous réserve que R3 et R4 puissent être liés l'un à l'autre afin de former un cycle en coopération avec les deux atomes d'oxygène qui sont liés à ces groupes, R5 représente un atome d'hydrogène ou un groupe protecteur d'azote, et X représente un atome de soufre ou d'oxygène, sous réserve que lorsque R1 représente un groupe méthyle, alors X ne représente pas d'atome d'oxygène), ou un sel de ce dérivé.
PCT/JP2003/000985 2002-07-30 2003-01-31 Derive de phosmidosine et procede de production associe WO2004011481A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8044056B2 (en) 2007-03-20 2011-10-25 Dainippon Sumitomo Pharma Co., Ltd. Adenine compound
US8067411B2 (en) 2006-12-14 2011-11-29 Astrazeneca Ab Compounds
US8138172B2 (en) 2006-07-05 2012-03-20 Astrazeneca Ab 8-oxoadenine derivatives acting as modulators of TLR7
US8575180B2 (en) 2004-03-26 2013-11-05 Astrazeneca Aktiebolag 9-substituted 8-oxoadenine compound
US8673907B2 (en) 2007-12-17 2014-03-18 Astrazeneca Ab Pharmaceutically acceptable salts of methyl (3-{ [[3-(6-amino- 2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl) propyl] (3-morpholin-4-ylpropyl) amino] methyl }phenyl) acetate and their use in therapy
US8895570B2 (en) 2010-12-17 2014-11-25 Astrazeneca Ab Purine derivatives
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds

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JPH093091A (ja) * 1995-06-21 1997-01-07 Rikagaku Kenkyusho ヌクレオシド誘導体物質、その製造法及び抗腫瘍剤

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WO1996008256A1 (fr) * 1994-09-14 1996-03-21 Temple University - Of The Commonwealth System Of Higher Education Oligoadenylates de 2',5' phosphorothioate/phosphodiester et utilisations antivirales de ces derniers
JPH093091A (ja) * 1995-06-21 1997-01-07 Rikagaku Kenkyusho ヌクレオシド誘導体物質、その製造法及び抗腫瘍剤

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SEKINE M. ET AL.: "Total synthesis of agrocin 84 and phosmidosine as naturally occurring nucleotidic antibiotics having P-N bond linkages", J. SYNTH. ORG. CHEM., JPN, vol. 59, no. 11, 2001, pages 1109 - 1120, XP002965224 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575180B2 (en) 2004-03-26 2013-11-05 Astrazeneca Aktiebolag 9-substituted 8-oxoadenine compound
US8969362B2 (en) 2004-03-26 2015-03-03 Astrazeneca Aktiebolag 9-substituted 8-oxoadenine compound
US8138172B2 (en) 2006-07-05 2012-03-20 Astrazeneca Ab 8-oxoadenine derivatives acting as modulators of TLR7
US8067411B2 (en) 2006-12-14 2011-11-29 Astrazeneca Ab Compounds
US8044056B2 (en) 2007-03-20 2011-10-25 Dainippon Sumitomo Pharma Co., Ltd. Adenine compound
US8673907B2 (en) 2007-12-17 2014-03-18 Astrazeneca Ab Pharmaceutically acceptable salts of methyl (3-{ [[3-(6-amino- 2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl) propyl] (3-morpholin-4-ylpropyl) amino] methyl }phenyl) acetate and their use in therapy
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds
US8895570B2 (en) 2010-12-17 2014-11-25 Astrazeneca Ab Purine derivatives

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