JPS5859997A - 2-amino-6-carbamoylmethylpurine nucleoside - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R<1> is ribose residue, 2-deoxyribose residue, 3-deoxyribose residue, arabinose residue or xylose residue which may have a protecting group). USE:An enzymic inhibitor, reagent for biochemical research, medicine or ultraviolet light absorber having adenyl deaminase inhibitory action. PROCESS:A 2-amino-6-alkoxycarbonylmethylpurine nucleoside of formula II (R<2> is lower alkyl; R<3> is H or protecting group), e.g. 2-acetamide-6-ethoxycarbonylmethyl-9-(2,3,5-tri-O-acetyl-beta-D-ribofu ranosyl)purine, is treated with methanol- ammonia to give the compound of formulaI. The starting material of formula II is a novel substance and can be prepared by reacting a 2-amino-6-alkylsulfonylpurine or 2-amino-6-arenesulfonylpurine nucleoside of formula III (R<4> is alkyl or aryl) with an alkylacetoacetate of formula IV in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel compound, 2-amino-6-carbamoylmethylpurine nucleoside, and a process for producing the same.

2-Amino-6-carbamoylmethylpurine nucleoside, which is the object compound of the present invention, is a compound represented by the following general formula (1).

1 In the formula, R1 is a ribose residue that may have a protecting group,
A 2-deoxyribose residue, an 8-deoxyribose residue, an arabinose residue or a xylose residue is shown. The compound of the present invention is a novel compound that has not been described in any literature, and those in which the sugar residue is a ribose residue have adenyl deaminase inhibitory activity, and are not only useful as enzyme inhibitors, but also have various other physiological activities. It is expected that it will have the following properties, and its physiological activity may lead to the development of its usefulness as a reagent for biochemical research or as a medicine. The compounds of the present invention are also useful as ultraviolet absorbers.

The compound of the present invention has the general formula (1) [wherein R1 is a ribose residue which may have a protecting group,
2-deoxyribose residue, 8-deoxyribose residue, arabinose residue X, +1 sylose residue, R2 is a lower alkyl group, and R8 is hydrogen or a protecting group. It can be synthesized by using an alkoxycarbonylmethylpurine nucleoside as a raw material compound and treating it with methanol-'ammonia.

The lower alkyl group represented by R2 in the general formula of raw material compounds specifically means methyl, ethyl, propyl, butyl and the like. In addition, the protecting group for R1 and/or R8 may be any group used in the field of nucleoside chemistry, such as acyl groups such as acetyl, butyryl, and benzoyl, alkylidene groups such as impropylidene-1 and ethylidene, and benzylidene groups. Examples include aralkyl groups such as trityl and benzyl, alkoxyalkylidene groups such as methoxymethylene, ethoxymethylene and ethoxyethylene, and ranyl groups such as tetrahydro.

This raw material compound is also a new compound;
2-amino-6-alkyl or arenesulfonylpurine nucleoside represented by the following general formula [厘],
It can be produced by a method of reacting an alkyl mistyl acetoacetate represented by the following general formula [■] in the presence of a base.

l CH3C0CH2GOOR2 (II') R4 in the general formula [厘] is an alkyl group (e.g. methyl, ethyl, butyl, etc.) or an aryl group (e.g. 4-methylphenyl, 4-bromophenyl, 2,4.6 -drimethylphenylnato), and R2 in the general formula (IV) has the same meaning as in the general formula (,1). The base is used for the purpose of extracting the alkyl ester carafroton acetoacetate to produce a carbanion, and specific examples thereof include sodium hydride, n-butylpotassium, phenylpotassium, n-butyllithium, phenylsodium, and potassium. Examples include amide, sodium amide, and the like.

The raw material synthesis reaction is usually carried out using an aprotic polar solvent (e.g., tetrahydrofuran, hexamethylphosphoramide, dimethylsulfoxide, dimethylformamide,
dimethylacetamide, dimethoxyethane, dioxane, acetonitrile, etc.) under heating conditions from room temperature to solvent reflux temperature.

The conditions for the methanol-ammonia treatment in the method of the present invention are not particularly limited; for example, the reaction may be carried out at room temperature for several tens of hours.

The reaction solution of the compound of the present invention may be purified and isolated by a conventional method that can be used in the field of nuclear chemistry. For example, adsorption chromatography, recrystallization, etc. may be used as appropriate.

Hereinafter, the present invention will be explained more specifically by reference examples showing synthesis examples of raw material compounds in the method of the present invention and examples showing synthesis examples of the compounds of the present invention.

Reference Example 5096 To a suspension of 608 g of sodium hydride in 70 g of tetrahydrofuran, 24 g of ethyl acetoacetate was added.
．． A mixed solution of 89 and 15g+/of tetrahydrofuran was added dropwise to form a clear solution. This solution was mixed with 0(6)-paratoluenesulfonyl-N+21. OF2. Of8'l.

Add Oi5'l-tetraacetylguanosine 8859 to a solution of 290 ml of tetrahydrofuran and add 2
．． The mixture was heated under reflux for 5 hours.

After cooling the reaction solution, it was neutralized with acetic acid and concentrated to dryness under reduced pressure.

The residue was partitioned between water and chloroform, the chloroform layer was dried over 8 ml of magnesium sulfate, and then washed with 1.5 k silica gel.
It was adsorbed on a Li column and chloroform-methanol (
The eluate was concentrated to dryness to give 2-acetamido-6-nitoquinecarbonylmethyl-9- (2
, 8, 5-) Lee~acetyl-β-D-ribofuranosyl) purine (20 g) was obtained (yield: 6o%).

Ultraviolet absorption spectrum: 825 nm, 289 nm Mass spectrometry spectrum: ml 512 (M+) Nuclear magnetic resonance spectrum (CDCl2): 899 m8, 85
(I H,, b, s, NH)8.04 (IH,
S, 8-H) 6.19 (IH, d, 1'-H) 5, 86 (I H, m, 2'-H) 5°75
(IH, m, 8'-H) 4.42 (8H, m, 4'-H, 5'-H) 4.1
2 (2H,s,6-CH2-)4.18 (2H
,g+ -0CH2CH8)1,26 (8H,
t, -OCH2CHg) Example 2-acetamido-6-nitoxycarponylmethyl-9
- 1.27M of (2,8,5-)di-0-acetyl-β-D-ribofura/sil)purine was dissolved in 100 ml of anhydrous saturated ammonia methanol and then left at room temperature for 8 days.

The reaction solution was concentrated to dryness, and the residue was recrystallized from water to obtain 607 μl of needle-shaped crystals of 2-amino-6-carpamoylmethyl-9-β-D-ribofuranosyl preene (yield: 77.5
96).

Melting point 189°C Elemental analysis Cl2H16N605-1/2 H2O
t, -r calculated value (fl: C, 48, 24; H,
5,14;N, 26.40 Experimental value m: C,48,
58; I(, 4,95; N, 25.85 UV absorption spectrum nm λW cloud 806.244.221 λ0., lN-HCl 3.7.250 (sh), 22
6λ0゛1N″NaOH3o5.244 (sh), 2
27ax nuclear magnetic resonance x hector (DMSO-d6) a pp
m8.18 (IH, S, 8-H) 7.45.6.95 (2H, b, s, 6-CH2
CONH2) 5.80 (IH, d, 1'-H)

Claims (1)

[Claims] 1) General formula (1) represents a s residue and a xylose residue. 2-amino-6-carbamoylmethylpurine nucleoside represented by: 2) General formula (1) [wherein, R1 is a ribose residue that may have a protecting group,
It represents a 2-deoxyribose residue, an 8-deoxyribose residue, an arabinose residue M, and a xylose residue, R2 represents a lower alkyl group, and R8 represents hydrogen or a protective group. The 2-amino-6-alkoxycarbonylmethylpurine nucleoside represented by the above formula is treated with methanol-ammonia to form a compound of the general formula (1)' [wherein R1 has the same meaning as defined above]. A method for producing 2-amino-6-carbamoylmethylpurine nucleoside, which comprises synthesizing 2-amino-6-carbamoylmethylpurine nucleoside represented by the following.