CA1060004A - 1-(beta-d-ribofuranosyl)-1,2,4-triazole acid esters - Google Patents

Abstract

S P E C I F I C A T I O N
1-(.beta.-D-RIBOFURANOSYL)-1,2,4-TRIAZOLE
ACID ESTERS
Abstract of the Disclosure Phosphate and carboxylic acid esters of 1-(.beta.-D-ribofuranosyl)-1,2,4-triazoles are prepared by a variety of methods and their antiviral activity reported.

Description

10~0004 In our United States Patent 3,798,209, dated March 19, 1974, are described and claimed compounds of structure 1 ~

HO
'k~'~
HO OH

wherein Rl is carboxamido, thiocarboxamido or carboxamidino and its physiologically acceptable acid addition salts, as well as 5'-phosphates and 3',S'-cyclic phocphates thereof, and compounds in which otherwise free glycosyl hydroxyls bear C1-C18 acyl groups. The compound~ are diAclosed in the above Patent to possess potent antiviral activity. In one e~bodiment of the present invention, we provide analogous compounds having the same aglycon whose glycosidic moiety is of structure -xo~~l 1~1 :~ - ' XO OX
wberein at least one X i9 Cl-C18 acyl and at least one X is hydrogen. According to another embodiment of thi~ invention there-are provided analogous nucleotides, viz., 2',3'-cyclic ;~;. pho~phates and mixed 2'- and 3'-phosphates of nucleosides of structure (a). Compounds prepared according to this invention ~: exhibit significant antiviral activity in in vivo animal testing, ~ -and may be adminlstered generally as in our U.S. Patent 3,927,216, ~20 dated Dece~ber 16, 1975.
: There are thus provided in accordance with the invention, ~ -D-ribofuranosyl)-1,2,4-triazole nucleosides of structure . ~ :

.: :
' .,,.,. . . :, : ~ . . .. .

R~
N (I) o XO ~ \

~ ~X

wherein Rl i~ selected from the group consisting of ta) carbox-amido, (b) thiocarboxamido, and (c3 carboxamidino groups and physiologically acceptable acid addition salts of (c); and where-in X i9 hydrogen or Cl-C18 acyl, at lPast one X being hydrogen and at least one X being acyl or when X in the 5'-position is hydrogen or Cl-C18 acyl, the X in the 2'- and 3'-positions together represent the group 0~ \ ' .
OH
or one X in said 2'- or 3'-position in a group of formula o = P - OH
OH
and the other is H or Cl-C18 acyl.
The nucleoside~ of the invention can be prepared in ~ .
accordance with another aspect of the invention, in a process which~comprise A, acylating a 1-(2,3-O-isopropylidene-~-D-ribo- : -~ ~ .
furanosyl)-1,2,4-triazole-3-carboxamide, 3-thiocarboxamide or -3-carboxam~dine followed by deisopropylidenation,or B. electively deacylating a (2,3,5-tri-O-acyl-~-D-~; 20 ribofuranosyl)-1,2,4-triazole-3-carboxamide,-3-thiocarboxamide - or -3-carboxamidine, to give a compound of structure (I) wherein ~ .
X i~ hydrogen or Cl-C18 acyl, at least one X being hydrogen and at least one X being ac~l, C. treating a l-(~-~-ribofuranosyl)-1,2,4-triazole-nucleoside of ~tructure I wherein Rl is the same as above and .
_. .
~ ~ - 2 -. ,~...,~

X in 5'-position is hydrogen or Cl-C18 acyl, the remaining X's are hydrogen with the tri-n-butyl amune salt of pyrophosphoric acid, to give a l-(~-D-ribofuranosyl)-1,2,4-triazole-3-R1 2',3'-cyclic phosphate, or D. cleavage of a l-(~-D-ribofuranosyl)-1,2,4-triazole-3-Rl, 2',3'-cyclic phosphate, as defined in C, at the cyclic phosphate group to produce a triazole-nucleoside of structure(I) with a monophosphate group O = P - OH
OH
in the 2'- or 3'-position, and, when desired Cl-C18 acylating otherwise free glycosyl hydroxyl groups and separating 2'- and 3'-phosphates, and, when desired, converting a compound of structure (I) in which Rl is carboxamidino into a physiologically acceptable acid addition salt thereof.
Preferred 5'-O-acyl compounds are prepared by a variety of methods chosen according to the particular acyl group desired.
In the main (Method~ 1-3, infra), syntheses of 5'-O-acyl compounds involve isopropylidene blocking of the 2'- and 3'-positions, acylation at the 5'-position, and deisopropylidenation. Methods 1 and 2 involve acylation reaction in solvent media (e.g., pyridine) and are employed fox the higher molecular weight acyl groups. In Method 1 anhydride reactants are employed while Method 2 will serve where the corresponding acyl haLides are more readily obtainable. Lower molecular weight acyl group~ whose correspond-ing anhydrides are liquid at normal te~peratures are attached by ~;
Method 3, employing 4-alkylaminopyridine as catalyst. A fourth method of`choice, particularly for preparation of 5-O-benzoyl compounds, involves selective deacylation. ~ -Following Examples 1-5 illustrate 5'-O-acylation of the preferred 1-(3-D-ribofuranoqyl)-1,2,4-triazole-3-carboxamide. -~

Esse~tially the same procedures may be employed in forming corres-ponding 3-thiocarboxamides and 3-carboxamidines, mutatis mutandis.
~~~ ' In each of following Examples(1-3) of preferred embodiments of the invention, the starting material 1-(2,3-0-Isopropylidene-~- D-ribofuranosyl)-1,2,4-triazole-3-carboxamide was prepared as follows:
1-(2~3-o-Isopropylidene-~-D-ribofuranosyl)-l~2~4-triazole-3 carboxamide ~ D-Ribofuranosyl)-1,2,4-triazole-3-carboxamide (30.0 g, 123 mole) was suspended in a mixture of acetone (400 ml) and 2,2-dimethoxy-propane (200 ml). The mixture was cooled in an ice bath and 7~/~ per-chloric acid (6 ml) was added. The mixture was kept at room temperature for 3 hr and at 5 overnight. The resulting orange solution was neutralized with 2N potassium hydroxide, filtered, and evaporated to dryness.
The solid residue was treated with methanol and the insoluble product was removed by filtration. The methanolic solution was concentrated to a small volume and the crystalline product wa~ collected. Recrystallization from a mixture of ethyl-acetate and methanol gave 1-(2,3-0-isopropylidene-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (31.0 g, 90/O) with mp 153-154.
Anal- Calcd for CllH16N4s C~ 46-47; H~ 5-67; ~ 19.71.
Found: C, 46.38; ~, 5.73~ ~, 19.50.

~ .'.

:: .

.
": . , , . ~:

Depending upon the particular 5-0-acyl derivative under preparation, one or more of the following methods was employed.
Method l. A mixture of 1-(2,3-0-isopropylidene-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide, anhydrous pyridine and the appropriate acyl anhydride is stirred at 60 until the reaction is complete as shown by thin-layer chromato--graphy (24-72 hr). Water is added to the mixture after the re-action is complete and the product is collected by filtration or evaporation and extraction.
The intermediate l-(S-0-acyl-2,3-0-isopropylidene-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide is converted to the 1-(5-0-acyl-~-D-ribofuranosyl)-1,2,4-triazole-3-carbox-amide by treatment with aqueous acid. A mixture of the isopro-pylidene intermediate is heated at 100 with a 4:1 (volume/volum~
mixture of acetic acid and water until the reaction is complete as shown by thin-layer chromatography (2-5 hr). The solvent ~-i9 removed by evaporation and the 5-0-acyl product is obtained by crystallization.
Alternatively, the isopropylidene group may be removed from the intermediate 5'-0-acyl-2',3'-0-isopropylidene derivative by treatment with a 9:1 (volume/volume) mixture of trifluoroacetic acid and water at room temperature for 5 min.
The reaction mixture is evaporated to dryness and the 5'-0-acyl product is purified by crystallization.

.~

,~,,.~. .. . . , . : . .

Method 2. A mixture of 1-(2,3-0-isopropylidene-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide and anhydrous pyridine is cooled in an ice bath and the appropriate acyl halide is slowly added with stirring. The reaction mixture is kept at room temperature until the reaction is complete as shown by thin-layer chromatography (2-24 hr). Water is added to the mixture and the product is obtained by filtration or evaporation and extraction. The intermediate 1-(5-0-acyl-2,3-0-isopropylidene-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide is converted to the 1-(5-0-acyl-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide as in Method 1.
Method 3. A mixture of 1-(2,3-0-isopropylidene-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide and an excess of the appropriate acyl anhydride containing a catalytic amount (ca. 100 mg) of 4-dimethylaminopyridine is stirred at room temperature until the reaction is complete as shown by thin layer chromatography (1~-24 hr). The reaction mixture is evaporated to dryness and the product is isolated and converted to the 1-(5-0-acyl-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide as in Method 1. Alternatively, the crude 5'-0-acyl-2',3'-0-isopropylidene product obtained by evaporation may be converted directly without purification to the 1-(5-0-acyl-~-D-ribofurano-syl)-1,2,4-triazole-3-carboxamide by the deisopropylidenation procedures given in Method 1.

Method 4. A mixture of 1-(2,3,5-tri-0-benzoyl-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester and methanol saturated at 0 with anhydrous ammonia was stirred at 0 for 4 hr. The resulting solution was evaporated to dryness under reduced pressure and the product was crystallized from aqueous ethanol to give l-(5-0-benzoyl-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide with mp 182-184.
The particular methods employed in preparing the compounds of Example 1-5 appear from Table I, which reports certain of their properties.
: ' '~.

:.
' Properties of 1-(5-0-Acyl-~-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide O
H2N-C~,_N

R-o-~l/o 1 HO OH

Exam- _ Syn- Empirical Analyses R thesis MP(C) _ormula _ Calcd - Found (acetyl) N 19.58 19.63

2 CH3(CH2)2CO- 3155.5-157C12H18~4O6 H 45 787 5 80 (butyryl) N 17.83 17.73

3 CH3(CH2)14CO 1159-16324H42N46 H 58 77 58 80 (Palmitoyl) N 11.61 11.63

4 ~ 2,4 182-la4C15Hl6N4O6 C 51 72 51 91 (benzoyl) N 16.09 16.19 - .

morphousCl9H26~46 H 56 44 56 51 ~;
(adamantoyl) N 13.78 13~83 - ~ .
: ~ ~

~, ~ , . , ~ - 8 - ~
: .
~ ' :
~'~

Of course, compounds within the scope of this invention may be otherwise secured. For example, 5'-0-acyl analogs may be approached via selective acylation, as may be, e.g., 2t-0-acyl, 3'-0-acyl, and di-0-acyl analogs, with con-sequent separation via column chromatography. See, e.g., C.A. Decker and L. Goodman, The Carbohydrates, vol. 2A, p. 26 (2d.ed. 1970) Academic Press, ~.Y.

~ ~' Example 6 Various of the compounds prepared in the preceding examples are tested for activity in vivo against Influenza A2 (Japan 305) induced deaths in male Swiss mice (19-20 gm) and the results compared with those obtained with l~ D-ribofurano-syl)-1,2,4-triazole-3-carboxamide. The mice were intranasally inoculated with virus and treated with compound undex test by oral administration tw1ce daily for 8 days commencing 2 hours pre- and 4 hours post-virus inoculation. Virus dosage was 3.2 LD50. Infected mice were observed for 21 days. The `~ results of testing are presented in Table I. All compounds ~; tested were orally non-toxic at the dosages tested.

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~E~

,~
~_ ~
h u~ ~ ~ _I o ~u~ ~ ~ ~ ~ ~ r~ ~ ~D ~ O c~
O U~ . . . . . . . . ~ . . . . . ..

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1~ . ~ ''.
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N ~ h a~
O Cq In H :1 ~ ~ 115 ~O 1` 1` ~ ~D 1` ~ ~) ~ 1` 0 d' 1` 1`
_I ~ hl~ d~9~ ~ d' ~ d' d' d' ~ O d' ~ ~9 q~ Ul ~O~ .. .... .. -. ....
E'3 H J~ Cl~ H O O O O O O O O O O O O O O
,:1 ~ a ...
m o ~ ~
f C ~ ~ E
E~ ~ ~ . X ~ ~ :

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O ~ ~ t~ U
C) U-rl~ O 00 0000 0000 0 00 I
~: , O ~ O ~ ~ 1 ~r),1 h E~ ~ ~ ~ ~ ~ I ~1 O H CQ ~1 ~1 0 0--I ~1 0--I ~1 ~1 0 lo--I O O ~
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u~ n ~ ~ :

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~060004 The compound of Example 4 was similarly tested, save that the mice were 17-18 g. male Swiss mice, virus dose was 3.2 LD50, and drug was first administered 15 minutes prior to virus inoculation.
The results appear in Table II.

: . ;

.: :

.
' 0 U~
~rl a1 h ~-1 U ~ O ~1 ~ ~U O N o O ~r) u~ H P~ .. ...

~: ~ V V V V A
a) '1 E~

g gQ
h al bq .r~ ) N IS~
tl U~rl (11 -. - . .
O ~ ~ `D ~ ~ S) N r-0 ~
~ : .
I~
~I
0 .1 h al N ~ ~ O ~1 O ~1 ~ --i H I ~1 ~ h0 .. ...
H ~1 h O Pl 0 0 0 0 0 ~: ~~ H V V V V A ~
H ~) C : .

3~1 g - l o o o o o oU ,, ~ ,, ,, ,, ,, ,, ~ , 0 ~,~ ~ o q I h E~ ~ ~ l OH U~ O . o~

~: U h E~
_ d' fd . ~ ~ a) o ..
l` O O It) I -. h U
~0 .~ t` ~) O ~ I ~ ~Q 3 ~u . ~ _ ,~ U~ ~ ~ - .-: -, ~ o ~ a ,4 u , , ",, ~. :' : :' The l~ D-ribofuranosyl)-1,2,4-triazole-3-Rl 2',3'-cyclic phosphates of the invention are prepared by an adaptation of the procedure of T. Ueda and I. Kawai, Chem. Pharm. Bull (Japan) 18, 2303 (1970) wherein the corresponding nucleoside is refluxed in dimethylformamide with the tri-n-butyl amine salt of pyrophosphoric acid. Product is purified by cellulose ion exchange chromatography. 5'-0-acyl 2~,3'-cyclic phosphates may be similarly prepared, commencing with the 5'-0-acylated nucleosides.
Mixed (2',3') phosphates are secured by cleavage of corresponding cyclic phosphates, as with dilute acid, If desired, otherwise free glycosyl hydroxyls of the resulting mixture may be acylated and 0-acyl 2'-and 3'-phosphates separated, one from the other.

..

.

1 , :
~,,~ ', ', ' .

` Example 7 Preparation of l~~-D-Ribofuranosyl-1,2,4-triazole-3-carboxamide . ............................................................. :

21,3~-cyclic phosphate A solution of l-~-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (1.22 g., 5.0 mmole), pyrophosphoric acid (10.0 mmole) and tri-n-butyl-amine (40.0 mmole) in dimethylformamide (100 ml) was refluxed for 2.5 hr. The solvent was removed in vacuo and the residue was dissolved in LN ammonium hydroxide (100 ml). The solution wasextracted with ether and the aqueous phase was concentrated to a small volume. The solution was diluted with water to 60 ml and the pH was adjusted to 8.5 ~
with ammonium hydroxide. This solution was applied to a DE 52 -cellulose (130 g) column in the bicarbonate form. Elution was with a linear gradient of water (1000 ml) to 0.05 M triethylamine bicarbonate ~1000 ml) and fractions of 20 ml were collected. ~-The product was contained in fractions 35-50 which were combined and evaporated to dryness. The residue was dissolved in water (20 ml) and passed through a Dowex 50* X 8 (20 ml) column in the ammonium form. The column was eluted with water and the solution containing the product was evaporated to dryness. The residue was dissolved in methanol and a small amount of impurity was -removed by filtration. The filtrate was evaporated to dryness ~
and the residue was dissolved in water. The solution was ~ ~-, lyophilized to afford the ammonium salt of the 2',3'-cyclic phos-phate.

~; Anal- Calcd for C8H14N507P.H2o.
.
N, 21.13. Found: C, 28.16; H, 4.73 N, 20.53. -Alkali metal salts or the free 2',3' cyclic phosphate may be obtained from the ammonium salt by ion exchange.

* trademark ~060004 After brief treatment with dilute acid the 2',3'-cyclic phosphate was converted to the 2'(3')-phosphate as shown by thin layer chromatography on silica gel with 7:3 (v~v) acetonitrile: 0.1 N aqueous ammonium chloride.

Example 8 The compound of Example 7 was tested for antiviral activity by the virus rating (VR) method of Sidwell, et al Appl. Microbiol 22, 797 (1971) against type 1 herpes simplex virus (HSV/l), type 13 rhinovirus (RV~13), type 3 parainfluenza 1~ virus (PIV/3), influenza virus type A, strain NWS (I Sj, _ ;~
and vaccinia virus ( W ), in the cell lines shown in Table III
below. V.R. > 1.0 is indicative of definite antiviral activity, V.R. of 0.5 - 0.9 is indicative of moderate antiviral activity, and V.R. < 0.5 suggests slight or no apparent anti-viral activity. To demonstrate the antiviral activity of the compounds resulting when the cyclic phosphate was opened by acid hydrolysis, we acidified the solution (in cell culture medium) containing the highest concentration of compound to pE 1.5 with lN HCl. Formation of a mixture of l-(~-D-ribofuranosyl?-1,2,4-triazole 2'-and 3l-phosphates was confirmed by thin layer chromatography. This solution and similar solution which has not .
been acidified were incubated side-by-side at 37C for 2 hr.
The acidified solution was then neutralized by adding lN NaOH and the two incubated solutions were diluted and tested in cell culture along with a similar solution that had not been incubated.
The resulting VR data follow.

,, , ' .

.:

T A B L E III

Virus Rating of Certain 1,2,4-triazole-3-carboxamide l-~-D-Ribotides :

Compound KB RK-13 KB XB KB CE
Ammonium salt of -D-ribofuranosyl)-1,2,~-triazole-3-carboxamide 2 ,3 -cyclic phosphate0.8,1.2 1.1 0.6 0.2,0.3 1.1,1.1 0.4 .
~ : .
:- .
--do--(incubated) 0.8 -- -- 0.2 1.0 0,4 mixed l-(~-D- ~.
ribofuranosyl)-1,2,4-triazole-3-carboxamide 2'- and 3l-phosphates (incubated) 0.8 -- -- 0.6,0.6 1.0 0.5 -,:
The mixture of 2'- and 3'-monophosphates exhibited . activity similar to that of the cyclic phosphate, save in the ::
~ . - : ..
case of RV/13, which proved more sensitive to the non-cyclic ~ -~
phosphate,s.
:~ :
-',~,:: ; , ,. -..-:

:-::

,, ~ , ~ - 16-;' ~ .
' - ':
. .

Claims (23)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a 1-(.beta. -D-ribofurano-syl)-1,2,4-triazole nucleoside of structure (I) wherein R1 is selected from the group consisting of (a) carboxamido, (b) thiocarboxamido, and (c) carboxamidino groups and physiologically acceptable acid addition salts of (c); and wherein X is hydrogen or C1-C18 acyl, at least one X being hydrogen and at least one X being acyl or when X in the 5'-position is hydrogen or C1-C18 acyl, the X in the 2'- and 3'-positions together represent the group or one X in said 2'- or 3'-position is a group of formula and the other is H or C1-C18 acyl, which comprises:
A. acylating a 1-(2,3-O-isopropylidene-.beta.-D-ribo-furanosyl)-1,2,4-triazole-3,carboxamide, 3-thio-carboxamide or -3-carboxamidine followed by deisopropylidenation or B. selectively deacylating a (2,3,5-tri-O-acyl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide,-3-thiocarboxamide or -3-carboxamidine, to give a compound of structure (I) wherein X is hydrogen or C1-C18 acyl, at least one X being hydrogen and at least one X being acyl, C. treating a 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole-nucleoside of structure (I) wherein R1 is the same as above and X in 5'-position is hydrogen or C1-C18 acyl, the remaining X's are hydrogen with the tri-n-butyl amine salt of pyrophosphoric acid, to give a 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole-3-R1 2',3'-cyclic phosphate, or D. cleavage of a 1-(.beta.-D-ribofuranosyl)-1,2,4-tria-zole-3-R1, 2', 3'-cyclic phosphate, as defined in C, at the cyclic phosphate group to produce a triazole-nucleoside of structure (I) with a monophosphate group in the 2'- or 3'- position and, when desired C1-C18 acylating otherwise free glycosyl hydroxyl groups and separating 2'-and 3'-phosphates; and, when desired converting a compound of structure (I) in which R1 is carboxamidino into a physio-logically acceptable acid addition salt thereof.

2. A process according to claim 1A comprising acylating a 1-(2,3-O-isopropylidene-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide and deisopropylidinating the resultant 1-(5-O-acyl-2,3-O-isopropylidene-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carbox-amide to produce 1-(5'-O-acyl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide.

3. A process according to claim 1A comprising acylating a 1-(2,3-O-isopropylidene-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-thiocarboxamide followed by deisopropylidenation to produce a 1-(5'-O-acyl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-thiocarbox-amide.

4. A process according to claim 1A comprising acylating a 1-(2,3-O-isopropylidene-.beta.-?-ribofuranosyl)-1,2,4-triazole-3-carboxamidine followed by deisopropylidenation to produce a 1-(5'-O-acyl-.beta.-?-ribofuranosyl)-1,2,4-triazole-3-carboxamidine and converting said 3-carboxamidine to a corresponding hydrochloride salt.

5. A process according to claim 1, wherein X is hydrogen or C1-C18 acyl, at least one X being hydrogen and at least one X being acyl.

6. A process according to claim 1C, wherein X in the 5'-position is hydrogen or C1-C18 acyl and X in the 2'- and 3'-positions together represent a group

7. A process according to claim 6, wherein X in the 5'-position is hydrogen.

8. A process according to claim 1, which comprises treat-ing 1-.beta.-?-ribofuranosyl-1,2,4-triazole-3-carboxamide 2',3'-cyclic phosphate with a dilute acid to cleave the cyclic phosphate group.

9. A process according to claim 1, which comprises treating 1-(2,3-O-isopropylidene-.beta.-?-ribofuranosyl)-1,2,4-triazole-3-carboxamide with benzoyl halide followed by treat-ment to remove the isopropylidene group to give 1-(5'-O-benzoyl-.beta.-?-ribofuranosyl)-1,2,4-triazole-3-carboxamide.

10. A process according to claim 1, which comprises treating 1-(2,3-O-isopropylidene-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide with an excess of acetic anhydride containing a catalytic amount of 4-dimethyl-aminopyridine, followed by treatment to remove the isopropylidene group to give 1-(5'-O-acetyl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide.

11. A process according to claim 1, which comprises treating 1-(2,3-O-isopropylidene-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide with an excess of butyric anhydride containing a catalytic amount of 4-dimethylaminopyridine, followed by treatment to remove the isopropylidene group to give 1-(5'-O-butyryl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide.

12. A process according to claim 1, which comprises reacting 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide with pyrophosphoric acid and tri-n-butyl-amine in dimethyl-formamide to give 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide 2',3'-cyclic phosphate.

13. A 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole nucleoside of the structure wherein R1 is selected from the group consisting of (a) carboxamido, (b) thiocarboxamido, and (c) carboxamidino groups and physiologically acceptable acid addition salts of (c);
and wherein X is hydrogen or C1-C18 acyl, at least one X being hydrogen and at least one X being acyl and when X in the 5'-position is hydrogen or C1-C18 acyl, the X in the 2'- and 3'-positions together represent the group or one X in said 2'- or 3'-position is a group of formula and the other is H or C1-C18 acyl, whenever produced by the process of claim 1, or its obvious chemical equivalents.

14. A 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole nucleoside of structure wherein R1 is selected from the group consisting of (a) carboxamido. (b) thiocarboxamido, and (c) carboxamidino groups and physiologically acceptable acid addition salt of (c); and wherein X is hydrogen or C1-C18 acyl, at least one X being hydrogen and at least one X being acyl, whenever produced by the process of claim 5, or its obvious chemical equivalents.

15. A compound 1-(5'-O-acyl-B-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide, whenever produced by the process of claim 2, or its obvious chemical equivalents.

16. A compound 1-(5'-O-acyl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-thiocarboxamide, whenever produced by the process of claim 3, or its obvious chemical equivalents.

17. A compound 1-(5'-O-acyl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamidine hydrochloride, whenever produced by the process of claim 4, or its obvious chemical equivalents.

18. 1-(5'-O-Benzoyl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide whenever produced by the process of claim 9, or its obvious chemical equivalents.

19. 1-(5'-O-acetyl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide whenever produced by the process of claim 10, or its obvious chemical equivalents.

20. 1-(5'-O-butyryl-.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide whenever produced by the process of claim 11, or its obvious chemical equivalents.

21. A 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole nucleotide of structure wherein R1 is selected from the group consisting of (a) carboxamido, (b) thiocarboxamido and (c) carboxamidino groups and physiologically acceptable acid addition salts of (c);
and wherein R is hydrogen or C1-C18 acyl, whenever produced by the process of claim 6, or its obvious chemical equivalents.

22. A 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole nucleoside of structure I, as defined in claim 1, wherein X in the 5'-position is hydrogen and X in the 2'- and 3'-positions together represent a group whenever prepared by the process of claim 7, or its obvious chemical equivalents.

23. 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide 2',3'-cyclic phosphate whenever produced by the process of claim 12, or its obvious chemical equivalents.