JPS63250396A - 3'-azido-3'-deoxythymidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (X is H or F; R is lower alkyl, benzyl, halogen-substituted benzyl, lower acyl or benzoyl). EXAMPLE:3'-Azido-5'-methyl-3'-deoxythymidine. USE:An antitumor agent and antiviral agent. PREPARATION:For example, 3'-azido-3'-deoxythymidine expressed by formula II or alpha,alpha,beta-trifluoro-3'-azido-3'-deoxythymidine expressed by formula III is reacted with a halogen compound expressed by the formula R'-Y (R' is lower alkyl, benzyl or halogen-substituted benzyl; Y is Cl, Br or I) in the presence of a base (e.g. sodium hydride) in a solvent (e.g. benzene, THF or acetonitrile) to afford the aimed compound expressed by formula I (group R is R').

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel 3'-azido-3'-deoxythymidine derivatives.

Prior art and its problems 3'-azido-3'-deoxythymidine (IIa) is H
orvltz et al. (J, Org, Chell,.

1964.29, 2074), α,α,α-trifluoro-3′-azido-3′-deoxythymidine (I
[b) Lin et al. (J, Med, Chem.

1983.26, 1691), and is known to have antiviral or antitumor effects. In particular, 3'-azido-3'-deoxythymidine is a virus that causes acquired immunodeficiency syndrome (AIDS).
I V (hua+an1mmunodef1c1e
nt virus), and is considered to be a very therapeutically useful compound (M 1 tusuga et al., Proc.

Natl, Acad, Sci, USA, 1985.82
゜7096).

(IIa) (IIb) Means for Solving the Problems The present inventors have investigated various derivatizations of these compounds (IIa) and (IIb) for the purpose of enhancing their effects and reducing their side effects. succeeded in synthesizing a derivative capable of achieving the original purpose and completed the present invention.

That is, the present invention is based on the general formula (In the formula, X represents a hydrogen atom or a fluorine atom.

R represents a lower alkyl group, a benzyl group, )\logen-substituted benzyl group, a lower acyl group, or a benzoyl group. 3'-azido-3'-deoxythymidine derivative represented by

The above-mentioned compounds of the present invention have antitumor and antiviral effects and are useful as medicines.

The lower alkyl group represented by R in the above general formula (I) is an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl,
Propyl, isopropyl, butyl, 5ec-butyl, t
Examples include linear and branched alkyl groups such as ert-butyl and hexyl groups. Examples of lower acyl groups include acyl groups having 2 to 6 carbon atoms, specifically acetyl, propionyl, 2-methylprobionyl, pivaloyl, 2-methylbutyryl, hexanoyl, and the like. Examples of halogen-substituted benzyl groups include those in which a halogen atom of fluorine, chlorine, bromine, or iodine is substituted on the phenyl ring, specifically 4-fluorobenzyl, 2-chlorobenzyl, 4-fluorobenzyl,
-chlorobenzyl, 2°4-dichlorobenzyl, 4-brombenzyl and the like.

The method for producing the derivative of the present invention will be described in detail below.

The compound of the present invention can be produced, for example, by the following two production methods.

Production method A> The compound in which R in the general formula (I) is a lower alkyl group, a benzyl group, or a halogen-substituted benzyl group is, for example, the known 3'-azido-3'-deoxythymidine (IIa) or α
, α,α-trifluoro-3'-azido-3'-deoxythymidine (nb) in a solvent in the presence of a base with the general formula % formula % () (wherein R' is a lower alkyl group, a benzyl group or a halogen-substituted benzyl group (Y represents a halogen atom of chlorine, bromine, or iodine).

The solvent used here is not particularly limited as long as it does not adversely affect the reaction, and a wide variety of conventionally known solvents can be used. Specifically, aromatic hydrocarbons such as benzene, toluene, xylene, ether, Ethers such as tetrahydrofuran and dioxane, and conventional aprotic solvents such as acetonitrile, pyridine, dimethylformamide and dimethyl sulfoxide can be used alone or in combination. As the base, any of the various bases commonly used in this type of reaction can be used, especially alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal waters such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. oxide, alkali metal alkoxide such as sodium methoxide, potassium ter
Organic alkali metals such as t-butoxide, butyllithium, potassium disilazide, silver oxide, silver nitrate, etc. are preferably used. The amount of the base to be used is the formula (na) or (
It is usually used in an amount of about 1 to 10 times, preferably about 2 to 5 times, the amount of the compound represented by nb). The proportion of the halogen compound (I[) to be used is usually 1 to 1 to the compound represented by formula (II a) or (II b').
A suitable molar ratio is 10 times, preferably 1 to 5 times. Although the reaction temperature is not particularly limited,
The temperature is usually about 0 to 100°C, preferably about room temperature to 60°C. Although the reaction time varies depending on the type of solvent and base used, the reaction is generally completed in about 0.5 to 10 hours.

Production method B> In addition, a compound in which R in the general formula (I) is a lower acyl group or a benzoyl group can be prepared by using, for example, a compound represented by the formula (IIb) as a starting material and converting the general formula % formula % () in a solvent. In the formula, R' represents a lower acyl group or a benzoyl group. Y' is a halogen atom of fluorine, chlorine, bromine, or iodine,
It can be obtained by reacting with a compound represented by a lower acyloxy group, a benzoyloxy group, a substituted benzoyloxy group, or an imidazole group. The solvent used here is not particularly limited as long as it does not adversely affect the reaction, and a wide variety of conventionally known solvents can be used.
Specifically, in addition to the solvent used in the above-mentioned production method A, solvents such as ketones such as methyl ethyl ketone and acetone, and halogenated hydrocarbons such as methylene chloride and chloroform can be used alone or in combination. It is preferable to have a base present in the reaction system, and any of the various bases commonly used in this type of reaction can be used, particularly sodium hydride, potassium tert, etc.
-butoxide, triethylamine, pyridine, imidazole, etc. are preferably used. The conditions in this reaction, such as the ratio of the base and the compound of general formula (IV) used, the reaction time, and the reaction temperature, are the same as those in Production Method A above.

Compound (I) obtained by the above method can be isolated and purified by commonly known separation and purification means, such as silica gel column chromatography.

The thus-obtained compounds of the present invention exhibit superior antitumor and antiviral effects compared to general formulas (IIa) and (IIb), and are useful for the treatment of these diseases.

EXAMPLES The compounds of the present invention will be explained in more detail with reference to Examples below. The analysis results of nuclear magnetic resonance spectra of the compounds obtained in each example are shown, but all of these are DM.
This is the δ value measured in SOds using TMS as an internal standard.

Example 1 Production of 3'-azido-5'-methyl-3'-deoxythymidine 2.67 g of 3'-azido-3'-deoxythymidine (
10 gmol) was dissolved in 30 g of tetrahydrofuran (hereinafter abbreviated as THF), and under water cooling, 2.8 g (25 in+ol) of potassium tert-butoxy and 1.0 g of methyl iodide were added.
56 g (11 mmol) was added, the temperature was returned to room temperature, and the mixture was stirred for 5 hours. After adding saturated ammonium chloride aqueous solution and stirring,
Extracted with toluene.

The extract was washed with water and dried over anhydrous sodium sulfate.

After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography and chloroform-acetone (
80: 20. V/V) 2.62 g of 3'-azido-5'-methyl-3'-deoxythymidine (
Yield: 93%) was obtained as a colorless oil.

NMR spectrum 1.79 (3H, s, 5-CH5) 2.2C1-2.58 (2H, m, H2') 3.35
(3H, s, OCH3) 3, 56 (2H, d, H5') 3, 89 (
LH, q, H3') 4.41 (IH, q, H4"
) 6.11 (IH, t, Hl') 7.55 (IH, s, H6) 11.30 (IH, brs, N, H) Example 2 3'-azido-5'-benzyl-3'- Production of deoxythymidine 2.67 g of 3'-azido-3'-deoxythymidine
(10 mmol) was dissolved in THF30-, and under water cooling, 6 g (25 mmol) of sodium hydride was added thereto, the temperature was returned to room temperature, and the mixture was stirred for 30 minutes. Benzyl bromide 1, 88g (1
1 mmol) was added thereto, and the mixture was heated and stirred at 50° C. for 4 hours. After cooling, a saturated aqueous ammonium chloride solution was added, stirred, and extracted with toluene. The extract was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography, and chloroform-
Acetone (85: 15. V/V) Elution area IQ
3.22 g (yield 90%) of 3'-7 dido 5'-benzyl-3'-deoxythymidine was obtained as a colorless oil.

NMR spectrum 1, 59 (3H,s, 5 CH3) 2.20
~2.60 (2H, m, H2')3.60~3
．． 80 (2H, m, H5') 3.88-4.10
(IH, s, H3') 4.38~4.64 (3
H, m, H” and 6, 13 (LH, t, H”
) 7.35 (5H, brs, aromatic H) 7.52
(IH, s, H6) 11, 30 (LH, brs, NH) Example 3 3'-azido-5'-p-chlorobenzyl-3'-
Production of deoxythymidine 3'-azido-3'-deoxythymidine 2, 67g
(10 mmol) was dissolved in 30 mQ of THF, and the solution was cooled with water with 0.0% sodium hydride. 6 g (25 mn+of) was added, the temperature was returned to room temperature, and the mixture was stirred for 30 minutes. p-chlorobenzyl chloride 1.77 g (11 mn+ol) and sodium iodide 0. 15 g (1 mmol) was added, and the mixture was heated and stirred at 50° C. for 5 hours. After cooling, a saturated aqueous ammonium chloride solution was added, stirred, and extracted with toluene.

The extract was washed with water and dried over anhydrous sodium sulfate.

After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography and chloroform-acetone (
85: 15. V/V) 3'-Azide-5 from the elution part
'-p-chlorobenzyl-3'-deoxythymidine3.
37 g (86% yield) was obtained as a colorless oil.

NMR spectrum 1.62 (3H, s, 5-CH3) 2.20-2.60 (2H, m, H2') 3, 6
0-3. 82 (2H, m, Hla')3.
92~4.12 (IH, m, H"') 4,40~
4.64 (3H, m, H” and 6.15 (IH,
t, Hl') 7.40 (IH, brs, aromatic H) 7.51 (I
H, s, H6) 11.33 (IH, brs, NH) Example 4 3'-azido-5'-methyl-3'-deoxy-α, α
, production of α-trifluorothymidine 3′-azide-3
'-deoxy-α,α,α-trifluorothymidine3.
21 g (10 mmol) of THF 30111Q
Dissolved in 0.6 g (25 g) of sodium hydride under water cooling.
mmol) was added thereto, the temperature was returned to room temperature, and the mixture was stirred for 30 minutes. Methyl iodide1. 56 g (III mol) was added and stirred at room temperature for 8 hours. After adding a saturated aqueous ammonium chloride solution and stirring, the mixture was extracted with toluene. Wash the extract with water,
It was dried with anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography, and chloroform-acetone (90:10.V/V
) 1.21 g of 3'-azido-5'-methyl-3'-deoxy-α,α,α-trifluorothymidine (
Yield: 36%) was obtained as a pale yellow oil.

NMR spectrum 2.30-2.62 (2H, m, H2') 3.33
(3H, s, OCH3) 3.40-3.80 (2H, m, H5') 3.9
6-4. 12 (IH, m, H3')4.39
(IH, q, H") 6.00 (IH, t, H") 8.44 (LH, d, H6) 11, 90 (IH, brs, NH) Example 5 3'-azido-5'- Acetyl-3'-deoxy-α,
Production of α, α-trifluorothymidine 3′-azide-3
'-deoxy-α,α,α-trifluorothymidine3.
21 g (10III mol) in dichloromethane 1
0 and triethylamine 2. 53g (25
mmol) and acetic anhydride 1.53 g (15 mmol)
was added and stirred at room temperature for 5 hours.

After adding 10 mQ of 5% aqueous hydrochloric acid and stirring, the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography, and 3'-azido-5'-acetyl-3'-deoxy was extracted from the taloloformacetone (90: 10. V/V) eluate. −
3.34 g (yield 92%) of α,α,α-trifluorothymidine was obtained as a colorless oil.

NMR spectrum 2.05 (3H, s, -CCH3) 2.20-2.80 (2H, m, H2')3.
96-4.56 (4H, m, H3'.

H4 and H5') 6.01 (IH, t, H'') 8.10 (IH, d, H6) 11.94 (IH, brs, NH) Example 6 3'-azido-5'-benzoyl- Preparation of 3'-deoxy-α,α,α-trifluorothymidine 3.21 g (10 mmol) of 3'-azido 3'-deoxy-α,α,α-trifluorothymidine was dissolved in 10 pyridine and chlorinated. Benzoyl 11.48g (10.5m
n+ol) and 4-dimethylaminopyridine 0. 12
2 g (1 mmol) was added and stirred at room temperature for 3 hours.

After concentrating the solvent, dichloromethane and water were added, followed by extraction with dichloromethane.

The extract was washed with saturated saline and dried over anhydrous sulfuric acid. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography, and 3'
-azido-5'-benzoyl-3'-deoxy-α,α
, α-trifluorothymidine 3.74g (yield 88%
) was obtained as a colorless oil.

NMR spectrum 2.30-2.90 (2H, m, H2') 4.18
~4.42 (IH, m, H3')4.40~4
．． 80 (3H, m, H" and H5') 6.08 (LH, t, H") 7, 30-8. 10 (5H, m, aromatic H)8.1
1 (IH, d, H6) 11.80 (IH, brs, NH) (or more)

Claims (1)

[Claims] [1] General formula ▲ Numerical formulas, chemical formulas, tables, etc. , lower acyl group or benzoyl group).