Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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.
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61. Adenosine-5'-[(N-(B-Hydroxyethyl)carboxamide]
whenever prepared by the process defined in claim 57, or an
obvious chemical equivalent thereof.