WO2004011481A1 - Phosmidosine derivative and process for producing the same - Google Patents
Phosmidosine derivative and process for producing the same Download PDFInfo
- Publication number
- 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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- WIPO (PCT)
- Prior art keywords
- compound
- salt
- general formula
- hydrogen atom
- group
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 19
- HBJDRXMCLFRSGN-CRDJCKMPSA-N phosmidosine Chemical class C([C@@H]1[C@H]([C@@H](O)[C@@H](O1)N1C(NC2=C(N)N=CN=C21)=O)O)OP(=O)(OC)NC(=O)[C@@H]1CCCN1 HBJDRXMCLFRSGN-CRDJCKMPSA-N 0.000 title abstract description 28
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- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
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- SEHSCEYJWJDMSC-UHFFFAOYSA-N phosmidosine B Natural products O=C1NC=2C(N)=NC=NC=2N1C(C(C1O)O)OC1COP(O)(=O)NC(=O)C1CCCN1 SEHSCEYJWJDMSC-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—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
A phosmidosine derivative with excellent stability which is represented by the following general formula (I): (I) (wherein R1 represents C1-8 alkyl; R2 represents hydrogen or a nitrogen-protecting group; R3 and R4 each independently represents hydrogen or a hydroxy-protecting group, provided that R3 and R4 may be bonded to each other to form a ring in cooperation with the two oxygen atoms bonded to these; R5 represents hydrogen or a nitrogen-protecting group; and X represents oxygen or sulfur; provided that when R1 is methyl, then X is not oxygen); or a salt of the derivative.
Description
明 細 書 ホスミ ドシン誘導体及びその製造方法 技術分野 Description Phosmidosine derivative and method for producing the same
本発明は、 ヌクレオチド系抗生物質ホスミ ドシン誘導体及びその製造方法に 関するものである。 背景技術 The present invention relates to a nucleotide antibiotic phosmidosine derivative and a method for producing the same. Background art
ホスミ ドシンは、 ス トレプトミセス属の放線菌 RK- 16株が生産する抗生物質 であり、様々な野菜や果物の灰色力ビ病の原因菌である Botrytis cinereaの胞 子形成を特異的に阻害する作用をもつものとして単離された（Uramoto, M. et al. , J. Antibiot. , 44， 375， 1991)。 その後、 ホスミ ドシンは下記の構造をも つヌクレオチド系の抗生物質であることが明らかにされた（Phillips, D. R. et al. , J. Org. Chem. , 58， 854. 1993)。 ホスミ ドシンの構造上の特徴は、 ヌク レオチド成分として 8-ォキソアデノシン - 5' -モノリン酸を含むこと、及びアミ ノ酸成分としてプロリンを含むことであり、 さらに各成分が N-ァシルリン酸ァ ミ ド結合で連結されていることにある。 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.
ホスミ ドシンの生物作用については、 温度感受性の癌遺伝子 v-srcによって 形質転換され、 温度変化によって形態が変化したラット腎細胞に対してホスミ ドシンが形態復帰活性をもつこと、 及ぴホスミ ドシンが細胞周期の進行を G1
期で停止させることが報告され、 ホスミ ドシンが抗癌作用を有することが示唆 されている（Matsuura, N. et al. , J. Antibiot. , 49, 361， 1996)。 現在用い られている抗癌剤を細胞周期上の作用点からみると、 S期に作用する DNA合成 阻害剤又は Μ期に作用する細胞分裂阻害剤等、 活発に増殖している細胞に対し て作用するものが多いが、近年、細胞周期の G1期を新たな抗癌剤のターゲット とする動きが盛んであり、 G1期で細胞周期を阻害するホスミ ドシンやその類縁 体は新たな抗癌剤としての利用が期待できる（実験医学増刊「癌と細胞周期 細 胞癌化へのプロセス」 田矢洋ー編集， 2章 ρ. 71 「細胞周期をターゲットにした 抗癌剤」 長田裕之）。 Regarding the biological action of phosmidosine, 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). Looking at the currently used anticancer drugs from the point of action on the cell cycle, they act on actively proliferating cells such as DNA synthesis inhibitors that act in the S phase or cell division inhibitors that act in the Μ phase In recent years, there is an active movement to target the G1 phase of the cell cycle as a new anticancer drug, and phosmidosine and its analogs that inhibit the cell cycle in the G1 phase can be expected to be used as new anticancer drugs (Experimental Medicine Special Issue: Cancer and the Cell Cycle: The Process of Cell Carcinogenesis) edited by Hiroshi Taya, Chapter 2, ρ.71 “Anti-cancer drugs targeting the cell cycle” by Hiroyuki Nagata.
さらに、 ヒ ト肺繊維芽細胞 WI- 38 をホスミドシンで処理したところ、 （1)細 胞周期が G1期で停止すること； （2)ホスミ ドシン処理後の細胞ではホスミ ドシ ンの濃度依存的に細胞周期調節因子である RB タンパク質のリン酸化が阻害さ れていること； （3)ホスミドシン処理細胞では血清刺激してもサイクリン D1の 発現量が増加しないこと； 及び（4)これらのサイクリン D1 の発現量減少と RB タンパク質リン酸化が同調していることが示され、 ホスミ ドシンはサイクリン D1の発現量を抑制することで RBタンパク質のリン酸化を阻害することが明ら かになつた（Kakeya, H. et al. , Cancer Res. , 58, 704, 1998)。 Furthermore, treatment of human lung fibroblast WI-38 with fosmidosine resulted in (1) cell cycle arrest in G1 phase; (2) concentration of fosmidosine in cells treated with fosmidosine. In addition, phosphorylation of RB protein, a cell cycle regulator, is inhibited; (3) In phosmidosine-treated cells, expression of cyclin D1 does not increase even when stimulated with serum; and (4) these cyclin D1s It was shown that RB protein phosphorylation was synchronized with the decrease in RB protein expression, and it was clarified that phosmidosine inhibited RB protein phosphorylation by suppressing cyclin D1 expression (Kakeya , H. et al., Cancer Res., 58, 704, 1998).
ホスミ ドシン誘導体の製造方法に関しては、 森口らによりホスミ ドシンの脱 メチル体及びその N6-ァセチル体の合成が報告されている（Moriguchi, T. et al. , Tetrahedron Lett. , 39， 3725， 1998； Moriguchi, T. et al. , J. Org. Chem. , 64, 8229, 2000： 上記論文ではホスミドシンの脱メチル体を 「ホスミドシン B」 と呼んでいるが、 この物質を最初に報告した長田らの命名に従つて本明細書で はこの物質を 「ホスミ ドシン A」 と呼ぶ）。 この合成は、森口らのアミノアシル アデ二レートアナログ合成に関連して達成された（Moriguchi, T. et al. , Tetrahedron Lett. , 41, 5881, 2000)。 また、 ホスミ ドシン Α及び Ν 6 -ァセチ ル体は 8. 8-190 μ Μの範囲で各細胞株に対して増殖抑制効果を示し、胃ガン、大
腸ガン由来の細胞に対しては他組織由来のがん細胞よりも若干高い増殖抑制効 果を示すが ·、 全体としては由来組織によらない特徴的な細胞増殖抑制効果を発 揮することが明らかにされた。 Regarding the method for producing the phosmidosine derivative, Moriguchi et al. Reported the synthesis of a demethylated form of phosmidosine and its N6-acetyl derivative (Moriguchi, T. et al., Tetrahedron Lett., 39, 3725, 1998; Moriguchi, T. et al., J. Org. Chem., 64, 8229, 2000: In the above paper, the demethylated form of fosmidosine is referred to as “fosmidosine B”. This material is referred to herein as "phosmidosine A" according to the nomenclature). This synthesis was achieved in connection with the synthesis of aminoacyl adenylate analogs by Moriguchi et al. (Moriguchi, T. et al., Tetrahedron Lett., 41, 5881, 2000). In addition, phosmidosine Α and Ν6-acetyl derivatives have a growth inhibitory effect on each cell line in the range of 8.8 to 190 μΜ, Intestinal cancer-derived cells show a slightly higher growth inhibitory effect than cancer cells derived from other tissues, but as a whole, they exhibit a characteristic cell growth inhibitory effect independent of the source tissue. Revealed.
さらに、 ホスミ ドシンの合成も森口らによって達成され、 ホスミ ドシンはホ スミ ドシン Aよりも約 10倍活性が高いことが明らかにされた（Sekine, M. et al. , J. Org. Synth. Chem. Jpn. , 59， 1109, 2000)。 もっとも、 この合成法は 収率が低く、 ホスミ ドシンを大量かつ安定に供給することができないという問 題があった。 またホスミ ドシンのリン酸部位のメチルエステルは化学的安定性 に乏しく、 水溶液中でメチルエステルが分解しやすいという問題を有している ことから、 高活性で、 かつ安定性に優れたホスミ ドシン誘導体を提供すること が望まれていた。 発明の開示 Furthermore, the synthesis of 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). However, this synthesis method had a problem that the yield was low and phosmidosine could not be supplied stably in large quantities. In addition, 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
本発明の課題は、 ホスミドシン及びその誘導体を効率的に製造するための方 法を提供することにある。 また、 本発明の別の課題は、 ホスミドシンの誘導体 であって、 がん細胞に対して優れた細胞増殖抑制効果を有しており、 かつ化学 的に安定な誘導体を提供することにある。 An object of the present invention is to provide a method for efficiently producing fosmidosine and its derivatives. Another object of the present invention is to provide a derivative of fosmidosine, which has an excellent cell growth inhibitory effect on cancer cells and is chemically stable.
本発明者らは上記の課題を解決すベく銳意研究を行った結果、 8 -ォキソアデ ノシン誘導体とプロリンアミ ドから N-ホスフイチル化により合成したアミダ イト試薬とを反応させ、 続いて生成物の酸化を行うことにより、 ホスミ ドシン 又はその誘導体の製造用中間体として有用な縮合生成物を極めて効率的に製造 できることを見出した。 また、 上記の反応において酸化に替えて硫化を行うこ とにより、 ホスミ.ドシン誘導体の製造用中間体として有用なホスホロチォエー ト化合物を得ることができることも見出した。 さらに、 本発明者らは、 これら の製造用中間体からホスミドシンのアルキル置換体及びホスホロチォエート誘 導体を製造して、その細胞增殖抑制効果及び物理化学的性状を検討したところ、
これらの化合物がホスミドシンと同等の生物活性を有しており、 しかもアルキ ルエステルの分解が全く認めらず、 医薬として極めて望ましい性質を有してい ることを見出した。 本発明は上記の知見を基にして完成されたものである。 すなわち 発明は、 下記の一般式 （I ) ： 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. Furthermore, 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):
(I )(I)
(式中、 R1は（ 8アルキル基を示し； R2は水素原子又は窒素原子の保護基を示 し； R3及び R4はそれぞれ独立に水素原子又は水酸基の保護基を示すが、 及び R4は互いに結合してそれらが結合する 2個の酸素原子とともに環を形成しても よく ； R5は水素原子又は窒素原子の保護基を示し； Xは 0又は Sを示す。 ただ し、 R1がメチル基であり、 かつ Xが 0である場合を除く。） で表される化合物又 はその塩を提供するものである。 (In the formula, 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.
この発明の好ましい態様によれば、 R1が C2_8アルキル基であり、 R2が水素原 子であり、 R3及び R4が共に水素原子であり、 R5が水素原子であり、 Xが 0であ る上記化合物又はその塩；及び R1が _8アルキル基であり、 R2が水素原子であ り、 R3及ぴ R4が共に水素原子であり、 R5が水素原子であり、 Xが Sである上記 化合物又はその塩が提供される。 According to a preferred embodiment of the invention, 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及Pi R 4 are both hydrogen atom, R 5 is a hydrogen atom And the compound or a salt thereof, wherein X is S.
別の観点からは、 本発明により、 化合物 I A (上記一般式 （I ) で表される 化合物において、 R1が C2_8アルキル基であり、 R2が水素原子であり、 R3及び R4 が共に水素原子であり、 R5が水素原子であり、 かつ Xが 0である力、 あるいは が _8アルキル基であり、 R2が水素原子であり、 R3及び R4が共に水素原子で あり、 R5が水素原子であり、 かつ Xが Sである化合物を意味する） 又は生理学 的に許容されるその塩を有効成分として含む医薬が提供される。 この医薬は抗 腫瘍剤として各種の固形癌又は非固形癌の治療に用いることができる。
さらに別の観点からは、 本発明により、 上記の医薬の製造のための上記化合 物 I A又は生理学的に許容されるその塩の使用、及ぴ、癌の治療方法であって、 上記化合物 I A又は生理学的に許容されるその塩の治療有効量をヒトを含む哺 乳類動物に投与する工程を含む方法が提供される。 また、 本発明により、 上記 化合物 I A又は生理学的に許容されるその塩を含む癌細胞増殖抑制剤；上記化 合物 I A又は生理学的に許容されるその塩を含む G1期細胞周期停止剤；上記化 合物 I A又は生理学的に許容されるその塩を含む RB タンパク質のリン酸化阻 害剤が提供される。 From another aspect, 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. In still another aspect, 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. Also, according to the present invention, 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.
また、 ホスミドシン若しくは上記化合物 I A又はそれらの塩の製造のために 有用な製造用中間体として、 化合物 I B (上記一般式 （I ) で表される化合物 において、 R R2、 R3、 R4、 R5、 及び Xが上記と同義であり、 ただし、 R1が C2一 8 アルキル基であり、 R2が水素原子であり、 R3及び R4が共に水素原子であり、 R5 が水素原子であり、 かつ Xが 0である場合、 及ぴ R1が — 8アルキル基であり、 R2が水素原子であり、 R3及び が共に水素原子であり、 が水素原子であり、 かつ Xが Sである場合を除く化合物を意味する） 又はその塩が提供される。 さらに、 本発明により、 上記化合物 I Bの製造方法であって、 下記の一般式Further, as a production intermediate useful for producing fosmidosine or the above compound IA or a salt thereof, 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,及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,
(II) ： (II):
(式中、 R12は窒素原子の保護基を示し； R13及び R14はそれぞれ独立に水酸基の 保護基を示すが、 R13及び R14は互いに結合してそれらが結合する 2個の酸素原 子とともに環を形成してもよい） で表される化合物と、 下記の一般式 （III) ：
(Wherein 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) and the following general formula (III):
(式中、 R11は _8アルキル基を示し； R15は窒素原子の保護基を示し； R16及び R17はそれぞれ独立に _8アルキル基を示す） で表される化合物とを反応させ、 得られた反応物を酸化又は硫化する工程を含む方法が本発明により提供される。 この方法の好ましい態様によれば、 上記の一般式 （II) で表される化合物と上 記の一般式 （III) で表される化合物との反応を 5 -メルカプト- 1-メチルテトラ ゾーノレの存在下に行うことができる。 (Wherein, 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. According to a preferred embodiment of this method, 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.
また、 本発明により、 ホスミ ドシン若しくは上記化合物 I A又はそれらの塩 の製造方法であって、 上記化合物 I B又はその塩を脱保護する工程を含む方 法；及びホスミ ドシン若しくは上記化合物 I A又はそれらの塩の製造方法であ つて、下記の工程：（a)上記の一般式（II)で表される化合物と上記の一般式（III) で表される化合物とを反応させ、 得られた反応物を酸化又は硫化して化合物 I Bを得る工程、 及び (b)上記工程 (a)で得られた化合物 I Bを脱保護する工程を 含む方法が提供される。 上記一般式（III) で表される化合物は本発明により初 めて提供された新規化合物であり、 ホスミドシン若しくは上記化合物 I A又は それらの塩の製造用中間体として有用である。 Also, according to the present invention, there is provided 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. Wherein 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.
さらに、 本発明により、 ホスミ ドシン若しくは上記化合物 I A又はそれらの 塩の製造のための上記化合物 I B又はその塩の使用；ホスミ ドシン若しくは上 記化合物 I A又はそれらの塩の製造のための上記一般式 （II) で表される化合 物の使用；ホスミ ドシン若しくは上記化合物 I A又はそれらの塩の製造のため の上記一般式（III) で表される化合物の使用；上記化合物 I B又はその塩の製 造のための上記一般式 （II) で表される化合物の使用；及ぴ上記化合物 I B又 はその塩の製造のための上記一般式（III)で表される化合物の使用が提供され る。 '
さらにまた、 本発明により、 ホスミ ドシン若しくは上記化合物 I A又はそれ らの塩の製造用中間体である上記化合物 I B又はその塩；ホスミ ドシン若しく は上記化合物 I A又はそれらの塩の製造用中間体である上記一般式 （II) で表 される化合物；ホスミ ドシン若しくは上記化合物 I A又はそれらの塩の製造用 中間体である上記一般式 （ΙΠ) で表される化合物；上記化合物 I B又はその塩 の製造用中間体である上記一般式 （II) で表される化合物；及び上記化合物 I B又はその塩の製造用中間体である上記一般式（III) で表される化合物が本発 明により提供される。 発明を実施するための最良の形態 Further, according to the present invention, use of the above compound IB or a salt thereof for the production of phosmidosine or the above compound IA or a salt thereof; and the above general formula (I) for the production of phosmidosine or the above compound IA or a salt thereof Use of the compound represented by the formula (III) for the production of fosmidosine or the above compound IA or a salt thereof; use of the compound represented by the above general formula (III) for the production of the compound IB or a salt thereof And use of the compound represented by the general formula (III) for the production of the compound IB or a salt thereof. ' Further, according to the present invention, there is provided 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. . BEST MODE FOR CARRYING OUT THE INVENTION
本明細書において、 アルキル基とは直鎖状、 分枝鎖状、 環状、 又はそれらの 組み合わせからなるアルキル基を意味している。 アルキル部分を有する他の置 換基 （例えばアルコキシ基ゃァラルキル基等） のアルキル部分についても同様 である。 R1が示す アルキル基どしては、 メチル基、 ェチル基、 n-プロピル 基、 イソプロピル基、 n-ブチル基、 イソブチル基、 sec-ブチル基、 tert-ブチル 基、 n-ペンチル基、 イソペンチル基、 2-メチルブチル基、 1-メチルブチル基、 ネオペンチル基、 1, 2-ジメチルプロピル基、 1-ェチルプロピル基、 n-へキシル 基、 4-メチノレペンチル基、 3-メチルペンチノレ基、 2-メチルペンチル基、 1-メチ ルペンチル、 3， 3-ジメチルブチル基、 2， 2 -ジメチルプチル基、 1, 1-ジメチルブ チル基、 1, 2-ジメチルブチル基、 1，3-ジメチルプチル基、 2, 3 -ジメチルブチル 基、 2-ェチルブチル基、 1-ェチルプチル基、 1-ェチル -1-メチルプロピル基、 n- へプチノレ基、 n-ォクチノレ基、 シクロプロピ/レ基、 シクロプチノレ基、 シクロペン チル基、 シクロへキシル基、 シクロへプチル基、 シクロォクチル基、 シクロプ 口ピルメチル基、 シクロブチルメチル基、 シクロペンチルメチル基、 シクロプ 口ピルェチル基等を例示することができる力 S、これらに限定されることはない。 R11が示すアルキル基についても同様である。
R2が示す窒素原子の保護基の種類は特に限定されず、 上記一般式 （II) で表 される化合物と上記一般式（III)で表される化合物との反応において不活性で あり、その反応の後に他の官能基に影響を与えずに脱保護できるものであれば、 いかなる保護基を用いてもよい。窒素原子の保護基については、例えば、 「プロ テクティブ'グ /レープス'イン'オーガニック'シンセシス」 （Protective Groups in Organic Syntheses, T. W. Green and P. G. M. Wuts, 3rd Ed. , 1999， John Wiley & Sons) 等に記載された保護基から当業者が適宜選択することが可能である。 R2が示す窒素原子の保護基としては、 例えば、 塩基性条件で安定であり、 かつ 酸性条件で容易に脱保護可能な保護基を選択することが好ましいが、 より具体 的には、 tert-ブトキシカルポニル (B0C)等の保護基を選択することができる。 R12が示す保護基についても同様である。 In the present specification, the alkyl group means a linear, branched, cyclic, or a combination thereof. The same applies to the alkyl portion of another substituent having an alkyl portion (for example, an alkoxy group or an aralkyl group). 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 group, n-heptinole group, n-octynole group, cyclopropyl / le group, cyclopentinole group, cyclopentyl group, cyclohexyl Group, heptyl group cycloalkyl, Shikurookuchiru group, Shikuropu port Pirumechiru group, cyclobutylmethyl group, cyclopentylmethyl group, a force can be exemplified Shikuropu port Piruechiru group S, but is not limited thereto. The same applies to the alkyl group R 11 represents. 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. Regarding 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. As the 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. The same applies to the protective group R 12 represents.
R3及び が示す水酸基の保護基の種類は特に限定されず、 上記一般式 （II) で表される化合物と上記一般式（III)で表される化合物との反応において不活 性であり、 その反応の後に他の官能基に影響を与えずに脱保護できるものであ れば、 いかなる保護基を用いてもよい。 水酸基の保護基についても、 例えば、 上記の「プロテクティブ'グループス'ィン-オーガニック 'シンセシス」等に記載 された保護基から当業者が適宜選択することが可能である。 R3及び R4が示す水 酸基の保護基としては、 例えば、 塩基性条件で安定であり、 かつ酸性条件で容 易に脱保護可能な保護基を選択することが好ましいが、 例えば、 R3及び R4が互 いに結合したィソプロピリデン基等を挙げることができる。 R13及び R14が示す 保護基についても同様である。 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 .
R5が示す窒素原子の保護基の種類は特に限定されず、 上記一般式 （II) で表 される化合物と上記一般式（III)で表される化合物との反応において不活性で あり、その反応の後に他の官能基に影響を与えずに脱保護できるものであれば、 いかなる保護基を用いてもよい。例えば、上記の「プロテクティブ 'グループス' イン'オーガニック.シンセシス」等に記載された窒素原子の保護基から当業者
が適宜選択することが可能である。 R5が示す窒素原子の保護基としては、 例え ば、 塩基性条件で安定であり、 かつ酸性条件で容易に脱保護可能な保護基を選 . 択することが好ましいが、 より具体的には、 トリチル (Tr)等の保護基を選択す ることができる。 R15が示す保護基についても同様である。 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は 0又は Sを示すが、 一般式 （I ) で表される化合物において、 R1がメチ ル基であり、 かつ Xが 0である化合物は、 一般式 （I ) で表される新規化合物 に係る本発明の範囲には包含されない。 上記一般式 （I ) で表される化合物又 はその塩は、 水和物又は溶媒和物として存在する場合もあるが、 本発明の範囲 にはこれらの物質も包含される。 また、 上記一般式 （I ) で表される化合物は 複数の不斉炭素を有しているが、 置換基の種類により、 さらに 1以上の不斉炭 素を有する場合がある。 そのような複数の不斉炭素の存在に基づく光学活性体 ゃジァステレオマー等の純粋な形態の立体異性体、 あるいは任意の立体異性体 の混合物又はラセミ体等は、 いずれも本発明の範囲に包含される。 なお、 本明 細書において示される化学式における立体表示は絶対配置を示す。 X represents 0 or S. In the compound represented by the general formula (I), 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. Further, 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. Pure forms of 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. In addition, the three-dimensional display in the chemical formula shown in this specification indicates an absolute configuration.
本発明により提供される化合物 I Aは、上記一般式（I ) において、 R1が C2_8 アルキル基であり、 R2が水素原子であり、 R3及び R4が共に水素原子であり、 R5 が水素原子であり、かつ Xが 0である力 あるいは R1が アルキル基であり、 R2が水素原子であり、 R3及び R4が共に水素原子であり、 R5が水素原子であり、 かつ Xが Sである化合物であり、上記一般式（ I )に包含される化合物である。 この化合物 I A又は生理学的に許容されるその塩は、 医薬の有効成分として有 用である。 上記化合物 I Aは癌細胞増殖抑制作用を有しており、 細胞周期を G1 期で停止する作用を有していることから、 癌の治療のための医薬の有効成分と して有用である。 いかなる特定の理論に拘泥するわけではないが、 上記化合物 I Aはサイクリン D1の発現量を抑制する作用を有しており、その結果、細胞周 期調節因子である RBタンパク質のリン酸化を阻害することによって GI期で細 胞周期を阻害することができる。
本発明により提供される医薬は、 化合物 I A及び生理学的に許容されるその 塩、 並びにそれらの水和物及ぴそれらの溶媒和物からなる群から選ばれる物質 の 1種又は 2種以上を有効成分として含み、 抗腫瘍剤として^:種の固形癌又は 非固形癌の治療に用いることができる。 本発明の医薬は、 経口的又は非経口的 にヒトを含む哺乳類動物に投与することができる。 本発明の医薬としては、 上 記の物質をそのまま投与してもよいが、 一般的には、 上記の物質の 1種又は 2 種以上と、 1種又は 2種以上の製剤用添加物とを含む医薬組成物を調製して投 与することが望ましい。 Compound IA provided by the present invention, in the above general formula (I), 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, and R 5 is a hydrogen atom And 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. Without being bound by any particular theory, 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. As the medicament of the present invention, 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.
医薬組成物の形態は特に限定されず、 投与経路に応じて適宜の形態を選択す ることが可能である。経口投与に適する医薬組成物としては、例えば、顆粒剤、 細粒剤、 散剤、 硬カプセル剤、 軟カプセル剤、 シロップ剤、 乳剤、 懸濁剤、 又 は液剤等を挙げることができ、 非経口投与に適する医薬組成物としては、 例え ば、 静脈内投与、 筋肉内投与、 若しくは皮下投与用の注射剤、 点滴剤、 坐剤、 経皮吸収剤、 経粘膜吸収剤、 点鼻剤、 点耳剤、 点眼剤、 吸入剤等を挙げること ができる。 粉末の形態の医薬組成物として調製された製剤を用時に溶解して注 射剤又は点滴剤として使用してもよい。 もっとも、 医薬組成物の形態はこれら に限定されることはない。 The form of the pharmaceutical composition is not particularly limited, and an appropriate form can be selected according to the administration route. Pharmaceutical 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. However, the form of the pharmaceutical composition is not limited to these.
医薬用組成物の製造には、 固体又は液体の製剤用添加物を用いることができ る。 製剤用添加物は有機又は無機のいずれであってもよい。 経口用の固形の医 薬組成物の製造には、 例えば、 賦形剤、 結合剤、 崩壊剤、 滑沢剤、 着色剤、 又 は矯味矯臭剤等を用いることができる。賦形剤としては、例えば、乳糖、蔗糖、 白糖、 ブドウ糖、 コーンスターチ、 デンプン、 タルク、 ソルビット、 結晶セル ロース、 デキストリン、 カオリン、 炭酸カルシウム、 又は二酸化ケイ素等を挙 げることができる。 結合-剤としては、 例えば、 ポリビエルアルコール、 ポリビ ニルエーテル、 ェチルセルロース、 メチルセルロース、 アラビアゴム、 トラガ ント、 ゼラチン、 シヱラック、 ヒ ドロキシプロピノレセ ロース、 ヒドロキシプ
口ピルメチルセルロース、 クェン酸カルシウム、 デキストリン、 又はべクチン 等を挙げることができる。 滑沢剤としては、 例えば、 ステアリン酸マグネシゥ ム、 タルク、 ポリエチレングリコール、 シリカ、 又は硬化直物油等を挙げるこ とができる。 着色剤としては、 通常医薬への添加が許可されているものであれ ばいずれも使用することができる。矯味矯臭剤としては、ココア末、ハツ力脳、 芳香酸、 ハツ力油、 龍脳、 又は桂皮末等を使用することができる。 医薬組成物 として錠剤や顆粒剤を調製する場合には、 糖衣又はゼラチン衣等の適宜のコー ティングを施すことができ、 必要に応じて防腐剤ゃ抗酸化剤等を添加すること もできる。 For the production of pharmaceutical compositions, solid or liquid pharmaceutical additives can be used. The pharmaceutical additives may be either organic or inorganic. 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. Examples of the excipient include lactose, sucrose, sucrose, glucose, corn starch, starch, talc, sorbitol, crystalline cellulose, dextrin, kaolin, calcium carbonate, and silicon dioxide. Examples of 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. Examples of 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. As the flavoring agent, cocoa powder, heart-shaped brain, aromatic acid, heart-shaped oil, dragon brain, cinnamon powder, or the like can be used. When preparing tablets or granules as a pharmaceutical composition, appropriate coating such as sugar coating or gelatin coating can be applied, and if necessary, a preservative and an antioxidant can be added.
経口投与のための液体の医薬組成物の製造には、 一般的に用いられる不活性 な希釈剤、 例えば水又は植物油等を用いることができ、 例えば、 湿潤剤、 懸濁 補助剤、 甘味剤、 芳香剤、 着色剤、 又は保存剤等を配合することができる。 液 体の医薬組成物を調製した後、 ゼラチンのような吸収性物質のカプセル中に充 填してもよい。液体の医薬組成物の調製に用いられる溶剤又は懸濁剤としては、 例えば、 水、 プロピレングリコール、 ポリエチレングリコール、 ベンジルアル コール、 ォレイン酸ェチル、 又はレシチン等を挙げることができる。 坐剤の製 造に用いられる基剤としては、例えば、カカオ脂、乳化カカオ脂、 ラウリン脂、 又はウイテッブゾール等を挙げることができる。 For preparing a liquid pharmaceutical composition for oral administration, 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. After preparing the liquid pharmaceutical composition, it may be filled into capsules of an absorbent material such as gelatin. Examples of the solvent or suspending agent used for preparing a liquid pharmaceutical composition include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, and lecithin. As the base used in the production of suppositories, for example, cocoa butter, emulsified cocoa butter, laurin fat, witebsol, and the like can be given.
非経口投与のための医薬組成物として注射剤を調製する場合には、 担体とし て、 例えば、 水、 エチルアルコール、 マクロゴール、 又はプロピレングリコー ル、 あるいはこれらの混合物等を用いることができ、 塩酸、 クェン酸、 酢酸、 リン酸、 乳酸、 乳酸ナトリウム、 硫酸、 又は水酸化ナトリウム等の PH調節剤、 クェン酸ナトリウム、 酢酸ナトリウム、 又はリン酸ナトリウム等の緩衝剤、 ピ 口亜硫酸ナトリウム、 エチレンジァミン四酢酸、 チォグリコール酸、 又はチォ 乳酸等の安定化剤等、 食塩、 ブドウ糖、 マンニトール、 又はグリセリン等の等 張化剤を添加してもよい。 また、 溶解補助剤、 無痛化剤、 又は局所麻酔剤等を
使用することもできる。 When preparing an injection as a pharmaceutical composition for parenteral administration, for example, 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. In addition, solubilizers, soothing agents, or local anesthetics Can also be used.
軟膏剤やクリーム剤等の形態の外用の医薬組成物を調製する場合には、 基剤、 安定剤、 湿潤剤、 及び保存剤等を用いることができ、 常法により有効成分であ る上記物質を混合して医薬組成物を調製することができる。 基剤としては、 例 えば、白色ワセリン、 ポリエチレン、 パラフィン、グリセリン、 セルロース誘導 体、 ポリエチレングリコール、 シリコン、 又はベントナイト等を使用すること ができる。 保存剤としては、 パラォキシ安息香酸メチル、 パラォキシ安息香酸 ェチル、 又はパラォキシ安息香酸プロピル等を使用することができる。 貼付剤 の形態の医薬組成物を調製する場合には、通常の支持体に上記軟膏、クリーム、 ゲル又はペースト等を常法により塗布することができる。支持体としては、綿、 スフ、 若しくは化学繊維等からなる織布又は不織布、 軟質塩化ビニル、 ポリエ チレン、 又はポリウレタン等からなるフィルム、 あるいは発泡体シート等を好 適に使用できる。 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. As the base, for example, white petrolatum, polyethylene, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicon, bentonite, or the like can be used. As a preservative, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, or the like can be used. When preparing a pharmaceutical composition in the form of a patch, the above-mentioned ointment, cream, gel, paste, or the like can be applied to a usual support in a conventional manner. As the support, 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.
本発明の医薬の投与量は特に限定されないが、 経口投与の場合には、 成人一 日あたり有効成分である上記化合物 I Aの質量として通常 1 0〜1 , 0 0 0 m g程度である。 この投与量を患者の年令、 病態、 症状に応じて適宜増減するこ とが好ましい。 前記一日量は一日に一回、 又は適当な間隔をおいて一日に 2〜 3回に分けて投与してもよく、 あるいは数日おきに間歇投与してもよレ、。 注射 剤として用いる場合には、 成人一日あたり有効成分である化合物 I Aの質量と して 5〜5 0 O m g程度である。 The dose of the medicament of the present invention is not particularly limited. In the case of oral administration, 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. When used as an injection, the mass of compound IA as an active ingredient per adult day is about 5 to 50 Omg.
本発明の別の観点から提供される化合物 I Bは、上記一般式（I )において、 R\ R2、 、 R\ R5、 及び Xが上記と同義であり、 ただし、 R1が C2_8アルキル基 であり、 R2が水素原子であり、 R3及ぴ が共に水素原子であり、 R5が水素原子 であり、 かつ Xが 0である場合、 及び R1が — 8アルキル基であり、 R2が水素原 子であり、 R3及ぴ R4が共に水素原子であり、 R5が水素原子であり、 かつ Xが S である場合を除く化^物であり、 上記一般式 （I ) に包含される。 この化合物
I B又はその塩は、 ホスミ ドシン （上記一般式 （I ) において、 R1がメチル基 であり、 R2が水素原子であり、 R3及び R4が共に水素原子であり、 R5が水素原子 であり、 Xが 0の場合に相当する化合物である） 又は上記化合物 I Aの製造の ための製造用中間体として有用である。 In the compound IB provided from another viewpoint of the present invention, in the above general formula (I), 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及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.
化合物 I Bは、 本発明により提供される製造方法に従って、 下記のスキーム に示す第一工程により製造することができる。 また、 ホスミ ドシン及ぴ上記化 合物 I Aは、 化合物 I Bより脱保護を行う第二工程により製造することができ る。 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.
I A ドシン I A Dosin
A
A
化合物 IB Compound IB
(x-s) (x-s)
第一工程では、 上記一般式 （II) で表される化合物と上記一般式 （I II) で 表される化合物とを反応させ、得られた反応物を酸化又は硫化する工程を含む。
上記の酸化工程により Xが 0の化合物を製造することができ、 硫化工程により Xが Sの化合物を製造することができる。 記一般式 （II) で表される化合物と 上記一般式 （III) で表される化合物との反応は、 例えば 5-メルカプト - 1 -メチ ルテ ト ラゾールの存在下に行う こ とができ る （Filippov, D. et al. , Tetrahedron Lett. , 39, 4891, 1998)。 酸化工程は、 例えば tert-ブチルハイ ドロパーォキサイ ドなどの酸化剤を好適に用いることができ、 硫化には Ν, Ν, Ν' , Ν' -テトラェチルチウラムジスルフィ ドゃ S8を用いることができる。 もっとも、 酸化及ぴ硫化のための試薬はこれらに限定されることはなく、 当 業者が通常用いられる酸化剤から適宜選択できることは言うまでもない。 例え ば、「ジエージェンッ ·フォー ·オーガ二ック ·シンセシス」 (Reagents for Organic Synthesis, Vol. 1， 1967 to Vol. 16， 1992, John Wiley & Sons) などの成書 に記載された酸化剤及ぴ硫化剤を適宜選択し、保護基の性質に関して「プロテク ティブ'グノレープス'イン'オーガニック 'シンセシス」 （Protective Groups in Organic Syntheses, T. W. Green and P. G. M. Wuts, 3rd Ed. , 1999， John Wiley & Sons) を参照することにより、 適宜の反応条件を選択することができる。 上記一般式 （II) で表される化合物と上記一般式 （III) で表される化合物 との反応は、通常は溶媒の存在下において無水の環境で行うことができ、 0°Cか ら溶媒の還流温度までの範囲の温度、 好ましくは室温で行うことができる。 反 応に用いる溶媒は、 反応種に対して充分な溶解性を有し、 かつ反応において不 活性であれば、 特に限定されることはない。 例えば、 ァセトニトリルなどの二 トリル系溶媒、 塩化メチレンやクロ口ホルムなどの塩素系溶媒、 ベンゼン、 ト ルェン、 キシレンなどの芳香族系溶媒、 ジェチルエーテル、 テトラヒ ドロフラ ン、 ジォキサンなどのエーテル系溶媒などを用いることができる。 反応には、 一般式 （II) で表される化合物に対して一般式 （III) で表される化合物を約 1 〜 1 0モル程度、 好ましくは 2〜 3モル程度を用いることができる。 反応はァ ルゴンゃ窒素などの不活性ガス下で行うことが望ましい。
酸化反応は、 上記一般式 （Π) で表される化合物と上記一般式 （III) で表 される化合物との反応が終了した後、 反応系に酸化剤を加えて o°cから溶媒の 還流温度までの範囲の温度、 好ましくは室温で行うことができる。 酸化剤とし て、 例えば tert-ブチルハイドロパーォキサイドなどを用いる場合には、 上記 一般式 （II) で表される化合物に対して約 5〜2 0モル程度、 好ましくは 1 0 モル程度の酸化剤を用いることができる。 硫化反応は、 上記一般式 （II) で表 される化合物と上記一般式（III) で表される化合物との反応が終了した後、反 応系に硫化剤を加えて 0°Cから溶媒の還流温度までの範囲の温度、 好ましくは 室温で行うことができる。硫化剤として例えば Ν, Ν, Ν' , Ν' -テトラェチルチウラ ムジスルフィ ドなどを用いる場合には、 上記一般式 （II) で表される化合物に 対して約 1〜1 0モル程度、 好ましくは 2〜 5モル程度の硫化剤を用いること ができる。 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. By the above oxidation step, a compound in which X is 0 can be produced, and in the sulfurization step, 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 Ν, Ν, Ν ', Ν ' - can be used tetra E chill thiuram disulfinate Doya S 8 . However, 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. For example, oxidizing agents and oxidants described in books such as "Reagents for Organic Synthesis, Vol. 1, 1967 to Vol. 16, 1992, John Wiley &Sons". Select the appropriate sulphiding agent and refer to "Protective Groups in Organic Syntheses, TW Green and PGM Wuts, 3rd Ed., 1999, John Wiley &Sons" for the nature of the protecting groups. By doing so, appropriate reaction conditions can be selected. 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. For example, 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. Can be used. In the reaction, about 1 to 10 mol, preferably about 2 to 3 mol of the compound represented by the general formula (III) can be used based on the compound represented by the general formula (II). The reaction is desirably performed under an inert gas such as argon-nitrogen. In the oxidation reaction, after the reaction between the compound represented by the above general formula (Π) and the compound represented by the above general formula (III) is completed, 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. When, for example, 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. After the reaction between the compound represented by the above general formula (II) and the compound represented by the above general formula (III) is completed, 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. When, for example, Ν, Ν, Ν ′, Ν′-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.
上記の第一工程の後、 得られた化合物 I Βを脱保護反応に付することにより、 ホスミ ドシン又は化合物 I Αを製造することができるが、 脱保護反応は用いた 保護基の種類に応じて適宜の反応条件を選択することにより行われる。 脱保護 の条件は、例えば、 「プロテクティブ'グループス'イン'オーガニック 'シンセシ ス」 (Protective Groups in Organic Syntheses, T. W. Green and P. G. M. Wuts, 3rd Ed.， 1999， John Wiley & Sons) などの成書を参照することにより、 当業 者は適宜の条件を選択することが可能である。 After the above first step, phosmidosine or compound I で き る can be produced by subjecting the obtained compound IΒ 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.
一般式 （II) で表される化合物のうち、 R12が tert-ブトキシカルボニル基で ある化合物は公知であり（Sekine, M. et al. , J. Org. Synth. Chem. Jpn.， 59, 1109, 2000)、 文献記載の方法により容易に入手することができる。 R12が tert- ブトキシカルボニル基以外の保護基である化合物については、例えば、 「プロテ クティブ'グループス 'ィン 'オーガ二ック 'シンセシス」 (Protective Groups in Organic Syntheses, T. W. Green and P. G. M. Wuts, 3rd Ed. , 1999, John Wiley & Sons) を参照することにより、 上記スキーム中の第一工程における反応条件
を考慮しつつ適宜の保護基を選択することができ、 上記刊行物に記載された方 法に従って窒素原子上への保護基導入を行うことができる。 Among the compounds represented by the general formula (II), a compound in which R 12 is a tert-butoxycarbonyl group is known (Sekine, M. et al., J. Org. Synth. Chem. Jpn., 59, 1109, 2000), and can be easily obtained by the method described in the literature. Compounds in which R 12 is a protecting group other than a tert-butoxycarbonyl group 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 In consideration of the above, 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.
一般式 （III) で表される化合物は、 環構成窒素原子がトリチル基などで保 護されたプロリンアミ ドと一般式（IV)： R210-P [N (R24) (R25) ] [N (R26) (R27) ] (式中、 R21、 R24、 R25、 R26、 及ぴ R27はそれぞれ独立に（ 8アルキル基を示す） で表され る化合物とを適当な活性化剤、 例えば 1H -テトラゾール、 N，N-ジイソプロピル アンモニゥム 1H-テトラゾリデートなどの酸触媒の存在下で反応させて選択的 N -ホスフイチル化を行うことにより容易に製造することができる。一般式（IV) において、 R24、 R25、 R26、 及び R27はすべて同一のアルキル基であることが好ま しく、より好ましいのはこれらの基がすべてィソプロピル基である場合である。 一般式（IV) で表される化合物において適宜の（ 8アルキル基を R21として選択 することにより、 このアルキル基を有する一般式（III) で表されるアミダイト 化合物を製造することができ、 このアミダイ ト化合物を用いることにより、 R21 として選択された アルキル基を有する化合物 I B並びに化合物 I A及びホ スミ ドシンを製造することができる （これらの化合物における R1が R21に対応 する）。 - 環構成窒素原子が保護されたプロリンアミ ドと一般式 （IV) で表される化合 物との反応は、通常は溶媒の存在下において無水の環境で行うことができ、 0°C から溶媒の還流温度までの範囲の温度、 好ましくは室温で行うことができる。 反応に用いる溶媒は、 反応種に対して充分な溶解性を有し、 かつ反応において 不活性であれば、 特に限定されることはない。 例えば、 塩化メチレンやクロ口 ホルムなどの塩素系溶媒、ベンゼン、 トルエン、キシレンなどの芳香族系溶媒、 ジェチルエーテル、 テトラヒドロフラン、 ジォキサンなどのエーテル系溶媒、 ァセトニトリルなどの二トリル系溶媒などを用いることができる。 反応には、 環構成窒素原子が保護されたプロリンアミ ド 1モルに対して一般式 （IV) で表 される化合物を約 1〜 1 0モル程度、 好ましくは 1〜 3モル程度及び活性化剤
を 0 . 1〜1 0モル程度用いることができる。 反応はアルゴンや窒素などの不 活性ガス下で行うことが望ましい。 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. In the general formula (IV), 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. By selecting an appropriate ( 8 alkyl group as R 21 ) in the compound represented by the formula (IV), Thus, an amidite compound represented by the general formula (III) having the alkyl group can be produced. By using the amidite compound, 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) 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. There is no particular limitation as long as it has sufficient solubility in the reaction and is inert in the reaction, for example, 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. About 1 to 10 mol, preferably about 1 to 3 mol, of the compound represented by the general formula (IV) per mol of Can be used in an amount of about 0.1 to 10 mol. The reaction is preferably performed under an inert gas such as argon or nitrogen.
上記の製造方法で生成する製造用中間体及び目的化合物は、 有機合成化学の 分野で通常用いられる分離精製法、 例えば、 中和、 濾過、 抽出、 乾燥、 濃縮、 再結晶、 各種クロマトグラフィーなどの手段を用いて単離 ·精製することがで きるが、 製造用中間体を特に精製することなく次の反応に供することも可能で ある。 例えば、 化合物 I Bはリン原子上に不斉があるためジァステレオマーと して得られるが、 例えば、 酸化生成物であるホスミ ドシン誘導体については逆 相 HPLC操作による異性体分取を行うことによりに、いずれのジァステレオマー についても純粋に分離することができる。 この方法については実施例に具体的 に示した。 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. For example, compound IB can be obtained as a diastereomer because of its chirality on the phosphorus atom.For example, 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.
製造用中間体及ぴ目的化合物の塩を取得したい場合には、 反応系から化合物 が塩の形態で得られる場合にはそのまま精製すればよく、 化合物が遊離形態で 得られる場合には、 適当な有機溶媒に溶解又は懸濁させ、 酸又は塩基を加える 方法により塩を形成させればよい。 また、 塩の形態で得られた化合物を遊離形 態の化合物に変換した後、適宜の塩の形態に変換することも可能である。なお、 上記の各工程の反応に関して、 以下の実施例にはさらに具体的な説明が開示さ れているので、 当業者は、 上記の一般的な説明及び実施例に記載された具体的 な説明を参照しつつ、 反応条件、 出発原料、 及び反応試薬などを適宜選択し、 必要に応じてこれらの方法に適宜の修飾ないし改変を加えることにより、 所望 の化合物を容易に製造することができる。 実施例 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. In addition, regarding the reactions of the above steps, further detailed explanations are disclosed in the following examples, and those skilled in the art will understand the above general explanations and the specific explanations described in the examples. 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
以下、 実施例により本発明をさらに具体的に説明するが、 本発明の範囲は下 記の実施例に限定されることはない。 Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.
実施例 1
本発明の化合物を以下のスキームに従って合成した。 以下、 化合物番号はスキ -ム中の化合物番号に対応させてある。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.
1.5 equi 0,6 equiv 1.5 equi 0,6 equiv
18 18
替え用紙觀！ ¾)
View replacement paper! ¾)
5(a~c) 6(a- -c， retention time fast or slow) 5 (a ~ c) 6 (a- -c, retention time fast or slow)
Et 47%(6a-fast), 53% (6a- s 1 ow) -Pr 37%(6b-fast), 60% (6b- s I ow) Et 47% (6a-fast), 53% (6a- s 1 ow) -Pr 37% (6b-fast), 60% (6b- s I ow)
Bu 16%(6c-fast), 19% (6G-S I ow) Bu 16% (6c-fast), 19% (6G-S I ow)
36% 36%
羞替え用紙（規則 26)
化合物 2 ： Shuffle paper (Rule 26) Compound 2:
8 -ォキソアデノシン（1) (5.66 g, 20 mmol)をァセトン（200 raL)中に懸濁させ、 ァセトンジメチルァセタール（49.2 ml, 400 mmol)及ぴ p-トルエンスルホン酸 1水和物（7.61 g, 40 mmol)を加え 4時間室温で撹拌した。 その後飽和炭酸水素 ナトリウム水溶液 （200 ml) を加え、 系内を中和した後、 溶媒を減圧下留去し た。 つぎにクロ口ホルム-イソプロピルアルコール（3 ： 1， v/v)及ぴ飽和炭酸水 素ナトリゥム水溶液で抽出し、 集めた有機層を無水硫酸ナトリゥムで乾燥し、 溶媒を減圧下留去した。得られた残渣をメタノール-トリェチルァミンの混合溶 媒 （9:1 v/v, 200 mL) に溶解し、 二炭酸-ジ- tert-ブチル（5.97 mL, 26 mmol) を加え室温で 2時間撹拌した。 その後反応系をクロ口ホルムで希釈し、 飽和炭 酸水素ナトリゥム水溶液で有機層を 3回洗浄した。 回収した有機層を無水硫酸 ナトリウムで乾燥した後に、 溶媒を減圧下留去して、 残渣をシリカゲルカラム クロマトグラフィー （クロ口ホルム-メタノール =100:0- 97:3) で精製し、 白色 フォーム状物質として目的物（2) (6.14 g， 73%)を得た。 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. Next, 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. After the collected organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol = 100: 0-97: 3) to give a white foam. The desired product (2) (6.14 g, 73%) was obtained as a substance.
¾- NMR (270 MHz, CDC13) δ 1.29 (3Η, s, CH3 of isop), 1.49 (3H, s， CH3 of isop, 1.56 (9H， s, (CH3) 3C of Boc) , 3.46—3.58 (2H, m, 5，— H), 4.04-4.09 (1H, m, 4' -H) , 4.87-4.91 (2H, ra， 3，— H, 5，— OH)， 5.35—5.38 (1H， dd， 2，— H)， 5.91-5.92 (1H， d 1'— H)， 7.03 (2H, bs， NH2), 8.11 (1H, s, 2— H) ¾- NMR (270 MHz, CDC1 3 ) δ 1.29 (3Η, s, CH 3 of isop), 1.49 (3H, s, CH 3 of isop, 1.56 (9H, s, (CH 3) 3 C of Boc), 3.46-3.58 (2H, m, 5, -H), 4.04-4.09 (1H, m, 4'-H), 4.87-4.91 (2H, ra, 3, -H, 5, -OH), 5.35-5.38 (1H, dd, 2, - H), 5.91-5.92 (1H, d 1'- H), 7.03 (2H, bs, NH 2), 8.11 (1H, s, 2H)
13C NMR (CDC13) δ 25.49, 27.68, 27.99, 63.41, 81.19， 81.26, 85.16， 87.00, 89.11， 102.08， 113.94, 147.12, 147.87, 149.04, 149.76， 153.07； 化合物 4 1 3 C NMR (CDC1 3) δ 25.49, 27.68, 27.99, 63.41, 81.19, 81.26, 85.16, 87.00, 89.11, 102.08, 113.94, 147.12, 147.87, 149.04, 149.76, 153.07; Compound 4
N-トリチルプロリンアミ ド（3) (2.14 g, 6 mmol)及び Ν,Ν-ジィソプロピルァ ンモニゥムテトラゾリ ド（616 mg, 3.6 mmol)を無水ピリジンで 3回、 無水トノレ ェンで 3回共沸脱水し、 無水塩化メチレン（60 mL) に溶解させた。 ェチル (Ν,Ν,Ν',Ν，-テトライソプロピル） ホスホロジアミダイ ト（2.46 mL， 9 讓 ol) N-Tritylproline amide (3) (2.14 g, 6 mmol) and Ν, Ν-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 (Ν, Ν, Ν ', Ν, -tetraisopropyl) phosphorodiamidite (2.46 mL, 9 carbonyl)
19
を加え、 アルゴン雰囲気下室温で 3時間撹拌した。 反応液をクロ口ホルムで希 釈して 5%炭酸水素ナトリゥム水溶液で有機層を 3回洗浄した。 回収した有機層 を無水硫酸ナトリウムで乾燥し、 溶媒を減圧下留去した後、 残渣をシリカゲル カラムク ロマ トグラフィー（へキサン-酢酸ェチル -ト リ ェチルアミ ン=19 Was added, and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. The reaction solution was diluted with chloroform and the organic layer was washed three times with a 5% aqueous sodium hydrogen carbonate solution. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate-triethylamine = hexane).
100:0:卜 85:15:1)で精製し、 目的物（4a) (2.31 g， 71%)を白色フォーム状物質で 得た。Purification was carried out with 100: 0: to 85: 15: 1) to obtain the desired product (4a) (2.31 g, 71%) as a white foam.
- NMR (270 MHz, CDC13) δ 0.81-1.1.47 (20Η, m, 3 "-Ha, 4"-H, CH3 of i- Pr, CH3 of POEt) , 1.65-1.70 (IH, ra, 3"— Hb)， 2.97-3.04 (1H， m, 5"-Ha), 3.23-3.27 (IH, m， 5"-Hb) , 3.63-3.87 (5H, m, 2〃-H， CH2 of POEt, CH of i— Pr) - NMR (270 MHz, CDC1 3 ) δ 0.81-1.1.47 (20Η, m, 3 "-Ha, 4" -H, CH 3 of i- Pr, CH 3 of POEt), 1.65-1.70 (IH, ra , 3 "- Hb), 2.97-3.04 (1H, m, 5" -Ha), 3.23-3.27 (IH, m, 5 "-Hb), 3.63-3.87 (5H, m, 2〃-H, CH 2 of POEt, CH of i— Pr)
13C丽 R (CDC13) δ 18.63, 18.70, 18.75， 18.81, 25.65, 25.79, 25.86, 25.96， 26.05， 26.13， 32.50, 32.60， 45.62, 45.81, 45.88, 46.07, 51.94， 56.64, 62.15, 62.50, 67.13， 67.23， 127.72， 129.08， 130.52, 130.56, 145.88, 146.06, 179.65， 179.82; 1 3 C丽R (CDC1 3) δ 18.63, 18.70, 18.75, 18.81, 25.65, 25.79, 25.86, 25.96, 26.05, 26.13, 32.50, 32.60, 45.62, 45.81, 45.88, 46.07, 51.94, 56.64, 62.15, 62.50, 67.13, 67.23, 127.72, 129.08, 130.52, 130.56, 145.88, 146.06, 179.65, 179.82;
31P NMR (CDCI3) δ 112.96， 114. 9 化合物 5 ： 31 P NMR (CDCI3) δ 112.96, 114.9 Compound 5:
8-ォキソアデノシン誘導体（2) (805 mg, 1.9 mmol) 及ぴアミダイ ト試薬 (4a) (2.09 g， 3.6 mmol)を無水ァセトニトリルで 4回共沸脱水した後、 無水ァ セトニトリル（30 mL)に溶解させ、 5-メルカプト- 1-メチルテトラゾール（552 mg, 4.75 mmol)を加えてアルゴン雰囲気下室温で 1時間撹拌した。その後、 6M tert - プチルハイ ドロパーォキサイド-デカン溶液（3.17 mL， 19 mmol) を加えて、 室 温でさらに 10分間撹拌した。反応系をクロ口ホルムで希釈して有機層を蒸留水 で 3回洗浄した後、 回収した有機層を無水硫酸ナトリウムで乾燥し、 溶媒を減 圧下留去した。 残渣をシリカゲルカラムクロマトグラフィー（へキサン-酢酸ェ チル-ピリジン = 50:50:1- 40:60:1)で精製し、 目的物（5b) (1.57 g， 95%)を白色 フォーム状物質で得た。 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. After the reaction system was diluted with chloroform and the organic layer was washed three times with distilled water, the collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate-pyridine = 50: 50: 1-40: 60: 1) to give the desired product (5b) (1.57 g, 95%) as a white foam. Obtained.
20
一 NMR (270 MHz, CDC13) δ 0.81—0.88 (IH, m， 4"-Ha) , 1.07—1.50 (9H, m， 4"一 Hb， 3"-H, CH3 of isop, CH3 of POEt) , 1.54—1.57 (IH, 2s, CH3 of isop), 1.62 (9H， s, (CH3)3C of Boc), 2.96—3.03 (IH, m, 5"- Ha), 3.31-3.36 (IH, m, 5" - Hb)， 3.89-3.94 (2H， m， CH2 of POEt) , 4.19-4.50 (4H， m, 2"- H， 4'一 H， 5，一 H), 5.08-5.13 (1H， m, 3'— H)， 5.43-5.45 (IH, m, 2'-H)， 6.23—6.26 (IH, m, 1，一 H)， 6.62 (2H, bs, NH2), 7.13-7.32 (9H， m， Ar-H) , 7.45—7.67 (6H， m， Ar - H)， 8.15-8.16 (1H， 2s, 2 - H) 20 One NMR (270 MHz, CDC1 3) δ 0.81-0.88 (IH, m, 4 "-Ha), 1.07-1.50 (9H, m, 4" one Hb, 3 "-H, CH 3 of isop, CH 3 of POEt), 1.54-1.57 (IH, 2s, CH 3 of isop), 1.62 (9H, s, (CH 3 ) 3 C of Boc), 2.96-3.03 (IH, m, 5 "-Ha), 3.31-3.36 (IH, m, 5 "-Hb), 3.89-3.94 (2H, m, CH 2 of POEt), 4.19-4.50 (4H, m, 2" -H, 4'-H, 5, 1H), 5.08 -5.13 (1H, m, 3'- H ), 5.43-5.45 (IH, m, 2'-H), 6.23-6.26 (IH, m, 1, one H), 6.62 (2H, bs , NH 2) , 7.13-7.32 (9H, m, Ar-H), 7.45-7.67 (6H, m, Ar-H), 8.15-8.16 (1H, 2s, 2-H)
13C NMR (CDC13) δ 15.93， 16.00， 16.0316.11, 24.06, 24.10, 24.27， 26.96, 27.75, 30.98, 31.38， 31.4450.22, 50.39, 50.45, 63.93， 63.97, 64.03， 64.05， 64.80， 65, 25, 65.3367.01, 77.20, 77.95， 78.04， 81.64, 81.83, 82.56， 82.73, 85.38, 85.50， 85.63， 86.30, 86.33， 86.86, 86.92， 101.67， 101.70, 113.65, 113.67， 126.09, 126.22, 127.45, 127.55, 128.86, 142.94, 143.82， 144.31, 147.22， 147.25, 147.80， 148.68, 148.72， 149.53， 149.56， 153.30, 177.18， 177.22, 177.25, 177.29 13 C NMR (CDC1 3) δ 15.93, 16.00, 16.0316.11, 24.06, 24.10, 24.27, 26.96, 27.75, 30.98, 31.38, 31.4450.22, 50.39, 50.45, 63.93, 63.97, 64.03, 64.05, 64.80, 65, 25, 65.3367.01, 77.20, 77.95, 78.04, 81.64, 81.83, 82.56, 82.73, 85.38, 85.50, 85.63, 86.30, 86.33, 86.86, 86.92, 101.67, 101.70, 113.65, 113.67, 126.09, 126.22, 127.45, 127.55, 128.86, 142.94, 143.82, 144.31, 147.22, 147.25, 147.80, 148.68, 148.72, 149.53, 149.56, 153.30, 177.18, 177.22, 177.25, 177.29
上記生成物（5a) (1.57 g， 1.81 膽 ol)を 80%ギ酸水溶液（20 mL)に溶解し、 室 温で 12時間撹拌した。反応系を蒸留水で希釈し、酢酸ェチルで水層を 3回洗浄 した後、 回収した水層を減圧下留去した。 その後、 さらに 3回蒸留水で共沸し た後、残渣を C- 18シリカゲル逆相カラムクロマトグラフィー（水-ァセトニトリ ル =100:0- 95:5)で精製し、水溶液から凍結乾燥することにより目的物のジァス テレオマー（733 mg, 83%)を白色フォーム状物質で得た。 ジァステレオマーの分 離は分取用 HPLC (水-メタノール-トリフルォロ酢酸 = 93:7:0.1) で行った。 流 出速度の早い方を fast体、 遅い方を slow体とし、 水溶液から凍結乾燥するこ とにより、 トリフルォロ酢酸の塩としてそれぞれ純粋に分離した。 その他のァ 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. The reaction system was diluted with distilled water, and the aqueous layer was washed three times with ethyl acetate. The collected aqueous layer was distilled off under reduced pressure. After azeotropic distillation with distilled water three times, the residue was purified by C-18 silica gel reverse phase column chromatography (water-acetonitrile = 100: 0-95: 5) and lyophilized from the aqueous solution. The desired diastereomer (733 mg, 83%) was obtained as a white foam. Separation of diastereomers was performed by preparative HPLC (water-methanol-trifluoroacetic acid = 93: 7: 0.1). The faster outflow rate was the fast form and the slower outflow rate was the slow form. Lyophilization from the aqueous solution resulted in pure separation of the trifluoroacetic acid salt. Others
21
ルキルエステル体（6b， 6c, fast or slow) についても同様に合成して分離する ことができた。 twenty one The alkyl esters (6b, 6c, fast or slow) were similarly synthesized and separated.
6a-f ast 6a-f ast
JH-NMR (270 MHz, D20) δ 1.23-1.28 (3H， t, CH3 of POEt) , 1.96-2.13 (3H, m, 3"- Ha, 4" - H)， 2.42-2.52 (IH, m， 3"-H), 3.34-3.47 (2H， m, 5〃- H), 4.10—4.25 (3H, m, 2〃— H， CH2 of POEt) , 4.31-4.47 (3H, m, 4，— H， 5，- H)， 4.63-4.67 (1H， m， 3， - H), 5.02-5.06 (IH, dd, 2' - H)， 5.92-5.94 (1H， d, 1' - H)， 8.34 (1H， s, 2-H) J H-NMR (270 MHz, D 20 ) δ 1.23-1.28 (3H, t, CH 3 of POEt), 1.96-2.13 (3H, m, 3 "-Ha, 4" -H), 2.42-2.52 ( IH, m, 3 "-H), 3.34-3.47 (2H, m, 5〃-H), 4.10—4.25 (3H, m, 2〃—H, CH 2 of POEt), 4.31-4.47 (3H, m , 4,-H, 5, -H), 4.63-4.67 (1H, m, 3, -H), 5.02-5.06 (IH, dd, 2'-H), 5.92-5.94 (1H, d, 1 ' -H), 8.34 (1H, s, 2-H)
13C NMR (D20) δ 17.88, 17.97， 26.16, 31.95， 49.12, 63.04, 63.22, 68.44, 68.53, 69.63, 69.71, 72.15, 73.76， 84.26, 84.37, 89.29， 107.05， 112.39， 116.68, 120.96, 125.25, 144.55， 146.78, 149.04, 154.84, 164.44, 164.96， 165.47, 165.99， 173.92, 173.94 13 C NMR (D 20 ) δ 17.88, 17.97, 26.16, 31.95, 49.12, 63.04, 63.22, 68.44, 68.53, 69.63, 69.71, 72.15, 73.76, 84.26, 84.37, 89.29, 107.05, 112.39, 116.68, 120.96, 125.25 , 144.55, 146.78, 149.04, 154.84, 164.44, 164.96, 165.47, 165.99, 173.92, 173.94
31P NMR (D20) δ 一 1.35; 3 1 P NMR (D 20 ) δ 1.35;
6a— slow6a—slow
- NMR (270 MHz, D20) δ 1.24—1.29 (3H, t, CH3 of POEt) , 2.01-2.22 (3H， m， 3 "-Ha, 4"-H) , 2.44-2.57 (IH, m, 3"— H), 3.35-3.51 (2H, m, 5"— H)， 4.11—4.22 (2H, m, CH2 of POEt) , 4.27-4.30 (IH, m, 2" - H)， 4.39-4.52 (3H， m, 4，— H， 5' - H), 4.65-4.69 (IH, m, 3，— H)， 5.08—5.12 (1H， dd, 2， - H) , 5.96-5.98 (1H， d, 1，— H) , 8.38 (IH, s， 2-H) -NMR (270 MHz, D 2 0) δ 1.24-1.29 (3H, t, CH 3 of POEt), 2.01-2.22 (3H, m, 3 "-Ha, 4" -H), 2.44-2.57 (IH, m, 3 "-H), 3.35-3.51 (2H, m, 5" -H), 4.11-4.22 (2H, m, CH 2 of POEt), 4.27-4.30 (IH, m, 2 "-H), 4.39-4.52 (3H, m, 4, -H, 5'-H), 4.65-4.69 (IH, m, 3, -H), 5.08-5.12 (1H, dd, 2, -H), 5.96-5.98 (1H, d, 1, -H), 8.38 (IH, s, 2-H)
13C NMR (D20) δ 17.80， 17.89, 26.11， 31.89， 49.08， 63.00, 63.19, 68.40， 68.49, 69.66， 69.75， 72.18, 73.66, 84.33, 84.42, 89.20, 107.03, 112.50， 116.79, 121.08, 125.36， 144.59, 146.81, 148.98, 154.84, 164.50, 165.02， 165.54, 166.06, 173.91, 173.93 13 C NMR (D 20 ) δ 17.80, 17.89, 26.11, 31.89, 49.08, 63.00, 63.19, 68.40, 68.49, 69.66, 69.75, 72.18, 73.66, 84.33, 84.42, 89.20, 107.03, 112.50, 116.79, 121.08, 125.36 , 144.59, 146.81, 148.98, 154.84, 164.50, 165.02, 165.54, 166.06, 173.91, 173.93
31P NMR (D20) δ -1.40 3 1 P NMR (D 20 ) δ -1.40
22
6b - fasttwenty two 6b-fast
-丽 R (270 MHz, D20) δ 1.05-1.07 (6H, dd, CH3 of i-Pr), 1.77-1.89 (3H, ra, 3 "-Ha, 4" - H) , 2.23-2· 29 (III, m, 3"_Hb) , 3.15-3.27 (2H， m, 5〃— H)， 4.02-4.03 (1H， m, CH of i— Pr), 4.12-4.27 (3H, m， 2" - H， 5'-H), 4.46-4.56 (2H, m, 3 H， 4， - H), 4.85-4.88 (1H， m， 2，— H), 5.71-5.72 (1H， d, l'-H), 8.09 (1H， s， 2-H) -丽 R (270 MHz, D 20 ) δ 1.05-1.07 (6H, dd, CH 3 of i-Pr), 1.77-1.89 (3H, ra, 3 "-Ha, 4"-H), 2.23-2 · 29 (III, m, 3 "_Hb), 3.15-3.27 (2H, m, 5〃—H), 4.02-4.03 (1H, m, CH of i—Pr), 4.12-4.27 (3H, m, 2 "-H, 5'-H), 4.46-4.56 (2H, m, 3H, 4, -H), 4.85-4.88 (1H, m, 2, -H), 5.71-5.72 (1H, d, l '-H), 8.09 (1H, s, 2-H)
13C NMR (D20) δ 25.24, 25.32， 25.35， 25. 2, 26.13, 31.93, 49.09， 63.01, 63.20, 69.47, 69.56， 72.12, 73.67, 78.62， 78.71, 84.07， 84.19, 89.23， 106.91， 112.40, 116.68, 120.97, 125.26， 145.98, 148.70， 149.03, 154.88, 164.52, 165.04, 165.56， 166.08, 173.80, 173.83 13 C NMR (D 20 ) δ 25.24, 25.32, 25.35, 25.2, 26.13, 31.93, 49.09, 63.01, 63.20, 69.47, 69.56, 72.12, 73.67, 78.62, 78.71, 84.07, 84.19, 89.23, 106.91, 112.40 , 116.68, 120.97, 125.26, 145.98, 148.70, 149.03, 154.88, 164.52, 165.04, 165.56, 166.08, 173.80, 173.83
31 P NMR (D20) δ -2.71 31 P NMR (D 20 ) δ -2.71
6 b— slow 6 b— slow
¾-NMR (270 MHz, D20) δ 1.25—1.27 (6H, dd, CH3 of i— Pr)， 2.01-2.06 (3H， m, 3"-Ha, 4"-H) , 2.45—2.50 (1H， m, 3"— Hb), 3.41-3. 3 (2H, m, 5〃一 H)， 4.24-4.25 (1H, m, CH of i - Pr)， 4.31-4.47 (3H, m, 2"- H， 5，一 H), 4.64-4.73 (2H, m, 3，— H， 4，— H)， 5.08-5.12 (1H， m, 2，- H), 5.92-5.93 (1H， d, 1，一 H)， 8.31 (1H, s， 2-H) ¾-NMR (270 MHz, D 20 ) δ 1.25-1.27 (6H, dd, CH 3 of i-Pr), 2.01-2.06 (3H, m, 3 "-Ha, 4" -H), 2.45-2.50 (1H, m, 3 "—Hb), 3.41-3.3 (2H, m, 5-1-1H), 4.24-4.25 (1H, m, CH of i-Pr), 4.31-4.47 (3H, m, 2 "-H, 5, 1-H), 4.64-4.73 (2H, m, 3, -H, 4, -H), 5.08-5.12 (1H, m, 2, -H), 5.92-5.93 (1H, d, 1, one H), 8.31 (1H, s, 2-H)
13C NMR (D20) δ 25.19, 25.27, 25.33, 25.40, 26.12， 31.92， 49.08， 63.00, 63.19， 69.53, 69.61, 72.17， 73.57, 78.65, 78.74, 84.18, 84.29， 89.15, 106.93, 112.50, 116.78, 121.07， 125.36, 145.90, 148.57, 149.00, 154.94, 164.56， 165.08， 165.60， 166.12， 173.80, 173.83 13 C NMR (D 20 ) δ 25.19, 25.27, 25.33, 25.40, 26.12, 31.92, 49.08, 63.00, 63.19, 69.53, 69.61, 72.17, 73.57, 78.65, 78.74, 84.18, 84.29, 89.15, 106.93, 112.50, 116.78 , 121.07, 125.36, 145.90, 148.57, 149.00, 154.94, 164.56, 165.08, 165.60, 166.12, 173.80, 173.83
31P NMR (D20) δ -2.80 3 1 P NMR (D 20 ) δ -2.80
6c一 fast' 6c one fast '
23
¾-NMR (270 MHz, D20) δ 0.77-0.82 (3H, t, CH3 of POBu) , 1.16-1.27 (2H, m, CH2a of POBu) , 1.48-1.55 (2H, m, CH2i3 of POBu) , 1.99-2.10 (3H， m, 3 "-Ha, 4"-H) , 2.43-2.48 (IH, m, 3" - Hb), 3.39 (2H， m， 5"- H), 4.02-4.09 (2H, m, CH2 of POBu), 4.21 (IH, m, 2"— H)， 4.38-4.45 (3H， m, 4，—H， 5， - H), 4.64-4.66 (IH, m, 3，— H)， 5.05-5.08 (IH, m, 2，-H)， 5.90-5.91 (1H， d, 1' - H), 8.24 (IH, s, 2-H) twenty three ¾-NMR (270 MHz, D 2 0) δ 0.77-0.82 (3H, t, CH 3 of POBu), 1.16-1.27 (2H, m, CH 2 a of POBu), 1.48-1.55 (2H, m, CH 2 i3 of POBu), 1.99-2.10 (3H, m, 3 "-Ha, 4" -H), 2.43-2.48 (IH, m, 3 "-Hb), 3.39 (2H, m, 5" -H) , 4.02-4.09 (2H, m, CH 2 of POBu), 4.21 (IH, m, 2 "—H), 4.38-4.45 (3H, m, 4, —H, 5, -H), 4.64-4.66 ( IH, m, 3, -H), 5.05-5.08 (IH, m, 2, -H), 5.90-5.91 (1H, d, 1'-H), 8.24 (IH, s, 2-H)
13C NMR (D20) δ 15.28， 20.60， 26.13, 31.96， 33.96， 34.06， 49.09, 62.99, 63.18， 69.61， 69.68， 71.77, 71.8672.02, 73.65, 83.97, 84.08, 89.20, 106.87, 112.47, 116.76, 121.04, 125.33， 146.82, 149.04, 149.79, 154.92， 164.61, 165.13， 165.65, 166.17， 173.91, 173,93 13 C NMR (D 20 ) δ 15.28, 20.60, 26.13, 31.96, 33.96, 34.06, 49.09, 62.99, 63.18, 69.61, 69.68, 71.77, 71.8672.02, 73.65, 83.97, 84.08, 89.20, 106.87, 112.47, 116.76 , 121.04, 125.33, 146.82, 149.04, 149.79, 154.92, 164.61, 165.13, 165.65, 166.17, 173.91, 173,93
31 P NMR (D?0) δ 15 31 P NMR (D ? 0) δ 15
6 c-slow 6 c-slow
'H-NMR (270 MHz, D20) δ 0.78-0.84 (3H， t， CH3 of POBu) , 1.23-1.28 (2H, m, CH2a of POBu) , 1.52-1.54 (2H， m, 0Η2β of POBu) , 2.08 (3H， m， 3'し Ha, 4〃— H)， 2.49 (1H， m， 3"-Hb) , 3.43 (2H， m, 5"— H)， 4.05-4.08 (2H， m, CH2 of POBu), 4.26 (1H， m， 2' H)， 4.40-4.49 (3H, m， 4，一 H， 5， - H)， 4.65-4.69 (IH, m, 3， - H), 5.11—5.12 (IH, m, 2，— H), 5.94-5.95 (IH, d， 1，一 H)， 8.32 (1H， s, 2-H) 13C NMR (D20) δ 15.27， 20.57, 26.14， 31.95， 33.92, 34.02， 49.09, 62.99， 63.18， 69.76, 69.84, 71.76， 71.85, 72.16， 73.60, 84.24, 84.36, 89.13, 106.89, 112.56， 116.85, 121.14, 125.42， 146.11, 148.87, 149.00, 154.94, 164.60, 165.12, 165.64, 166.16, 173.92, 173.94 'H-NMR (270 MHz, D 20 ) δ 0.78-0.84 (3H, t, CH 3 of POBu), 1.23-1.28 (2H, m, CH 2 a of POBu), 1.52-1.54 (2H, m, 0Η 2 β of POBu), 2.08 (3H, m, 3'-Ha, 4〃-H), 2.49 (1H, m, 3 "-Hb), 3.43 (2H, m, 5" -H), 4.05- 4.08 (2H, m, CH 2 of POBu), 4.26 (1H, m, 2'H), 4.40-4.49 (3H, m, 4, 1H, 5, -H), 4.65-4.69 (IH, m, 3, - H), 5.11-5.12 ( IH, m, 2, - H), 5.94-5.95 (IH, d, 1, one H), 8.32 (1H, s , 2-H) 13 C NMR (D 2 0) δ 15.27, 20.57, 26.14, 31.95, 33.92, 34.02, 49.09, 62.99, 63.18, 69.76, 69.84, 71.76, 71.85, 72.16, 73.60, 84.24, 84.36, 89.13, 106.89, 112.56, 116.85, 121.14, 125.42 , 148.87, 149.00, 154.94, 164.60, 165.12, 165.64, 166.16, 173.92, 173.94
31P NMR (D20) δ -1.35 化合物 7 3 1 P NMR (D 20 ) δ -1.35 Compound 7
8 -ォキソアデノシン誘導体（2) (829 mg, 1.96 mmol)及びアミダイ ト試薬 8-oxoadenosine derivative (2) (829 mg, 1.96 mmol) and amidite reagent
24
(4b) (2.08 g, 3.91 mmol)を無水ァセトニトリルで 4回共沸脱水した後、 無水ァ セトニトリル （30mL) に溶解し、 5-メルカプト- 1-メチルテトラゾ^ ~ル（568 mg, 4.89匪 ol)を加えアルゴン雰囲気下室温で 1時間撹拌した。その後、 N， N, N' , N' - テトラエチルチウラムジスルフイ ド（1.74 g， 5.87 mmol) を加えさらに室温で さらに 3時間撹拌した。 反応系をクロ口ホルムで希釈して有機層を蒸留水で 3 回洗浄した後、 回収した有機層を無水硫酸ナトリウムで乾燥し、 溶媒を減圧下 留去した。残渣をシリカゲルカラムクロマトグラフィー（クロ口ホルム-メタノ ール-ピリジン = 100:0:1- 98:2:1) で精製し、溶媒を減圧下留去した後、 さらに ドライシリカゲル（25 g)を用いたシリカゲルカラムクロマトグラフィー (へキ サン-酢酸ェチル -ピリジン = 100:0:1- 70:30:1)で精製することにより、 目的物 (7) (1.03 g, 59%)を白色フォーム状物質で得た。 — NMR (270 MHz, CDC13) δ 0.62-1.38 (10Η, m, 4"- H， 3〃- H， CH3 of isop, CH3 of POEt) , 1.47-1.50 (3H， 2s, CH3 of isop) 1.54—1.57 (9H， 2s, (CH3)3C of Boc), 2.86-2.95 (1H, m, 5"- Ha) , 3.18-3.28 (1H, m, 5"- Hb)， 3.82—3.90 (2H， m， CH2 of POEt) , 4.07-4.45 (4H, m, 2"— H， 4，— H, 5，— H), 5.05 (1H, m， 3，一 H)， 5.36—5.42 (1H, m, 2，一 H), 6.17—6.22 (1H， d, 1，一 H) 6.48 (2H, bs， NH2) 7.09-7.21 (9H， m， Ar-H) , 7.36-7. 4 (6H, m, Ar - H)， 8.09—8.11 (1H, 2s, 2— H) twenty four (4b) (2.08 g, 3.91 mmol) was azeotropically dehydrated with anhydrous acetonitrile four times and then dissolved in anhydrous acetonitrile (30 mL) to give 5-mercapto-1-methyltetrazole (568 mg, 4.89 bandol). Was added and stirred at room temperature for 1 hour under an argon atmosphere. Thereafter, N, N, N ', N'-tetraethylthiuram disulfide (1.74 g, 5.87 mmol) was added, and the mixture was further stirred at room temperature for 3 hours. After diluting the reaction system with chloroform and washing the organic layer three times with distilled water, the collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol-pyridine = 100: 0: 1-98: 2: 1), the solvent was distilled off under reduced pressure, and dry silica gel (25 g) was further added. Purification by silica gel column chromatography (hexane-ethyl acetate-pyridine = 100: 0: 1-70: 30: 1) gave the desired product (7) (1.03 g, 59%) as a white foam. Obtained with the substance. - NMR (270 MHz, CDC1 3 ) δ 0.62-1.38 (10Η, m, 4 "- H, 3〃- H, CH 3 of isop, CH 3 of POEt), 1.47-1.50 (3H, 2s, CH 3 of isop) 1.54-1.57 (9H, 2s, (CH 3 ) 3 C of Boc), 2.86-2.95 (1H, m, 5 "-Ha), 3.18-3.28 (1H, m, 5" -Hb), 3.82— 3.90 (2H, m, CH 2 of POEt), 4.07-4.45 (4H, m, 2 "—H, 4, —H, 5, —H), 5.05 (1H, m, 3, 1H), 5.36— 5.42 (1H, m, 2, one H), 6.17-6.22 (1H, d , 1, one H) 6.48 (2H, bs, NH 2) 7.09-7.21 (9H, m, Ar-H), 7.36-7 . 4 (6H, m, Ar-H), 8.09—8.11 (1H, 2s, 2—H)
13C画 R (CDC13) δ 15.72, 15.78, 15.83, 15.90， 24.08, 24.15， 25.27, 25.31, 26.91, 26.93， 27.79, 31.23， 31.30， 50.38， 50.47, 64.09， 64.17, 64.32, 64.40, 65.38， 65.43, 77.25， 81.85, 81.92， 82.83, 82.92, 86.39， 86.41, 87.00， 87.06, 101.72， 101.77， 113.47, 126.28， 127.62, 127.64, 128.87, 143.78, 143.83 147.31, 147.33, 147.91， 148.65， 148.67, 149.54, 153.33, 175.68， 175.76; 31P NMR (CDCI3) δ 63.15， 63.22 化合物 8 ： 1 3 C-image R (CDC1 3) δ 15.72, 15.78, 15.83, 15.90, 24.08, 24.15, 25.27, 25.31, 26.91, 26.93, 27.79, 31.23, 31.30, 50.38, 50.47, 64.09, 64.17, 64.32, 64.40, 65.38, 65.43, 77.25, 81.85, 81.92, 82.83, 82.92, 86.39, 86.41, 87.00, 87.06, 101.72, 101.77, 113.47, 126.28, 127.62, 127.64, 128.87, 143.78, 143.83 147.31, 147.33, 147.91, 148.65, 148.67, 149.53 , 175.68, 175.76; 31 P NMR (CDCI3) δ 63.15, 63.22 Compound 8:
25
上記生成物（7) (1. 03 g， 1. 16 mmol)を 80%ギ酸水溶液（10 mL)に溶解し、 室温 で 1 2時間撹拌した。 反応系を蒸留水で希釈し、 酢酸ェチルで水層を 3回洗浄 した後、 回収した水層を減圧下留去した。 その後、 さらに 3回蒸留水で共沸し た後、残渣を C- 18シリカゲル逆相カラムクロマトグラフィー（水-ァセトニトリ ル = 100 : 0- 96 : 4)で精製し、水溶液から凍結乾燥することにより目的物のジァス テレオマー（8) (209 mg, 36%)を白色フォーム状物質で得た。 twenty five The above product (7) (1.03 g, 1.16 mmol) was dissolved in an 80% aqueous formic acid solution (10 mL), and the mixture was stirred at room temperature for 12 hours. The reaction system was diluted with distilled water, and the aqueous layer was washed three times with ethyl acetate. The collected aqueous layer was distilled off under reduced pressure. After azeotropic distillation with distilled water three times, the residue was purified by reversed-phase column chromatography on C-18 silica gel (water-acetonitrile = 100: 0-96: 4) and lyophilized from the aqueous solution. The desired diastereomer (8) (209 mg, 36%) was obtained as a white foam.
¾一 NMR (270 MHz, D20) δ 0. 96—1. 03 (3H， t， CH3 of POEt) 1. 84-1. 96 (3H， m, 3 "-Ha, 4"-H) , 2. 19 (1H, m， 3" - H)， 3. 18—3. 27 (2H， m, 5"-H) , 3. 68—3. 85 (3H, m, 2"-H, CH2 of POEt) , 3. 94-4. 08 (3H， m, 4， -H, 5，— H) , 4. 51-4. 59 (1H, m, 3' -H) , 5. 01-5. 06 (1H, dd， 2，— H)， 5. 70-5. 72 (1H， d， 1， - H) , 7. 91 (1H, s， 2-H) 13C NMR (D20) 8 17. 71, 17. 82 , 26. 44, 32. 22 , 32. 25 , 48. 87 , 64. 78 , 65. 13, 65. 65， 65. 73, 65. 83, 67. 89, 67. 96, 72. 37, 72. 44， 73. 24, 84. 26, 84. 37， 84. 47, 88. 90, 88. 96, 106. 87， 149. 04, 149. 72, 153. 54, 155. 26, 177. 69, 177. 75¾-1 NMR (270 MHz, D 2 0) δ 0.96-1.03 (3H, t, CH 3 of POEt) 1. 84-1.96 (3H, m, 3 "-Ha, 4" -H ), 2.19 (1H, m, 3 "-H), 3.18-3.27 (2H, m, 5" -H), 3.68-3.85 (3H, m, 2 "-H) , CH 2 of POEt), 3.94-4.08 (3H, m, 4, -H, 5, -H), 4.51-4.59 (1H, m, 3'-H), 5. 01-5.06 (1H, dd, 2, -H), 5.70-5.72 (1H, d, 1, -H), 7.91 (1H, s, 2-H) 13C NMR ( D 2 0) 8 17.71, 17.82, 26.44, 32.22, 32.25, 48.87, 64.78, 65.13, 65.65, 65.73, 65.83, 67 89, 67. 96, 72. 37, 72. 44, 73. 24, 84. 26, 84. 37, 84. 47, 88. 90, 88. 96, 106. 87, 149. 04, 149. 72 , 153. 54, 155. 26, 177. 69, 177. 75
31 P NMR (D20) δ 70. 00, 70. 05 試験例 1 31 P NMR (D 20 ) δ 70.00, 70.05 Test Example 1
上記の実施例 1で得られた化合物 6 a〜6 c (それぞれについて fast 及ぴ slowの異性体）及ぴ化合物 8の癌細胞に対する増殖抑制効果を文献記載の方法 (Moriguchi, T. et al. , Tetrahydron Lett. , 41, pp. 5881- 5885, 2000)に従つ て測定した。 その結果、 上記実施例で得られた化合物はいずれもホスミ ドシン に匹敵する優れた抗 J¾瘍活性を有していた。 産業上の利用可能性 The inhibitory effects of Compounds 6a to 6c (fast and slow isomers) and Compound 8 obtained in Example 1 on cancer cells in cancer cells described in the literature (Moriguchi, T. et al. , Tetrahydron Lett., 41, pp. 5881-5885, 2000). As a result, all of the compounds obtained in the above Examples had excellent anti-J tumor activity comparable to fosmidosine. Industrial applicability
本発明により提供される一般式 （I ) に包含される化合物 I Aはホスミ ドシ ンと同等の抗腫瘍活性を有しており、 しかも化学的に極めて安定であることか ら、 抗腫瘍剤などの医薬の有効成分として有用である。 また、 本発明により提 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. In addition, the present invention provides
26
供される一般式 （I ) に包含される化合物 I Bはホスミドシン又は化合物 I A などの製造のための製造用中間体として有用である。 26 The compound IB included in the general formula (I) provided is useful as a production intermediate for the production of fosmidosine or compound IA.
27
27
Claims
1 . 下記の一般式 （ I ) ： 1. The following general formula (I):
(I)(I)
(式中、 R1は _8アルキル基を示し； R2は水素原子又は窒素原子の保護基を示 'し； R3及び はそれぞれ独立に水素原子又は水酸基の保護基を示すが、 R3及び R4は互いに結合してそれらが結合する 2個の酸素原子とともに環を形成しても よく ； R5は水素原子又は窒素原子の保護基を示し； Xは 0又は Sを示す。 ただ し、 R1がメチル基であり、 かつ Xが 0である場合を除く。） で表される化合物又 はその塩。 (Wherein, R 1 represents a _ 8 alkyl group; R 2 is a hydrogen atom or a protecting group for the nitrogen atom shown 'by; exhibit R 3 and each independently represent a hydrogen atom or a hydroxyl-protecting group, R 3 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. And R 1 is a methyl group and X is 0.) or a salt thereof.
2 . が C2_8アルキル基であり、 が水素原子であり、 及ぴ R4が共に水素原 子であり、 R5が水素原子であり、 Xが 0である上記化合物又はその塩；及び R1 が（ 8アルキル基であり、 R2が水素原子であり、 R3及び R4が共に水素原子であ り、 R5が水素原子であり、 Xが Sである請求の範囲第 1項に記載の化合物又は その塩。 . 2 is a C 2 _ 8 alkyl group, but a hydrogen atom,及Pi R 4 are both hydrogen atom, R 5 is a hydrogen atom, the compound or a salt thereof wherein X is 0; and 2. The method according to claim 1, wherein R 1 is an ( 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 S. Or a salt thereof.
3 . 請求の範囲第 2項に記載の化合物及ぴ生理学的に許容されるその塩、 並ぴ にそれらの水和物及びそれらの溶媒和物からなる群から選ばれる物質を有効成 分として含む医薬。 3. The compound according to claim 2 and a physiologically acceptable salt thereof, as well as a substance selected from the group consisting of hydrates and solvates thereof as an effective component. Medicine.
4 . 抗腫瘍剤として用いる請求の範囲第 3項に記載の医薬。 4. The medicament according to claim 3, which is used as an antitumor agent.
5 . 請求の範囲第 3項に記載の物質を含む癌細胞増殖抑制剤。 5. A cancer cell growth inhibitor comprising the substance according to claim 3.
6 . 請求の範囲第 3項に記載の物質を含む G1期細胞周期停止剤。 6. A G1-phase cell cycle arresting agent comprising the substance according to claim 3.
7 . 請求の範囲第 3項に記載の物質を含む RBタンパク質のリン酸化阻害剤。 7. A RB protein phosphorylation inhibitor comprising the substance according to claim 3.
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8 . R\ R2、 R3、 R R5、 及び Xが上記と同義であり、 ただし、 R1が C2_8アルキ ル基であり、 R2が水素原子であり、 R3及び R4が共に水素原子であり、 R5が水素 原子であり、 かつ Xが 0である場合、 及ぴ R1が _8アルキル基であり、 R2が水 素原子であり、 R3及び が共に水素原子であり、 R5が水素原子であり、 かつ X が Sである場合を除く請求の範囲第 1項に記載の化合物又はその塩。 8. R \ R 2, R 3, RR 5, and X are as defined above, provided that, R 1 is C 2 _ 8 alkyl le group, R 2 is hydrogen atom, R 3 and R 4 There are both hydrogen atom, R 5 is a hydrogen atom, and when X is 0, a及Pi R 1 is _ 8 alkyl group, R 2 is water atom, R 3 and are both hydrogen 2. The compound according to claim 1, wherein R 5 is a hydrogen atom and X is S, or a salt thereof.
9 . ホスミ ドシン若しくは請求の範囲第 2項に記載の化合物又はそれらの塩の 製造用中間体である請求の範囲第 8項に記載の化合物又はその塩。 9. The compound according to claim 8, or a salt thereof, which is an intermediate for producing fosmidosine or the compound according to claim 2 or a salt thereof.
1 0 . 請求の範囲第 8項に記載の化合物又はその塩の製造方法であって、 下記 の一般式 （II) ： 10. A process for producing a compound or a salt thereof according to claim 8, comprising the following general formula (II):
(式中、 R12は窒素原子の保護基を示し； R13及び R14はそれぞれ独立に水酸基の 保護基を示すが、 R13及ぴ R14は互いに結合してそれらが結合する 2個の酸素原 子とともに環を形成してもよい） で表される化合物と、 下記の一般式 （III) ：
(Wherein, 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 Which may form a ring together with an oxygen atom), and a compound represented by the following general formula (III):
(式中、 R11は _8アルキル基を示し； R15は窒素原子の保護基を示し； R16及ぴ R17はそれぞれ独立に _8アルキル基を示す） で表される化合物とを反応させ、 得られた反応物を酸化又は硫化する工程を含む方法。 (Wherein, 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). And oxidizing or sulfurizing the obtained reactant.
1 1 . 上記の一般式 （II) で表される化合物と上記の一般式 （ΠΙ) で表される 化合物との反応を 5_メルカプト- 1 -メチルテトラゾールの存在下に行う請求の 範囲第 10項に記載の方法。 11. The reaction of the compound represented by the above general formula (II) with the compound represented by the above general formula (II) in the presence of 5_mercapto-1-methyltetrazole. The method described in the section.
29
29
1 2 . ホスミ ドシン若しくは請求の範囲第 2項に記載の化合物又はそれらの塩 の製造方法であって、 請求の範囲第 8項に記載の化合物又はその塩を脱保護す る工程を含む方法。 12. A method for producing fosmidosine or the compound or a salt thereof according to claim 2, wherein the method comprises a step of deprotecting the compound or a salt thereof according to claim 8.
1 3 . ホスミ ドシン若しくは請求の範囲第 2項に記載の化合物又はそれらの塩 の製造方法であって、 下記の工程： 13. A process for producing fosmidosine or a compound according to claim 2 or a salt thereof, comprising the following steps:
(a)請求の範囲第 10項に記載の一般式 （II) で表される化合物と請求の範囲第 10 項に記載の一般式 （ΙΠ) で表される化合物とを反応させ、 得られた反応物 を酸化又は硫化して請求の範囲第 8項に記載の化合物又はその塩を得る工程； 及び (a) reacting a compound represented by the general formula (II) described in claim 10 with a compound represented by the general formula (ΙΠ) described in claim 10 to obtain Oxidizing or sulfurizing the reactant to obtain a compound or a salt thereof according to claim 8; and
(b)上記工程 (a)で得られた請求の範囲第 8項に記載の化合物又はその塩を脱保 護する工程 (b) a step of deprotecting the compound or a salt thereof according to claim 8 obtained in the above step (a)
を含む方法。 A method that includes
1 4 . 請求の範囲第 10項に記載の一般式 （III) で表される化合物。 14. The compound represented by the general formula (III) according to claim 10.
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30
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003208084A AU2003208084A1 (en) | 2002-07-30 | 2003-01-31 | Phosmidosine derivative and process for producing the same |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002-220661 | 2002-07-30 | ||
| JP2002220661 | 2002-07-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004011481A1 true WO2004011481A1 (en) | 2004-02-05 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2003/000985 WO2004011481A1 (en) | 2002-07-30 | 2003-01-31 | Phosmidosine derivative and process for producing the same |
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| Country | Link |
|---|---|
| AU (1) | AU2003208084A1 (en) |
| WO (1) | WO2004011481A1 (en) |
Cited By (7)
| 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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| WO1996008256A1 (en) * | 1994-09-14 | 1996-03-21 | Temple University - Of The Commonwealth System Of Higher Education | 2',5' phosphorothioate/phosphodiester oligoadenylates and antiviral uses thereof |
| JPH093091A (en) * | 1995-06-21 | 1997-01-07 | Rikagaku Kenkyusho | Nucleoside derivative substance, its production and antitumor agent |
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- 2003-01-31 WO PCT/JP2003/000985 patent/WO2004011481A1/en not_active Application Discontinuation
- 2003-01-31 AU AU2003208084A patent/AU2003208084A1/en not_active Abandoned
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996008256A1 (en) * | 1994-09-14 | 1996-03-21 | Temple University - Of The Commonwealth System Of Higher Education | 2',5' phosphorothioate/phosphodiester oligoadenylates and antiviral uses thereof |
| JPH093091A (en) * | 1995-06-21 | 1997-01-07 | Rikagaku Kenkyusho | Nucleoside derivative substance, its production and antitumor agent |
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| Title |
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| MORIGUCHI T. ET AL.: "First synthesis and anticancer activity of phosmidosine and its related compounds", J. ORG. CHEM., vol. 67, no. 10, 2002, pages 3290 - 3300, XP002965225 * |
| 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)
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003208084A1 (en) | 2004-02-16 |
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