JP2010077085A - 5'-deoxyfluorouridine compound or its salt and antitumor agent containing the same - Google Patents

Abstract

で表される新規５’−デオキシフルオロウリジン化合物又はその塩を有効成分として含有する抗腫瘍剤。
【選択図】なしDisclosed is a compound that exhibits excellent antitumor activity, has excellent pharmacokinetics, and is useful as an antitumor agent.
The following general formula (1)

The antitumor agent which contains the novel 5'-deoxyfluoro uridine compound or its salt represented by these as an active ingredient.
[Selection figure] None

Description

  The present invention relates to a 5'-deoxyfluorouridine compound or a salt thereof having an excellent antitumor effect, and an antitumor agent.

  Cancers characterized by abnormal cell proliferation are still difficult to treat, and the development of effective therapeutic agents is desired. Nucleic acid biosynthesis is essential for cell growth, and so far, development of nucleic acid metabolism antagonists that inhibit nucleic acid metabolism has been vigorously conducted. In particular, as 5-FU antimetabolites, for example, as an oral derivative of 5-FU, for example, futraful (Non-patent Document 1) or Carmofur (non-patent document) that is activated mainly by liver P450 and releases 5-FU into the blood. Reference 2), and 5′-deoxyfluorouridine activated by thymidine phosphorylase expressed in liver and tumor (Non-patent Document 3, Patent Document 1) and the like have been developed and used in clinical treatment. In general, they are still not satisfactory because of efficacy and safety.

  5'-deoxyfluorouridine and 5'-deoxyfluorocytidine compounds that generate 5'-deoxyfluorouridine by being metabolized in the body are fluorinated pyrimidine drugs by oral administration in nude mice transplanted into human tumors. Is known to exhibit an excellent antitumor effect (Non-patent Document 4). However, 5'-deoxyfluorouridine has a poor pharmacokinetics, and therefore has a higher dose in terms of mole compared to a therapy in which other 5-FU drugs are used in combination with a DPD inhibitor (Non-patent Document 4).

Therefore, development of a drug that improves pharmacokinetics such as absorbability of 5′-deoxyfluorouridine and exhibits an antitumor activity higher than 5′-deoxyfluorouridine by oral administration is desired.
J Clin Oncol. 1983 Feb; 1 (2): 107-10 Recent Results Cancer Res. 1980; 70: 125-32. J Clin Oncol. 1983 Dec; 1 (12): 750-4. Eur J Cancer. 1998 Jul; 34 (8): 1274-81 US4071680 (A)

  An object of the present invention is to provide a novel 5′-deoxyfluorouridine compound or a salt thereof, which improves the existing 5′-deoxyfluorouridine compound in terms of pharmacokinetics so that it can be easily absorbed orally and exhibits an excellent antitumor effect, and It is to provide an antitumor agent.

  As a result of intensive studies to solve the above problems, the present inventors have found that the 5′-deoxyfluorouridine compound represented by the following general formula (1) or a salt thereof is more than the existing 5′-deoxyfluorouridine compound. Was found to exhibit excellent pharmacokinetics and excellent antitumor activity, and the present invention was completed.

  That is, the present invention relates to the general formula (1)

[Where
X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom,
Y represents a group represented by (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— or a hydrogen atom,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each have a linear or branched alkyl group having 1 to 10 carbon atoms which may have a substituent,
A C3-C7 cyclic alkyl group which may have a substituent,
An aryl group having 6 to 14 carbon atoms which may have a substituent;
Any one of 7 to 15 aralkyl groups which may have a substituent,
Except when both X and Y are hydrogen atoms]
The novel 5'-deoxyfluorouridine compound or its salt represented by these is provided as an active ingredient.

  Further, the present invention provides the following general formula (2)

[Where
X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom,
Y represents a group represented by (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— or a hydrogen atom,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each have a linear or branched alkyl group having 1 to 10 carbon atoms which may have a substituent,
A C3-C7 cyclic alkyl group which may have a substituent,
An aryl group having 6 to 14 carbon atoms which may have a substituent;
Any one of 7 to 15 aralkyl groups which may have a substituent,
Except when both X and Y are hydrogen atoms, 5′-deoxy-2′-O-tert-butyldimethylsilyl-5-fluorouridine, 5′-deoxy-3′-O-tert-butyldimethylsilyl- Excludes 5-fluorouridine. ]
The 5'-deoxyfluorouridine compound represented by these, or its salt is provided.

  The novel 5'-deoxyfluorouridine compound or a salt thereof of the present invention is useful as an antitumor agent exhibiting excellent pharmacokinetics and excellent antitumor activity.

  The 5'-deoxyfluorouridine compound or a salt thereof of the present invention is a compound having a chemical structure represented by the above general formula (1) and having a silyloxy group at the 2'-position and the 3'-position.

A 5′-deoxyfluorouridine compound having a silyloxy group at the 2′-position and the 3′-position is known as a synthesis intermediate of a 2′-O-lysophosphatidyl nucleic acid compound and a 3′-O-lysophosphatidyl nucleic acid compound ( Non-patent document 5). However, the antitumor activity of the synthetic intermediate is not described, and the pharmacokinetics has not been studied.
Eur. J. et al. Org. Chem. 2002. 3622-3631 "General linear or branched alkyl group having 1 to 10 carbon atoms" represented by R1, R2, R3, R4, R5 and R6 in general formula (1) and general formula (2) The “substituents” that may be present in the “cyclic alkyl group having 3 to 7 carbon atoms”, the “aryl group having 6 to 14 carbon atoms”, or the “aralkyl group having 7 to 15 carbon atoms” are the same or Differently, the number of substitution is 1 to 5, preferably 1 to 3, more preferably 1 to 2, for example, a straight chain having 1 to 5 carbon atoms such as methyl group, ethyl group, isopropyl group, tert-butyl group and the like. Linear or branched alkyl group, linear or branched perfluoroalkyl group having 1 to 10 carbon atoms, aryl group having 6 to 14 carbon atoms, hydroxyl group, methoxy group, ethoxy group, isopropoxy group, cyclopentoxy group etc A linear, branched or cyclic alkoxy group having 1 to 10 carbon atoms, an aryloxy group such as a phenoxy group, a naphthoxy group, and an anthoxy group, an aralkyloxy group such as a benzyloxy group, a phenethyloxy group, and a naphthylmethoxy group; Groups, halogeno groups such as chlorine and bromine, cyano groups, nitro groups and the like.

Formula (1) and the general formula ^{(2), R 1, R} 2, R 3, R 4, "linear or branched alkyl group having from 1 to 10 carbon atoms" ^{as R 5} and represented by ^{R 6} As the same or different, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, texyl group, n-pentyl group, n-hexyl group, n-heptyl group, An n-octyl group, an n-nonyl group, an n-decyl group and the like can be mentioned, and a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a texyl group, and an octyl group are more preferable. , Methyl group, tert-butyl group, and texyl group.

In the general formulas (1) and (2), examples of the “cyclic alkyl group having 3 to 7 carbon atoms” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ include cyclo A propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc. are mentioned.

In the general formula (1) and general formula (2), examples of the “aryl group having 6 to 14 carbon atoms” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ include, for example, a phenyl group And a naphthyl group.

In the general formulas (1) and (2), examples of the “aralkyl group having 7 to 15 carbon atoms” represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ include, for example, a benzyl group Phenethyl group, benzhydryl group, naphthylmethyl group and the like.

In the general formulas (1) and (2), “(R ¹ ) (R ² ) (R ³ ) Si—” represented by X and “(R ⁴ ) (R ⁵ ) (R ⁶ ) Si- "includes, for example, tert-butyldimethylsilyl, triisopropylsilyl, isopropyldiethylsilyl, triisobutylsilyl, dimethyloctylsilyl, texyldimethylsilyl, trimethylsilyl, triethylsilyl, tri -N-propylsilyl group, tri-n-butylsilyl group, tri-n-hexylsilyl group, n-propyldimethylsilyl group, n-butyldimethylsilyl group, isobutyldimethylsilyl group, n-pentyldimethylsilyl group, hexyldimethyl Silyl group, dimethyl-tert-hexylsilyl group, n-decyldimethylsilyl group, (3,3-dimethylbutane D) Dimethylsilyl group, 2,3-dimethylpropyldimethylsilyl group, di-tert-butylmethylsilyl group, di-n-butylmethylsilyl group, diethylisopropylsilyl group, n-octyldiisopropylsilyl group, n-octyldiisobutyl Silyl group, cyclohexyldimethylsilyl group, dicyclohexylmethylsilyl group, cyclotrimethylenemethylsilyl group, isopropyldiphenylsilyl group, triphenylsilyl group, dimethylphenylsilyl group, tert-butyldiphenylsilyl group, methyldiphenylsilyl group, diphenyl (diphenyl) Methyl) silyl group, p-toluyldimethylsilyl group, biphenyldimethylsilyl group, m-phenoxyphenyldimethylsilyl group, biphenyldiisopropylsilyl group, tri (2-biphenyl) silane Group, tri (o-toluyl) silyl group, tri (2-methoxyphenyl) silyl group, tribenzylsilyl group, benzyldimethylsilyl group, phenethyldimethylsilyl group, (3-phenylpropyl) dimethylsilyl group, p- ( tert-butyl) phenethyldimethylsilyl group, phenethyldiisopropylsilyl group, neophylldimethylsilyl group, bromomethyldimethylsilyl group, chloromethyldimethylsilyl group, 4-chlorobutyldimethylsilyl group, (dichloromethyl) dimethylsilyl group, 3- Chloropropyldimethylsilyl group, 3,3,3-trifluoropropyldimethylsilyl group, 1H, 1H, 2H, 2H-perfluorodecyldimethylsilyl group, 1H, 1H, 2H, 2H-perfluorooctyldimethylsilyl group, 3,3 , 4, 4, 5, 5, 6,6,6-nonafluorohexyldimethylsilyl group, bis (chloromethyl) methylsilyl group, pentafluorophenyldimethylsilyl group, pentafluorophenylpropyldimethylsilyl group, 3,5-bis (trifluoromethyl) phenyldimethylsilyl group , (3- (chloromethyl) phenylethyl) dimethylsilyl group, (4- (chloromethyl) phenylethyl) dimethylsilyl group, acetoxyethyldimethylsilyl group, 3-acetoxypropyldimethylsilyl group, 3-methacryloxypropyldimethylsilyl Group, 3-cyanopropyldiisopropylsilyl group, (3- (trimethylsiloxy) propyldimethylsilyl group or 3-phenoxypropyldimethylsilyl group, preferably tert-butyldimethylsilyl group, triiso Propylsilyl group, isopropyldiethylsilyl group, triisobutylsilyl group, dimethyloctylsilyl group, texyldimethylsilyl group, tri-n-propylsilyl group, tri-n-butylsilyl group, tri-n-hexylsilyl group, n- Propyldimethylsilyl group, n-butyldimethylsilyl group, isobutyldimethylsilyl group, n-pentyldimethylsilyl group, hexyldimethylsilyl group, dimethyl-tert-hexylsilyl group, (3,3-dimethylbutyl) dimethylsilyl group, 2 , 3-dimethylpropyldimethylsilyl group, di-tert-butylmethylsilyl group, di-n-butylmethylsilyl group, diethylisopropylsilyl group, n-octyldiisopropylsilyl group, bromomethyldimethylsilyl group, chloromethyldimethylsilyl group 4 Chlorobutyldimethylsilyl group, (dichloromethyl) dimethylsilyl group, 3-chloropropyldimethylsilyl group, 3,3,3-trifluoropropyldimethylsilyl group, 1H, 1H, 2H, 2H-perfluorodecyldimethylsilyl group, 1H , 1H, 2H, 2H-perfluorooctyldimethylsilyl group, 3,3,4,4,5,5,6,6,6-nonafluorohexyldimethylsilyl group, bis (chloromethyl) methylsilyl group, (3- ( Chloromethyl) phenylethyl) dimethylsilyl group, (4- (chloromethyl) phenylethyl) dimethylsilyl group, acetoxyethyldimethylsilyl group, 3-acetoxypropyldimethylsilyl group, 3-methacryloxypropyldimethylsilyl group, 3-cyano Propyldiisopropylsilyl group, (3- A trimethylsiloxy) propyldimethylsilyl group or a 3-phenoxypropyldimethylsilyl group, more preferably a tert-butyldimethylsilyl group, a triisopropylsilyl group, an isopropyldiethylsilyl group, a dimethyloctylsilyl group, or a texyldimethylsilyl group. And particularly preferably a tert-butyldimethylsilyl group or a texyldimethylsilyl group.

The antitumor agent of the present invention has the general formula (1)
[Where
X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom,
Y represents a group represented by (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— or a hydrogen atom,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each have a linear or branched alkyl group having 1 to 10 carbon atoms which may have a substituent,
A C3-C7 cyclic alkyl group which may have a substituent,
An aryl group having 6 to 14 carbon atoms which may have a substituent;
Any one of 7 to 15 aralkyl groups which may have a substituent,
Except when both X and Y are hydrogen atoms. ]
The antitumor agent which contains the novel 5'-deoxyfluoro uridine compound or its salt represented by these as an active ingredient is mentioned.

Preferably, in the general formula (1), R ¹ , R ² and R ³ each represents a linear or branched alkyl group having 1 to 8 carbon atoms which may have a substituent. One is the same or different and represents a linear or branched alkyl group having 1 to 3 carbon atoms, and any one of R ⁴ , R ⁵ and R ⁶ may have a substituent. A compound or a salt thereof, which represents a straight-chain or branched alkyl group of 1 to 8 and the other two are the same or different and are a straight-chain or branched alkyl group having 1 to 3 carbon atoms As an antitumor agent.

More preferably, in the general formula (1), R ¹ , R ² and R ³ each represents a linear or branched alkyl group having 3 to 8 carbon atoms which may have a substituent, Two are the same or different and represent a linear or branched alkyl group having 1 to 3 carbon atoms, and any one of R ⁴ , R ⁵ and R ⁶ may have a substituent; Effective compounds or salts thereof showing a linear or branched alkyl group of 3 to 8 and the other two being the same or different and being a linear or branched alkyl group having 1 to 3 carbon atoms It is an antitumor agent contained as a component.

Even more preferably, in the general formula (1), X is a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y is (R ⁴ ) (R ⁵ ) (R ⁶ ). A group represented by Si— or a hydrogen atom, (R ¹ ) (R ² ) (R ³ ) Si— and (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— are the same or different, It is an antitumor agent containing a compound showing a tert-butyldimethylsilyl group, triisopropylsilyl group, dimethyloctylsilyl group or texyldimethylsilyl group or a salt thereof as an active ingredient.

Even more preferably, in the general formula (1), X is a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y is (R ⁴ ) (R ⁵ ) (R ⁶ ). A group represented by Si— or a hydrogen atom, (R ¹ ) (R ² ) (R ³ ) Si— and (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— are the same or different, It is an antitumor agent containing, as an active ingredient, a compound showing a tert-butyldimethylsilyl group or a texyldimethylsilyl group or a salt thereof.

  Particularly preferably, 5′-deoxy-2′-O-tert-butyldimethylsilyl-5-fluorouridine, 5′-deoxy-3′-O-tert-butyldimethylsilyl-5-fluorouridine, 5′-deoxy- 2 ', 3'-O, O'-di-tert-butyldimethylsilyl-5-fluorouridine or 5'-deoxy-2'-O-hexyldimethylsilyl-5-fluorouridine or a salt thereof as an active ingredient It contains an antitumor agent.

The compound of the present invention has the general formula (2)
[Where
X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom,
Y represents a group represented by (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— or a hydrogen atom,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each have a linear or branched alkyl group having 1 to 10 carbon atoms which may have a substituent,
A C3-C7 cyclic alkyl group which may have a substituent,
An aryl group having 6 to 14 carbon atoms which may have a substituent;
Any one of 7 to 15 aralkyl groups which may have a substituent,
Except when both X and Y are hydrogen atoms, 5′-deoxy-2′-O-tert-butyldimethylsilyl-5-fluorouridine, 5′-deoxy-3′-O-tert-butyldimethylsilyl- Excludes 5-fluorouridine. ]
And a novel 5′-deoxyfluorouridine compound represented by the formula:

Preferably, in the general formula (2), R ¹ , R ² and R ³ each represents a linear or branched alkyl group having 1 to 8 carbon atoms which may have a substituent. One is the same or different and represents a linear or branched alkyl group having 1 to 3 carbon atoms, and any one of R ⁴ , R ⁵ and R ⁶ may have a substituent. To 8 linear or branched alkyl groups, and the other two are the same or different and indicate a linear or branched alkyl group having 1 to 3 carbon atoms.

More preferably, in the general formula (2), R ¹ , R ² and R ³ each represents a linear or branched alkyl group having 3 to 8 carbon atoms, any one of which may have a substituent, Two are the same or different and represent a linear or branched alkyl group having 1 to 3 carbon atoms, and any one of R ⁴ , R ⁵ and R ⁶ may have a substituent; It is a compound showing 3 to 8 linear or branched alkyl groups, and the other two being the same or different and showing linear or branched alkyl groups having 1 to 3 carbon atoms.

Even more preferably, in the general formula (2), X is a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y is (R ⁴ ) (R ⁵ ) (R ⁶ ). A group represented by Si— or a hydrogen atom, (R ¹ ) (R ² ) (R ³ ) Si— and (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— are the same or different, It is a compound showing that it is a tert-butyldimethylsilyl group, a triisopropylsilyl group, a dimethyloctylsilyl group or a texyldimethylsilyl group.

Even more preferably, in the general formula (2), X is a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y is (R ⁴ ) (R ⁵ ) (R ⁶ ). A group represented by Si— or a hydrogen atom, (R ¹ ) (R ² ) (R ³ ) Si— and (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— are the same or different, It is a compound which shows that it is a tert-butyldimethylsilyl group or a texyldimethylsilyl group.

  Particularly preferably, in the general formula (2), X represents a tert-butyldimethylsilyl group or texyldimethylsilyl group, and Y represents a hydrogen atom.

  The salt of the 5'-deoxyfluorouridine compound of the present invention may be any pharmaceutically acceptable salt. Examples of acid salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, tartrate, fumarate, maleate, malate Organic salts such as citrate, methanesulfonate, paratoluenesulfonate, and the like can be formed. As examples of basic salts, salts such as alkali metal salts such as sodium and potassium, or alkaline earth metal salts such as calcium and magnesium salts can be formed. In addition, the 5'-deoxyfluorouridine compound of the present invention may give rise to optical isomers or geometric isomers depending on the type of substituent, and the present invention includes both of them. These isomers can be used either as a mixture or as a mixture. Furthermore, the 5'-deoxyfluorouridine compounds and salts thereof of the present invention also include solvates represented by hydrates, amorphous (amorphous) or crystalline polymorphs.

The 5′-deoxyfluorouridine compound or a salt thereof of the present invention can be produced according to the following scheme 1.
[Scheme 1]

In the first step scheme 1, X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y represents (R ⁴ ) (R ⁵ ) (R ⁶ ) Si—. In which X and Y are both hydrogen atoms. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may have a linear or branched alkyl group having 1 to 10 carbon atoms which may have a substituent, or a carbon which may have a substituent. A cyclic alkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 14 carbon atoms which may have a substituent, or an aralkyl group having 7 to 15 carbon atoms which may have a substituent;

(First step)
In this step, 5′-deoxyfluorouridine represented by the general formula (3) or a salt thereof is
When reacted with a conventionally known silylating agent such as trialkylsilyl halide or trialkylsilyl trifluoromethylsulfonate, trialkylsilyl triflate or trialkylsilylacetamidodate, the compound represented by the general formula (1) can be produced. This reaction may be carried out in accordance with a generally known method, and any solvent that does not participate in the reaction may be used. For example, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, diethyl ether, benzene, Toluene, N, N-dimethylformamide, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in combination. In the reaction, a base may be used as necessary. Examples of the base include organic amines such as imidazole, 1-methylimidazole, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, lutidine, collidine and the like. And inorganic bases such as sodium bicarbonate and sodium carbonate, and only the base may be used as a solvent. In this reaction, the silylating agent is used in an amount of about 1 to 10 mol, preferably about 2 to 4 mol, and the base is about 1 to 100 mol, per 1 mol of the compound represented by the general formula (3). Preferably about 2-10 mol amount is used. The reaction temperature is −30 to 100 ° C., preferably 0 to 30 ° C., and the reaction time is 0.1 to 100 hours, preferably 1 to 20 hours.
Here, when a compound represented by the general formula (1) in which either X or Y is hydrogen is obtained, this is reacted by a method similar to the above using a silylating agent different from the silylating agent. Thus, a compound represented by the general formula (1) in which X and Y are different can also be produced.

  The compound of the present invention and the other compounds obtained as described above can form a salt, particularly a pharmaceutically acceptable salt, by a generally known method.

  The compound of the present invention or a salt thereof, or another compound or a salt thereof can be isolated and purified by using a generally known separation and purification means such as concentration, solvent extraction, filtration, recrystallization, various chromatography and the like.

  When the compound of the present invention is used as a medicament, it can be combined with a pharmaceutical carrier, and various administration forms can be adopted depending on the purpose of prevention or treatment. Examples of such forms include oral preparations, injections, and suppositories. Any of ointments, patches, and the like may be used, and oral preparations are preferably employed. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

  As a pharmaceutical carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations, solvents in liquid preparations, solubilizers, suspensions It is blended as an agent, isotonic agent, buffer, soothing agent and the like. In addition, formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used as necessary.

  When preparing an oral solid preparation, after adding an excipient, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. to the compound of the present invention, a tablet by a conventional method, Coated tablets, granules, powders, capsules and the like can be produced. Such additives may be those commonly used in the art. For example, excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid As the binder, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc. are used. Examples of the disintegrating agent include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Phosphate, borax, polyethylene glycol and the like, as the colorant, titanium oxide, iron oxide, white as the flavoring agent sugar, orange peel, citric acid, can be exemplified tartaric acid.

  When an oral liquid preparation is prepared, an oral solution, syrup, elixir and the like can be produced by adding a flavoring agent, a buffer, a stabilizer, a flavoring agent and the like to the compound of the present invention by a conventional method. In this case, the flavoring / flavoring agent may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods. Can be manufactured. Examples of the pH adjuster and buffer in this case include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

  When preparing a suppository, a formulation carrier known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and an interface such as Tween (registered trademark) as necessary are added to the compound of the present invention. After adding an activator etc., it can manufacture by a conventional method.

  When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are usually used for the compound of the present invention are blended as necessary, and mixed and formulated by a conventional method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.

  When preparing a patch, the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method. As the support, a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane, or a film or foam sheet made of cotton, suf, or chemical fiber is suitable.

  The amount of the compound of the present invention to be formulated in each of the above dosage unit forms is not constant depending on the symptom of the patient to which the compound is to be applied, or its dosage form, etc. 1 to 1000 mg, about 0.1 to 500 mg for injections, and about 5 to 1000 mg for suppositories are desirable. In addition, the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally, but is usually about 0.1 to 5000 mg per day for an adult, preferably It may be 1 to 1000 mg, and it is preferable to administer this once a day or divided into 2 to 4 times.

  Diseases that can be treated by administering a drug containing the compound of the present invention include, for example, malignant tumors, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, Examples include lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumor, etc. .

  The following examples and pharmacological test examples further illustrate the present invention. However, the present invention is not limited to these examples.

Examples 1, 2, 3
5′-deoxy-2′-O-tert-butyldimethylsilyl-5-fluorouridine (Compound 1) , 5′-deoxy-3′-O-tert-butyldimethylsilyl-5-fluorouridine (Compound 2) , 5′-Deoxy-2 ′, 3′-O, O′-di-tert-butyldimethylsilyl-5-fluorouridine (Compound 3)
5′-Deoxy-5-fluorouridine (10.0 g, 40.6 mmol) was dissolved in N, N-dimethylformamide (200 ml), and imidazole (11.1 g, 162 mmol), tert-butyldimethylchlorosilane ( 12.2 g, 81.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (40% ethyl acetate / n-hexane) to give compound 1 (3.78 g, 10.5 mmol, yield 26%), compound 2 (3. 31 g, 9.18 mmol, yield 23%) and compound 3 (1.27 g, 2.68 mmol, yield 6.6%) were obtained as white solids, respectively.

(Compound 1) ¹ H-NMR (CDCl ₃ ) δ 9.69 (1H, br), 7.38 (1H, d, J = 5.6 Hz), 5.71-5.70 (1H, m), 4.20-4.18 (1H, m), 4.07-4.01 (1H, m), 3.68-3.63 (1H, m), 2.49 (1H, d, J = 8) .4 Hz), 1.44 (3 H, d, J = 6.8 Hz), 0.92 (9 H, s), 0.18 (3 H, s), 0.13 (3 H, s); ESI-LRMS m / Z 361 (MH ⁺ ). Anal. _{Calcd for C 15 H 25 FN 2} O 5 Si: C, 49.98; H, 6.99; N, 7.77. Found: C, 49.99; H, 6.99; N, 7.54; mp122.0-123.8 ° C.
(Compound 2) ¹ H-NMR (CDCl ₃ ) δ 9.37 (1H, br), 7.36 (1H, d, J = 6.0 Hz), 5.67 (1H, dd, J = 3.6 Hz) , J = 0.8 Hz), 4.09 (1H, br), 4.04-3.98 (1 H, m), 3.93 (1 H, t, J = 6.0 Hz), 3.07 (1H , Br), 1.38 (3H, d, J = 6.4 Hz), 0.93 (9H, s), 0.15 (3H, s), 0.14 (3H, s); ESI-LRMS m / Z 361 (MH ⁺ ). Anal. _{Calcd for C 15 H 25 FN 2} O 5 Si: C, 49.98; H, 6.99; N, 7.77. Found: C, 49.84; H, 7.08; N; 7.70; mp 140.1-141.0 ° C.
(Compound 3) ¹ H-NMR (CDCl ₃ ) δ 8.79 (1H, br), 7.46 (1H, d, J = 6.0 Hz), 5.62-5.61 (1H, m), 4.23-4.17 (1H, m), 4.12-4.11 (1H, m), 3.57 (1H, dd, J = 6.8 Hz, J = 4.0 Hz), 1.39 (3H, d, J = 6.4 Hz), 0.91 (18H, s), 0.14 (3H, s), 0.10 (3H, s), 0.09 (3H, s), 0. 08 (3H, s); ESI-LRMS m / z 475 (MH ^<+> ). Anal. _{Calcd for C 21 H 39 FN 2} O 5 Si 2: C, 53.13; H, 8.28; N, 5.90. Found: C, 53.49; H, 8.42; N; 5.87; mp125.0-126.0 ° C.

Example 4
5′-Deoxy-2′-O-Texyldimethylsilyl-5-fluorouridine (Compound 4)
5′-Deoxy-5-fluorouridine (6.00 g, 24.4 mmol) was dissolved in N, N-dimethylformamide (100 ml), and imidazole (6.64 g, 97.5 mmol), texyldimethylchlorosilane ( (9.57 ml, 48.7 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (40% ethyl acetate / n-hexane) to obtain compound 4 (3.29 g, 8.47 mmol, yield 35%) as a white solid. .

(Compound 4) ¹ H-NMR (CDCl ₃ ) δ 9.27 (1H, br), 7.37 (1H, d, J = 5.6 Hz), 5.72-5.71 (1H, m), 4.19 (1H, dd, J = 5.2 Hz, 2.8 Hz), 4.06-4.00 (1H, m), 3.67-3.63 (1H, m), 2.46 (1H , D, J = 8.0 Hz), 1.69-1.58 (1H, m), 1.44 (3H, d, J = 6.4), 0.91-0.87 (12H, m) , 0.21 (3H, s), 0.16 (3H, s); ESI-LRMS m / z 389 (MH ^<+> ). Anal. _{Calcd for C 17 H 29 FN 2} O 5 Si: C, 52.26; H, 7.52; N, 7.21. Found: C, 52.74; H, 7.67; N, 7.11; mp 167.8-168.8 ° C.

Pharmacological test example 1
Antitumor effect of the compound of the present invention by oral administration on BALB / cAJcl-nu / nu mouse subcutaneous tumor transplantation system Human breast cancer tumor strain MX- subcultured subcutaneously in BALB / cAJcl-nu / nu mice (CLEA Japan) 1 was transplanted subcutaneously in the back of 6 week old BALB / cAJcl-nu / nu mice with a 2 × 2 × 2 mm fragment. Ten days after the transplantation, the body weight and the major axis and minor axis of the tumor were measured, and the tumor volume (Tumor Volume, TV) was calculated from the following formula 1. TV (mm ³ ) = [tumor major axis × tumor minor axis × tumor minor axis] / 2 (Formula 1)
The groups were divided so that there was no variation in the tumor volume of each group (5 mice per group).

  Each derivative was dissolved or suspended in a 0.5% hydroxypropylmethylcellulose solution and orally administered once a day for 14 days once a day from the grouping date. The dosage of the derivative was set to 0.67 mmol / kg / day with reference to the optimum dosage of 5'-deoxyfluorouridine (Non-patent Document 4). As a control agent, 5'-deoxyfluorouridine compound and equimolar number of 5'-deoxyfluorouridine were set.

  15 days after the grouping, the tumor volume of the subcutaneously transplanted tumor of the mice in the drug administration group was measured, and as the untreated group, the tumor volume when no drug was administered was measured. From the tumor volume at the time of grouping of the drug administration group and the non-treatment group and the tumor volume on the 15th day, each tumor volume increase ratio (Reactive Tumor Volume, RTV) was calculated by the following formula 2, and then tumor growth suppression The rate (Inhibition Rate, IR) was calculated from Equation 3 below, and the antitumor effect was determined.

RTV = TV judgment / TV grouping (Formula 2)
IR (%) = [1- (RTVtest) / (RTVcont)] × 100 (Formula 3)
[In Formula 3, RTVtest represents the average tumor volume increase ratio of the drug administration group, and RTVcont represents the average tumor volume increase ratio of the untreated group. ]
The test results are shown in Table 2.

  From the results in Table 2, it was revealed that the compound of the present invention exhibits an extremely excellent antitumor effect as compared with 5'-deoxyfluorouridine when administered orally.

Pharmacological test example 2
Compound 1 and Compound 2 (0.41 mmol / kg) of the present invention and 5′-deoxyfluorouridine (0.41 mmol / kg) as a control drug were orally administered to BALB / c male mice, and 5′- Deoxyfluorouridine concentration was measured. Table 3 shows blood parameters.

  From the results of Table 3, the compound of the present invention showed a particularly high area under the drug concentration time curve (AUC) as compared with 5'-deoxyfluorouridine. This indicates an improvement in the absorption of the compound and is considered to be a cause of the excellent antitumor effect.

  The 5'-deoxyfluorouridine compound or a salt thereof of the present invention exhibits excellent antitumor activity and has excellent pharmacokinetics, and is useful as an antitumor agent. Therefore, the problem of mental and physical distress to patients who receive drugs administered intravenously and the excessive burden of medical economic costs for hospital visits is eliminated, and it contributes greatly to improving the quality of life (QOL) of patients. It is expected.

Claims (9)

The following general formula (1)

[Where
X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom,
Y represents a group represented by (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— or a hydrogen atom,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each have a linear or branched alkyl group having 1 to 10 carbon atoms which may have a substituent,
A C3-C7 cyclic alkyl group which may have a substituent,
An aryl group having 6 to 14 carbon atoms which may have a substituent;
Any one of 7 to 15 aralkyl groups which may have a substituent,
Except when both X and Y are hydrogen atoms. ]
An antitumor agent comprising, as an active ingredient, a 5′-deoxyfluorouridine compound represented by the formula: In the general formula (1), X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y represents (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— Represents a group or a hydrogen atom represented by
R ¹ , R ² and R ³ are each a linear or branched alkyl group having 1 to 8 carbon atoms which may have a substituent, and the other two are the same or different, 1 to 3 linear or branched alkyl groups;
R ⁴ , R ⁵ and R ⁶ are each a linear or branched alkyl group having 1 to 8 carbon atoms which may have a substituent, and the other two are the same or different, and The antitumor agent containing the 5'-deoxyfluorouridine compound or its salt of Claim 1 as an active ingredient which is a 1-3 linear or branched alkyl group. In the general formula (1), X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y represents (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— Represents a group or a hydrogen atom represented by
One of R ¹ , R ² and R ³ is an isopropyl group, tert-butyl group, texyl group or octyl group, and the other two are the same or different and are a methyl group, an ethyl group, a propyl group or an isopropyl group. And
One of R ⁴ , R ⁵ and R ⁶ is an isopropyl group, tert-butyl group, texyl group or octyl group, and the other two are the same or different and are a methyl group, an ethyl group, a propyl group or an isopropyl group. Is,
An antitumor agent comprising the 5′-deoxyfluorouridine compound or a salt thereof according to claim 1 or 2 as an active ingredient. In the general formula (1), X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y represents (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— Represents a group or a hydrogen atom represented by
Any one of R ¹ , R ² and R ³ is a tert-butyl group or texyl group, and the other two are methyl groups;
Any one of R ⁴ , R ⁵ and R ⁶ is a tert-butyl group or a texyl group, and the other two are methyl groups;
The antitumor agent which contains the 5'-deoxyfluoro uridine compound or its salt in any one of Claims 1-3 as an active ingredient. 5′-deoxy-2′-O-tert-butyldimethylsilyl-5-fluorouridine, 5′-deoxy-3′-O-tert-butyldimethylsilyl-5-fluorouridine, 5′-deoxy-2 ′, At least one selected from the group consisting of 3′-O, O′-di-tert-butyldimethylsilyl-5-fluorouridine and 5′-deoxy-2′-O-texyldimethylsilyl-5-fluorouridine An antitumor agent comprising a compound or a salt thereof as an active ingredient. The following general formula (2)

[Where
X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom,
Y represents a group represented by (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— or a hydrogen atom,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each have a linear or branched alkyl group having 1 to 10 carbon atoms which may have a substituent,
A C3-C7 cyclic alkyl group which may have a substituent,
An aryl group having 6 to 14 carbon atoms which may have a substituent;
Any one of 7 to 15 aralkyl groups which may have a substituent,
Except when both X and Y are hydrogen atoms, 5′-deoxy-2′-O-tert-butyldimethylsilyl-5-fluorouridine, 5′-deoxy-3′-O-tert-butyldimethylsilyl- Excludes 5-fluorouridine. ]
A 5′-deoxyfluorouridine compound represented by the formula: In the general formula (2), X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y represents (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— Represents a group or a hydrogen atom represented by
R ¹ , R ² and R ³ are each a linear or branched alkyl group having 1 to 8 carbon atoms which may have a substituent, and the other two are the same or different, 1 to 3 linear or branched alkyl groups;
R ⁴ , R ⁵ and R ⁶ are each a linear or branched alkyl group having 1 to 8 carbon atoms which may have a substituent, and the other two are the same or different, and The 5'-deoxyfluorouridine compound or a salt thereof according to claim 6, which is a linear or branched alkyl group having 1 to 3 alkyl groups. In the general formula (2), X represents a group represented by (R ¹ ) (R ² ) (R ³ ) Si— or a hydrogen atom, and Y represents (R ⁴ ) (R ⁵ ) (R ⁶ ) Si— Represents a group or a hydrogen atom represented by
Any one of R ¹ , R ² and R ³ is an isopropyl group, a tert-butyl group, a texyl group or an octyl group; the other two are the same or different and are a methyl group, an ethyl group, a propyl group or an isopropyl group. And
One of R ⁴ , R ⁵ and R ⁶ is an isopropyl group, a tert-butyl group, a texyl group or an octyl group, and the other two are the same or different and are a methyl group, an ethyl group, a propyl group or an isopropyl group. Is,
The 5′-deoxyfluorouridine compound or a salt thereof according to claim 6 or 7. Either 5′-deoxy-2 ′, 3′-O, O′-di-tert-butyldimethylsilyl-5-fluorouridine or 5′-deoxy-2′-O-texyldimethylsilyl-5-fluorouridine The 5′-deoxyfluorouridine compound or a salt thereof.