ADENOSINE-5'-CARBOXYLIC ACID DERIVATIVES AND PROCESS FOR THEIR PREPARATION

DERIVES D'ACIDES ADENOSINE-5'-CARBOXYLIQUES; LEUR PREPARATION

English Abstract

ABSTRACT OF THE DISCLOSURE
Adenosine-5'-carboxylic acid derivatives of the formula:
<IMG>
wherein R1 and R2, which may be the same or different, are hydro-
gen atoms, hydroxyl or amino groups or lower alkyl, lower alkenyl,
optionally N-alkylated lower aminoalkyl, cycloalkyl or hydroxy-
alkyl radicals containing from 1 to 8 carbon atoms, preferably
from 1 to 6 carbon atoms, or piperidine residues or R1 and R2
together represent a divalent alkylene radical containing 4 - 7
carbon atoms, which can be interrupted by an oxygen or sulphur
atom or by an imino, alkylimino or arylimino radical and Z repre-
sents two hydrogen atoms or a lower alkylidene radical are pre-
pared by reacting an appropriate adenosine-5'-carboxylic acid re-
active derivative with an appropriate amine. The products and
their pharmacologically compatible salts, preferably in the form
of their pharmaceutical compositions are useful pharmacologically
and exhibit a very strong circulatory action.

Claims

The embodiments of the invention in which an exclu-
sive property or privilege is claimed are defined as follows:
1. Process for the preparation of adenosine-5'-carboxylic
acid derivatives of the general formula:
<IMG>
in which R1 and R2 which may be the same or different, are
hydrogen atoms, hydroxyl or amino groups or lower alkyl, lower
alkenyl, optionally N-alkylated lower aminoalkyl, cycloalkyl or
hydroxyalkyl radicals containing from 1 to 8 carbon atoms or
piperidine residues or R1 and R2 together form a divalent al-
kylene radical containing 4 - 7 carbon atoms which can be in-
terrupted by an oxygen or sulphur atom or by an imino, alkyl-
imino or arylimino radical and Z signifies two hydrogen atoms
or a lower alkylidene radical containing 1 to 3 carbon atoms;
and the pharmacologically compatible salts thereof, which com-
prises reacting a reactive derivative of an adenosine-5'-
carboxylic acid of the general formula:
12

<IMG>
in which Z has the same meaning as above, with an amine of
the general formula:
R1.NH.R2
in which R1 and R2 have the same meanings as above, whereafter,
when desired, the product obtained is reacted with a non-toxic
inorganic or organic acid to give an acid-addition salt.
2. Process according to claim 1, wherein said reactive
derivative is a halide, mixed anhydride, imidazolide or ester with
a lower aliphatic or araliphatic alcohol.
3. Process according to claim 2, wherein said reaction
takes place in an inert solvent at ambient temperature or with
slight warming.
4. Process according to claim 3, wherein the reaction
is carried out in a lower aliphatic alcohol.
5. Process according to claim 4, wherein the reaction
is carried out in methanol.
6. Process according to claim 1, wherein the process is
carried out with the use of a large excess of the amine and in
the absence of a solvent.
13

7. Process according to claim 1, wherein said non-toxic
inorganic or organic acid is selected from the group consisting
of hydrochloric acid, sulphuric acid, phosphoric acid, hydro-
bromic acid, acetic acid, lactic acid, citric acid, malic acid,
salicylic acid, malonic acid, maleic acid or succinic acid.
8. Process according to claim 1 for preparing adenosine-
5'-carboxamide which comprises reacting adenosine-5'-carboxylic
acid methyl ester with ammonia.
9. Process according to claim 1 for preparing 2',3'-0-
isopropylidene-adenosine-5'-carboxamide which comprises reacting
2',3'-isopropylidene-adenosine-5'-carboxylic acid methyl ester
or carboxylic acid chloride with ammonia.
10. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-allylamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with allylamine.
11. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-methylamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with methylamine.
12. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-ethylamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with ethylamine.
13. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-(.beta.-hydroxyethyl)-amide which comprises
reacting adenosine-5'-carboxylic acid methyl ester with hydroxy-
ethylamine.
14. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-isopropylamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with isopropylamine.
14

15. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-n-butylamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with butylamine.
16. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-isobutylamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with isobutylamine.
17. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-(2-dimethylaminoethyl)-amide which com-
prises reacting adenosine-5'-carboxylic acid methyl ester with
dimethylaminoethylamine.
18. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-cyclopentylamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with cyclopentylamine.
19. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-cyclohexylamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with cyclohexylamine.
20. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid morpholide which comprises reacting adenosine-
5'-carboxylic acid methyl ester with morpholine.
21. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N,N-pentamethylene-amide which comprises re-
acting adenosine-5'-carboxylic acid methyl ester with piperi-
dine.
22. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N,N-(3-methyl-3-azapentamethylene)-amide
which comprises reacting adenosine-5'-carboxylic acid methyl
ester with N-methyl-piperazine.

23. Process according to claim 1 for preparing adenosine-
5'-hydroxamic acid which comprises reacting adenosine-5'-
carboxylic acid methyl ester with hydroxylamine.
24. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid hydrazide which comprises reacting adenosine-
5'-carboxylic acid methyl ester with hydrazine hydrate.
25. Process according to claim 1 for preparing 2',3'-0-
isopropylidene-adenosine-5'-carboxylic acid N,N-dimethylamide
which comprises reacting 2',3'-0-isopropylidene-adenosine-5'-
carboxylic acid chloride with dimethylamine.
26. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-tert.-butylamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with tert.-butylamine.
27. Process according to claim 1 for preparing adenosine-
5'-carboxylic acid N-piperidinoamide which comprises reacting
adenosine-5'-carboxylic acid methyl ester with N-aminopiperi-
dine.
28. Adenosine-5'-carboxylic acid derivatives of the
general formula:
<IMG>
16

in which R1 and R2 which may be the same or different, are
hydrogen atoms, hydroxyl or amino groups or lower alkyl, lower
alkenyl, optionally N-alkylated lower aminoalkyl, cycloalkyl or
hydroxyalkyl radicals containing from 1 to 8 carbon atoms or
piperidine residues or R1 and R2 together form a divalent al-
kylene radical containing 4 - 7 carbon atoms which can be in-
terrupted by an oxygen or sulphur atom or by an imino, alkyl-
imino or arylimino radical and Z signifies two hydrogen atoms
or a lower alkylidene radical containing 1 to 3 carbon atoms;
and the pharmacologically compatible salts thereof, whenever
prepared by the process of claim 1, 2 or 3 or by an obvious
chemical equivalent.
29. Adenosine-5'-carboxylic acid derivatives of the
general formula:
<IMG>
in which R1 and R2 which may be the same or different, are
hydrogen atoms, hydroxyl or amino groups or lower alkyl, lower
alkenyl, optionally N-alkylated lower aminoalkyl, cycloalkyl or
hydroxyalkyl radicals containing from 1 to 8 carbon atoms or
piperidine residues or R1 and R2 together form a divalent al-
kylene radical containing 4 - 7 carbon atoms which can be in-
terrupted by an oxygen or sulphur atom or by an imino, alkyl-
imino or arylimino radical and Z signifies two hydrogen atoms
17

or a lower alkylidene radical containing 1 to 3 carbon atoms;
and the pharmacologically compatible salts thereof, whenever
prepared by the process of claim 4, 5 or 6 or by an obvious
chemical equivalent.
30. Adenosine-5'-carboxamide whenever prepared by the
process of claim 8 or by an obvious chemical equivalent.
31. 2',3'-0-Isopropylidene-adenosine-5'-carboxamide
whenever prepared by the process of claim 9 or by an obvious
chemical equivalent.
32. Adenosine-5'-carboxylic acid N-allylamide whenever
prepared by the process of claim 10 or by an obvious chemical
equivalent.
33. Adenosine-5' carboxylic acid N-methylamide whenever
prepared by the process of claim 11 or by an obvious chemical
equivalent.
34. Adenosine-5'-carboxylic acid N-ethylamide whenever
prepared by the process of claim 12 or by an obvious chemical
equivalent.
35. Adenosine-5'-carboxylic acid N-(.beta.-hydroxyethyl)-
amide whenever prepared by the process of claim 13 or by an
obvious chemical equivalent.
36. Adenosine-5'-carboxylic acid N-isopropylamide whenever
prepared by the process of claim 14 or by an obvious chemical
equivalent.
37. Adenosine-5'-carboxylic acid N-n-butylamide whenever
prepared by the process of claim 15 or by an obvious chemical
equivalent
18

38. Adenosine-5'-carboxylic acid N-isobutylamide whenever
prepared by the process of claim 16 or by an obvious chemical
equivalent.
39. Adenosine-5'-carboxylic acid N-(2-dimethylaminoethyl)-
amide whenever prepared by the process of claim 17 or by an
obvious chemical equivalent.
40. Adenosine-5'-carboxylic acid N-cyclopentylamide
whenever prepared by the process of claim 18 or by an obvious
chemical equivalent.
41. Adenosine-5'-carboxylic acid N-cyclohexylamide
whenever prepared by the process of claim 19 or by an obvious
chemical equivalent.
42. Adenosine-5'-carboxylic acid morpholide whenever
prepared by the process of claim 20 or by an obvious chemical
equivalent.
43. Adenosine-5'-carboxylic acid N,N-pentamethylene-
amide whenever prepared by the process of claim 21 or by an
obvious chemical equivalent.
44. Adenosine-5'-carboxylic acid N,N-(3-methyl-3-aza-
pentamethylene)-amide whenever prepared by the process of
claim 22 or by an obvious chemical equivalent.
45. Adenosine-5'-hydroxamic acid whenever prepared by
the process of claim 23 or by an obvious chemical equivalent.
46. Adenosine-5'-carboxylic acid hydrazide whenever
prepared by the process of claim 24 or by an obvious chemical
equivalent.
19

47. 2',3'-O-Isopropylidene-adenosine-5'-carboxylic acid
N,N-dimethylamide whenever prepared by the process of claim 25
or by an obvious chemical equivalent.
48. Adenosine-5'-carboxylic acid N-tert.-butylamide
whenever prepared by the process of claim 26 or by an obvious
chemical equivalent.
49. Adenosine-5'-carboxylic acid N-piperidino-amide
whenever prepared by the process of claim 27 or by an obvious
chemical equivalent.

50. A process for preparing an adenosine-5'-carboxamide
of the formula (I):
<IMG>
(I)
wherein Z represents a lower alkylidene radical containing
1 to 3 carbon atoms and R represents NH2, NHR1 or NR1R2,
where R1 and R2 are lower alkyl, which comprises reacting an
acid chloride of adenosine-5'-carboxylic acid of the formula
(II):
(II)
<IMG>
21

with ammonia or an alkylamine of the formula: NH2R1 or
HNR1R2, wherein R1, R2 and Z are as defined above, and recover-
ing the amide from the reaction mixture.
51. A process according to claim 50, for preparing
2',3 -0-isopropylidene adenosine-5'-carboxamide which comprises
reacting 2',3'-0-isopropylidene-adenosine-5'-carboxylic acid
chloride with ammonia.
52. An adenosine-5'-carboxamide of the formula (I):
<IMG> (I)
wherein the radicals R and Z have the meaning specified in
claim 50, whenever prepared by the process defined in claim
50, or an obvious chemical equivalent thereof.
53. 2',3'-0-Isopropylidene adenosine-5'-carboxamide
whenever prepared by the process defined in claim 51, or an
obvious chemical equivalent thereof.
54. A process for preparing an adenosine-5'-carboxamide
for the formula (III):
22

(III)
<IMG>
wherein R1 is hydrogen and R2 is selected from the group con-
sisting of lower alkyl, lower hydroxyalkyl, lower alkenyl
and lower cycloalkyl, which comprises reacting an ester of
adenosine-5'-carboxylic acid, or an acid addition salt thereof
of the formula (IV):
<IMG> (IV)
wherein R is an aliphatic or araliphatic group, with an amine
of the formula
<IMG>
wherein R1 and R2 are as defined above, and recovering the
amide from the reaction mixture.
23

55. A process as claimed in claim 54, wherein a compound
of formula (IV) is reacted with allyl amine.
56. A process as claimed in claim 54, wherein a compound
of formula (IV) is reacted with isopropylamine.
57. A process as claimed in claim 54, wherein a compound
of formula (IV) is reacted with ethanol amine.
58. An adenosine-5'-carboxamide of the formula (III):
<IMG> (III)
wherein the radicals R1 and R2 have the meaning specified
in claim 54, whenever prepared by the process defined in
claim 54, or an obvious chemical equivalent thereof.
59. Adenosine-5'-[(N-allyl)carboxamide] whenever pre-
pared by the process defined in claim 55, or an obvious
chemical equivalent thereof.
60. Adenosine-5'-[(N-isopropyl)carboxamide] whenever pre-
pared by the process defined in claim 56, or an obvious
chemical equivalent thereof.
24

61. Adenosine-5'-[(N-(B-Hydroxyethyl)carboxamide]
whenever prepared by the process defined in claim 57, or an
obvious chemical equivalent thereof.

Description

:; 1077~3~
.
The present invention relates in one aspect thereof
~ to new adenosine-5'-carboxylic acid derivatives and in another
; aspect thereof to the preparation of these derivatives. In a
further aspect~ the present invention relates to new pharmaceu-
tical compositions containing these new derivatives.
The new adenosine-5'-carboxylic acid derivatives
according to one aspect of the present invention are compounds
of the general formula:
,
NH
.- ~N~
N ~ N ~
R ,- (I),
1~ N - C~
.`` ~ Z
, .
~herein Rl and R2, which may be the same or different~ are
; hydrogen atoms~ hydroxyl or amino groups or lower alkyl~ lower
alkenyl~ optionally N-alkylated lower aminoalkyl~ cycloalkyl
or hydroxyalkyl radicals containing from 1 to 8 carbon atoms~
pre~erably from 1 to 6 carbon atoms~ or piperidine residues or
~, R1 and R2 together represent a divalolltalkylene radical con-
;;j taining 4 - 7 carbon atoms~ which can be interrupted by an
oxygen or sulphur atom or by an imino~ alkylimino or arylimino
~ .
radical and Z represents two hydrogen atom~ or a lower alkylidene
radical containing 1 to 3 carbon atoms; and the pharmacologically
, compatible salts thereof.
Applicants have found that the new compounds (I)
according to the present invention exhibit~ surprisingly~ a
~'' very strong circulatory action.
... .
.
.~.,
'

~077931
In accordance with a further aspect of the present
invention~ the new compounds according to the above general
formula I are prepared by reacting a reactive derivative of a
carboxylic acid of the general formula:
NH 2
N~
~ N ~ N
HOOC (II),
~0
)~
~ ~
Z
wherein Z has the same meaning as above~ with an amine of the
general formula:
Rl - NH - R2 (III),
wherein Rl and R2 have the same meaning as above~ whereafter,
when desired, the product obtained is converted into a pharma-
cologically compatible salt.
As reactive derivatives of the acids (II), there
can be used~ for example~ the halides~ mixed anhydrides~ imida-
zolides and~ in particular~ the esters with lower aliphatic or
araliphatic alcohols.
; The adenosine-5'-carboxylic acid esters which are
- pr0~erably used as starting materials~ can be prepared by re-
` acting an adenosine-5'-carboxylic acid of general formula (II)
with a lower aliphatic or araliphatic alcohol under mild condi-
tions and with the addition of dehydrating agents~ for example~
in the presence of a strong mineral acid~ especially concentrated
` sulphuric acid~ as described in copending application serial no.
118 019 filed July 12 1971 in the name of Erich Fauland et
al.
r,~
.....
~. ~

77931
, .
The esteriflcation of adenosine-5'-carboxylic acid
is best carried out at comparatively low temperatures in a
lars~e excess of the alcohol component in the presence of
a catalytic amount of a mineral acid. This also applies
to the case in which an ester is to be transesteri-
fied.
The adenosine-5'-carboxylic acid usea as starting
material has already been described (see J.C S.~ 1963~ p. 115
and Berichte~ 101~ 590/1968).
The reaction of the compounds (II) with the amines
(III) takes place in conventional manner in an inert solvent~
preferably in methanol~ at ambient temperature or with slight
, .
warming. However~ the solvent can also be omitted and the two
;~ reaction components reacted together directl~ in which case
it is expedient to use the amine in comparatively large excess.
The pharmacologically compatible salts can be obtained
in the usual manner~ for example~ by neutralisation of the com-
pounds (I) with non-toxic inorganic or organic acids~ for
~; example~ with hydrochloric acid~ sulphuric acid~ phosphoric
acid~ hydrobromic acid~ acetic acid~ lactic acid~ citric acid~
malic acid~ salicylic acid~ malonic acid~ maleic acid or
~ -
succinic acid.
~he new compounds (I) according to the present inven-
.: .
; tion and the pharmacologically acceptable salts thereof can be
... .
`~ administered enterally or parenterally in admixture ~ith solid
-~; or liquid pharmaceutical diluents or carriers. As injection
. . . ~
medium~ it is preferred to use water~ which contains conven-
~' tional additives for injection solutions~ such as stabilisation
agents~ solubilising agents and/or buffers. Additives of this
. ..:.
~ 30 type include~ for example~ tartrate and citrate buffers~
: ,.
thanol~ complex-forming agents (such as ethylene-diamine-
tetraacetic acid and the non-toxic salts thereof) and high
f~i,. ,
-- 3 --
' .:
. .
~:

1077931
molecular wei~ht polymers (such as liquid polyethyleneoxide)
for the regulation of viscosity. Solid carrier materials in-
clude~ for example~ starch~ lactose~ mannitol~ methyl-cellulose,
talc~ highly~dispersed silicic acid~ high molecular weight fatty
acids (such as stearic acid)~ gelatine~ agar-agar~ calcium
phosphate~ magnesium stearate~ animal and vegetable fats and
solid high molecular weight polymers (such as polyethylene
glycols); compositions suitable for oral administration can~
when desired~ also contain flavouring and/or sweetening agents.
The administration of the compounds according to the present
invention can be carried out in both single and multiple dosages.
More particularly~ the compounds of the present invention canbe ad-
ministered in a wide variety of different ~sage forms at concen-
tration levels ranging from about 0.01 to about 90% by weight
of the total composition, i.e. in amounts which are sufficient
to provide the desired unit dosage.
In dosage unit form~ the compounds as set out herein
are used in amounts of from 0.1 - 50 mg active ingredient per
- dosage unit. Preferably~ the compositions are compounded so
that for parenteral administration 0.5 - 5 mg of active com-
pound/dosage unit is present and for oral administration 2 - 10
. .
` mg of compound/dosage unit.
;ii Having thus generally described the present invention~
reference will now be made to the following examples which
illustrate prefarred embodiments thereof. It will be understood
that various modifications can be made thereto by thoseskilled
~ in the art~ having regard to the foregoing and following
. description.
~ ExamE~e 1.
i 30 Adenoslne-5'-carboxamlde.
.~ ' ', .
" ' '
. .' ~ '

1077931
5 g. adenosine-5'-carboxylic acid methyl ester are
mixed with 100 ml. 25% methanolic ammonia solution. A clear
solution is obtained from which~ after standing for some time~
crystals separate out. There are thus obtained 4.1 g. adenosine-
5'-carboxamide~ which has a melting point of 244 - 245C. After
recrystallisation from water~ this compound has a melting point
of 249 - 250C. The yield is 91% of theory.
The adenosine-5'-carboxylic acid methyl ester used
as starting material is prepared in the following manner:
46 g. adenosine-5'-carbox~?lic acid are introduced
into a mixture of 1.4 litres anhydrous methanol and 15 ml. con-
centrated sulphuric acid and the mixture boiled for 45 minutes.
The slightly cloudy solution is filtered and mixea with a solu-
tion of 27 g. sodium bicarbonate in 1 litre water. A further
500 ml. water are added to the neutralised reaction mixture~
which is then left to stand overnight in a refrigerator to crys-
tallise. The separated crystals are filtered off with suction
:, .
and the product is dried in a vacuum drying cabinet. There are
obtained 47~g. (92% of theory) adenosine-5'-carboxylic acid
20 methyl ester~ which has a melting point of 215 - 217C.
Example 2.
2'~3'-O-IsoE~ Ylidene-adenosin~3=5'-carboxamide.
Variar~t A:
2.5 g. 2' ~3'-O-isopropylidene-adenoside-5'-carboxylic
,
acld methyl ester are suspended in 250 ml. 25% methanolic
ammonia and che reaction mixture stirred for 4 days at ambient
temperature in a glass autoclave. The substance which separates
.:
is filtered off with suction and recrystallised from water.
There is obtained 1.7 g. (60% of theory) 2'~3'-O-isopropylidene-
; 30 adenosine-5'-carboxamide~ which melts~ with decomposition~ at
214 - 216C.
-- 5 _

~ (3 7793~
.
The 2',3'-0-isopropylidene-adenosine-5'-carboxylic
acid methyl ester used as starting material is prepared in the
following manner:
10 g. 2'~3'-0-isopropylidene-adenosine-5'-carboxylic
acid are allowed to react for 4 hours at arnbient temperature
with 0.~ litres anhydrous methanol and 6 ml. concentrated sul-
phuric acid~ whereafter the reaction mixture is neutralised with
sodium bicarbonate and then worked up in the manner described in
Example 1. The 2'~3'-0-isopropylidene-adenosine-5'-carboxylic
acid methyl ester thus obtained has a melting point of 239 -
240C.
Varlant B:
5.5 g. 2'~3'-0-isopropylidene-adenosine-5'-carboxylic
acid chloride are dissolved in 50 ml. 25% methanolic ammonia
and left to stand overnight at ambient temperature. The solvent
is then,distilled off in a vacuum and the residue recrystallised
;` from water. There are obtained 2.4 g~(46% of theory) 2'~3'-0-
iso~ropylidene-adenosine-5'-carboxamide~ which has a melting
..:
poi~t of 216 C.
~ 20 The acid chloride used as starting material is ob-
;- tained in conventional manner from 2'~3'-0-isopropylidene-
adenosine-5'-carboxylic acid b~ heating with thionyl chloride/
i :.
dimethyl formamide. Upon cooling~ the desired compound separates
out from the reaction mixture in crystalline form and~ after
filtering off with suction and washing with anhydrous chloroform
~ .
~ and ether~ can be further reacted directly.
,.
Exa_E~e 3.
Adenosin~ ---car--b--oxyli--c_--acid N-al;~amide.
5 g. adenosine~5'-carboxylic acid methyl ester are
suspended in 150 ml. methanol~ mixed with 15 g. allylamine and
stirred~ while warming~ for 1 hour. The resultant clear solu-
tion is left to stand for 2 days at ambient temperature and the
6 -
,
, . . .
.

~17793~
cryst:alline precipitate thereafter filtered off with suction and
the mother liquor concentrated. The crude product thus obtained
is recrystallised from methanol. There are thus obtained 2.8 g.
(54% of theory) adenosine-5'-carboxylic acid N-allylamide, which
has a melting point of 189 - 190C.
_xamE~e 3A.
Adenos e-5'-c3 boxylic acid N m thYlamid~.
In a manner analogous to that of Example 3 t adenosine-
5'-carboxylic acid methyl ester is reacted ~ith methylamine.
There is thus obtained adenosine-5'-carboxylic acid N-methyl-
amide; m.p. 237 - 238C.; yield 45% of theory.
Example_3B.
Adenosine-5'-carboxvl c_acid N-ethvlami~e.
In a manner analogous to that of Example 3~ adenosine-
5'-carboxylic acid methyl ester is reacted with ethylamine.
There is thus obtained adenosine-5'-carboxylic acid N-ethyl-
amide; m.p. 220 - 222C.; yield 67% of theory.
xam~le 3_.
Adenosine-5'-carboxvllc_3cid_ =(,~ hvdroxy Q hv ~ amide.
In a manner analogous to that of Example 3~ adenosine-
5'~carboxylic acid methyl ester is reacted with hydroxyethyl-
amine~ There is thus obtained adenosine-5'-carboxylic acid
N-(~-hydroxyethyl)-amide; m.p. 198 - 199C; yield 5~/0 of theory.
~x mPle 3D.
.
Aden sine=5'-c?rboxvl_c acid N-isopropylamlde.
In a manner analogous to that of Example 3~ adenosine-
5'-carboxylic acid methyl ester is reacted with isopropylamine.
There is thus obtained adenosine-5'-carboxylic acid N-isopropyl-
amide; m.p. 145 - 147 C; yield 53% of theory.
; 30 xamE~e 3E.
Adenosine-5'~carboxvl c acld _ n-butvlam~g.
:
-- 7 --

~077931
In a manner analo~ous to that of Example 3~ adenoslne-
5'-carboxylic acid methyl ester i.9 reacted with butylamine.
There is thus obtained adenosine-5'-carboxylic acid N-~-butyl-
amj,de; m.p. 109 - 111C.; yield 88% of theory.
Example_3F
Ad nosine-5'-c3 boxvlic,_ac d N-,iobutylam ~_.
In a manner analogous to that of Example 3~ adenosine-
5'-carboxylic acid methyl ester is reacted with isobutylamine.
There is thus obtained adenosine-5'-carboxylic acid N-isobutyl-
amide; m.p. 194 - 196C.;yield 85% of theory.
Exar~ple 3G.
Adenosine-5'=carboxYl c acid N-(2-aimethvlamlnoethvl)-amide.
In a manner analogous to that of Example 3~ adenosine-
5'-carboxylic acid methyl ester is reacted with dimethylamino-
ethylamine. There is thus obtained adenosine-5'-carboxylic
acid N-(2-dimethylaminoethyl)-amide; m.p. 136 - 138 C.; yield
,~ 84% of theory. ~ -
Exam~le_ 0
Adenosine-5'-,ca_boxylic acld_N cvclo~en_Yl_mide.
5 g. adenosine-5'-carboxylic acid methyl ester are
heated for 30 minutes on a steambath~ together with 20 ml. cyclo-
~,:, pentylamine~ a clear solution being obtained. Thereafter~
,, excess amine is distilled off and the residue is washed with
ether and subsequently recrystallised from methanol and iso-
propan,ol. There are thus obtained 2.4 ~. (43% of theory) adeno-
, sine-5'-carboxylic acid N-cyclopentylamide~ which has a melting
point of 201 - 202C.
Exam~le_ A.
Adenosine,-5'=_arboxylic acid_N-c~clohexY~amid,Q.
In a manner analo~ous to that of Example 4~ adenosine-
5'--carboxylic acid methyl ester is reactea with cyclohexylamine.
-- 8 --
:. .
.

~,.~ ` .

~(977931
There is thus obtained adenosine~5'-carboxvlic ac:id N-cyclo-
hexylamide; m.p. 134 - 136C.; yield 50% o~ theory.
Exam le 4B.
Adenosine-5'=carboxyllc acid_morPhol~le-
In a manner analogous -to that of Example 4~ adenosine-
5'-carboxylic acid methyl ester is reacted with morpholine.
There is thus obtained adenosine-5'-carboxylic acid morpholide;
m.p. 248 - 249C.; yield 37% of theory.
Ex3_Ele 4C.
Adenosine-5' carboxylic 3cid N~N=E~n ~methyle_e-amlde.
In a manner analogous to that of Example 4~ adenosine-
5'-carbo~ylic acid methyl ester is reacted with piperidine.
There is thus obtained adenosine-5'-carboxylic acid N~N-penta-
methylene-amide; m.p. 225.- 226 C.; yield 44% of theory.
~xamPle 4D.
- A~en_~ine-5'~c_rboxVlic 3c d N~N-(3_methvl=3=azaPenta~e_hvle e)-
~`I!r amide.
., .
i In a manner analogous to that of Example 4~ adenosine-
, ....
5'-carboxylic acid methyl ester is reacted with N-methyl-
piperazine. There is thus obtained adenosine-5'-carboxylic
acid N~N-(3-methyl-3-azapentamethylene)-amide; m.p.~ 155 - 157C.;
yield 48% of theory.
Exam~e 5.
A~nosine-5'-hvdroxam~c_3~.
5 g. adenosine-5'-carboxylic acid methyl ester in
alcoholic solution are mixed with an excess of hydroxylamine~
briefly heated to 60 C. until a clear solution is obtained and
then~ without additional heating~ stirred or a further 2 hours.
The crystalline precipitate obtained is filtered off with suc-
tion and recrystallised from water. There are thus obtained
~; 4.0 g. adenosine-5'-hydroxamic acid~ which melts~ with decomposi-
tion~ at 224 - 225C. The yield is 83% of theory.
.
.. _ g _
, ;i
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Exam~le 6.
~enosine-5'-carboxYllc-acid h~drazide.
5 g. adenosine-5'-carboxylic acid methyl ester are
suspended in 150 ml. methanol, mixed with 20 ml. hydrazine
hydrate and heated to the boil. The ester thereby goes into
solution~ while~ almost simultaneously7 the hydrazide precipi-
tates out in the form of a fine crystalline material. After
standing overnight~ it is filtered off with suction~ washed
with methanol and dried. There are obtained 4.4. g. adenosine-
5'-carboxylic acid hydrazide~ which melts~ with decomposition~
at 270 - 272C. The yield is 93% of theory. The compound can
be readily recrystallised from hot water.
E mple 7-
2~'-0-IsoPro~vlide e-adenosine-5'-carboxYlic acid N~N-
d me_hvlaml~e.
; 5 g. 2'~3'-0-isoprGpylidene-adenosine-5'-carboxvlic
acid chl~rlde are dissolved in 50 ml. of a 25% solution of
dimethylamine in methanol and left to stand for 1 day at ambient
temperature. Excess amine and methanol are then stripped off
in a vacuum and the residue is dissolved in chloroform and
`~ this solution washed twice with water. The chloroform solution
is dried over anhydrous calcium chloride~ the chloroform is
distilled off and the residue is dried in a vacuum. There are
thus obtained 2.3 g. (44% of theory) 2'~3'-O-isopropylidene-
adenosine-5'-carboxylic acid N~N-dimethylamide in the form of
amorphous~ very glossy flakes. The structure of the product
was confirmed by the mass spectrum.
; Examplg 8
Adenosine-5'-carboxYlic acid N-tert.-butvlamide.
5 ~. adenosine-5'-carboxylic acid methyl ester are
.
heated together with 100 ml. tert.-butylamine on a steambath
- until a clear solution is obtained and thereafter the reaction
1 0
,
. -

1077931
mixture is left to stand for 16 hours at ambient temperature.
Excess tert.-butylarnine is then distilled off and the residue
is mixed with methanol~ again evaporated to dryness and the
solid residue~ after slurrying in cold methanol~ is filtered off
with suction. After recrystallising twice from a little
methanol~ there are obtained 2.15 g. (38~/o of theory) adenosine-
5'-carboxylic acid N-ter_.-but~lamide~ which melts~ ~ith decom-
position, at 279 - 280C.
~ample 9.
.,
/ 10 Aden_sine=5 -carboxvllc_acld~ dino3mlde.
.,
5 g. adenosine-5'-carboxylic acid methyl ester and
25 g. N-aminppiperidine are heated on a steambath for 2 hours.
,~,. .
The reaction mixture is thereafter cooled and the product pre-
..
cipitated ov:t by the addition of 350 ml. ether. The solid pre-
cipitate is filtered off with suction and recrystallised from
methanol. There are thus obtained 2.6 g. (42% of theory)
. . .
adenosine-5'-carboxylic acid N-piperidinoamide~ which has a
melting point of 189 - 191C.
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