CA2064869A1 - Adenosine derivatives, their production and use - Google Patents
Adenosine derivatives, their production and useInfo
- Publication number
- CA2064869A1 CA2064869A1 CA002064869A CA2064869A CA2064869A1 CA 2064869 A1 CA2064869 A1 CA 2064869A1 CA 002064869 A CA002064869 A CA 002064869A CA 2064869 A CA2064869 A CA 2064869A CA 2064869 A1 CA2064869 A1 CA 2064869A1
- Authority
- CA
- Canada
- Prior art keywords
- carbonate
- ethylamide
- desoxy
- purinyl
- beta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Abstract
Case 100-7677 Abstract:
Adenosin-2',3'-carbonates of formula I
wherein R1. R2, R3 and X are defined in claim 1, their mode of preparation and their use for the treatment of raised blood pressure, for protection against cardiac insufficiency, for peripheral and coronary vasodilation, for reducing thrombosis, for protecting the vascular endothelium, for lowering the blood lipid level, for improving glucose tolerance and lowering the plasma insulin level, for the treatment of arrhythmia, for the treatment of claudicatio intermittens and the Raynaud's disease.
Adenosin-2',3'-carbonates of formula I
wherein R1. R2, R3 and X are defined in claim 1, their mode of preparation and their use for the treatment of raised blood pressure, for protection against cardiac insufficiency, for peripheral and coronary vasodilation, for reducing thrombosis, for protecting the vascular endothelium, for lowering the blood lipid level, for improving glucose tolerance and lowering the plasma insulin level, for the treatment of arrhythmia, for the treatment of claudicatio intermittens and the Raynaud's disease.
Description
2 ~ 3 NE~ ADENOSI~ DERIV~T~ T9BIR PRODUCTIO~ ~ND US~
The invention relates to new adenosine-2',3'-carbonates, processes for their production and their use, among other thing~, for ~he treatment of raised blood pressure.
The invention relates in particular to compounds of formula ~R,~
HtJ
R3 ~ \J
/
~1 o o c wherein Rl signifies (C1_6)alkyl, (C3_8)cycloalkyl, phenyl or phenyl(C1_6)alkyl? whereby the phenyl rings, independe~tly of one another, may be optionally mono- or di-substituted by halogen with an atomic number of 9 to 35, (Cl_4)alkyl, (Cl_4)alkoxy and/or CF3, and in the case of phenylalkyl, the . ` , ' :
.`: ; ' ' '. ' . -`` 2 ~
alkylene ch~in is straight-chain or branched, Rz denotes hydrogen, (C1_4)alkyl, halogen with an ato~ic number of 9 to 35, or (C3_8)cycloalkyl, R3 denotes groups of formulae -C~zO~ or -CONHR4, wherein R4 signifies hydrogen, (C1_6)alkyl or (C3_8)cycloalkyl, and X is O or S
,with the proviso when R2 signifies hydrogen or halogen with an atomic number of 9 to R3 signifies the group of formula -CON~ (Cl_6)alkyl and X - O
then R1 doe~ not signify (C1_6)alkyl Of the compounds of formula I, preferred compounds possess the formula ~ R~ `
~N
N ~ I~
~ ;' O O
wherein X
R1~ signifies p-methoxyphenyl, p-chlorophenyl, R2R signifies hydrogen or methyl and R3a signifies CONH (Cl_4)alkyl, and X signifies O or S.
.: - - ~ : . . .
: ` , - . , ~ 1 0 ~ 9 In formula I~ halogen with an atomic number of 9-35 is fluorine, chlorine or bromine, preferably fluorine or chlorine, a (Cl_4)-alkyl group is methyl, ethyl, n propyl, i-propyl9 n-butyl, i-butyl, tert.-butyl, and where the alkyl group has up to 6 carbon atoms, it is also n-pentyl, i-pentyl, 3-pentyl, n-hexyl, i-hexyl, etc., especially methyl, ethyl, isopropyl or 3-pentyl, a (Cl_4)alkoxy group i3 methoxy, ethoxy, n-propoxy, i-propoxy, n-buto~y, i-butoxy, tert.-butoxy, especially methoxy, (C3_a)-cycloalkyl signifies cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, especially cyclopsntyl or cyclohexyl. Substitution of the phenyl ring may be made in o-, m-or p-position, ~hereby in the case of disubstitution, substitution is preferably made in m- and p-position and in the case of monosubstitution, ~t is made in m- or p-position, but preferably in p-position. In phenylalkyl~ the alkylene chain and the phenyl substitution are as discussed above.
Certain adenosine carbonatec are already disclosed in US-Patent 4167565. The instant application is limited therefrom. The known adenosine carbonates are of a different use however they serve for controlling undesired ani~als including rodents, coyotes and birds.
Production of compounds of formula I, wherein R3 is a group of formula -C~20H, may be effected for example, whereby the protecting group is cleaved from compounds of formula 2 ~
_ 4 _ 100-7677 . HN
y ~ N~
R~L N N
D~0 ~ II
O O :~:
y ~.
wherein Rl, R2 and X are defined as above, and D~T is the 4,4'-dimethoxytrityl protecting group.
Cleavage of the 4,4'-dimethoxytrityl protectin~ group conveniently takes place in an acidic medium, for example in 80% ~.
acetic acid, at room temperature for 6 hours whilst stirring. ~`! `
Further agents which can be used instead of acetic acid are aqueous hydrochloric acid or aqueou9 for~ic acid.
Production of compound~ of ~ormula I9 wherein R3 is the group ;
-CONHR4 ~ iS effected by introducing the group C ~ X uherein X is defined as above, into compound of formula , .1 .
.~ '' . .
; ' `: ' . -- .
~,:
.
2 ~
hN
N~
o ~/ III
H0 o~
wherein Rl, R2 and R4 are defined as aboYe.
\
Introduction of ~he C - X
group into compounds of formula III conveniently takes place by reacting them with for example 1,1'-carbonyl- resp. 1,1'-thio-carbonyl-diimidazole in a solvent such a~ dimethylformamide whilst stirring for 5 hours at room temperature.
The compounds of formula III are known, i.or example irom German published application 3810551.
Production of the compounds of formula II may be effected for example whereby the 4,4'-dimethoxytrityl protectin~ group i9 introduced into compounds of formula a R~ N~) IV
HO--~
. . . ~ . . .. . .
'. ' ~ : ' ~ - ' :
. ~' ,' . . ' ...
-, . ': , , : :.
' ' ' ' . , 2 ~
wherein R~ is defined a~ above. This is effected by means of a reaction with 4,4'-dimethoxytrityl chloride in dimethylforma~ide at room temperaeure. The compounds of formula Cl R~
thereby formed, wherein R~ and DMT are defined as above, are reacted with a compound of formula Rl-N~29 wherein Rl is defined as above, in a solvent such as dioxane at: boiling temperature of the reaction mixture, and then the group C Y X, wherein X is defined as above, is introduced into the compounds of formula ~aO
R~J~N ~ N~ VI
~<~ y ~:
\~ " ~
: H O ~ ~ ~
' ~ . . ! . .
''`'''~. ' ~ "' ' ~' ' ,' '' --: . , . ~ , ' ': ' ' ~
' . ' ~, . , , . " . ' ' 2 ~
thereby formed, wherein R1, R2 and DMT are defined as above.
Introduction of the C = X group into compound of formula VI conveniently takes place by m2ans of a reaction with for example 1,1'-carbonyl- resp. 1~1'-thiocarbonyl-diimidazole in a solvent such as dimethylformamide whilst stirring for 5 hours at room temperature.
Insofar as the production of the required ~tarting materialQ is not described, these are known or may be produced by known processes resp. analogously to the processes described here or analogously to known processes.
In the following examples, all temperatures are given in degrees celsius and are uncorrected.
~ .
:
. ~ ~ . , .: .
~.. . ..
2 ~ g ~
~xample 1 1'-de~oxy-1'-(6-p-methoxyphenylamino-2-meth~l-9-~rinyl)-~-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 2.14 g of 1'-desoxy-1'-(6-p-methoxyphenylamino-2-methyl-9-purinyl~ D-ribofuranuronic acld-N-ethylamide and 3.0 g of 1,1'-carbonyldiimidazole are dissolved in 15 ml of dimethylformamide and stirred for 5 hours at room temperature. The solution is subsequently concentrated at reduced pressure and the residue is partitioned ~etween ethyl acetate and water. After drying over sodium sulphate, the organic phase is purified on silica gel. The compound named in the title is crystallized from ethyl acetate and diethyl ether. M.p. 168-170~.
Examplc 2 6-cyclohexy~adenosine-2',3'-carbonate 4.2 g of 6-cyclohexyl-5'-(4,4'-dimethoxy~rityl)-adenosine-2',3'-carbonate are dissolved in 21 ml of 80% acetic acid and stirred for 6 hours at room temperature. The solution is subsequently concentrated at 40 in a high vacuum, the residue i9 taken up in ethyl acetate and ad~usted to pa 8 with a~ lOX sodlum hydrogen carbonate solution whilst cooling. The aqueous phase i shaken out three times with ethyl acetate, and the combined organic `
extracts are dried over sodium sulphate. The product i9 purified by elution on silica gel wlth a mixture of ethyl acetate/n-hexane 8:2.
The compound named in the title is crystallized from ethyl acetate~diethyl ester. M.p. 152-154~.
The 6-cyclohexy1-5'-(4,4'-dimethoxytrityl)-adenosine-2'93'-carbonate used as starting material may be produced e.g. as ~ollows:
:` .
, ::; ' '' ' . :. :
: ~
_ 9 _ 105-7677 a) To a solution of 9.17 e of 6-chloropurine-9-~-ribofuranoside and 5.6 ml of triethylamine in 96 ml of dimethylformamide i~
added in drops at room tempe~aeure a solution of 14 g of 4,4'-dimethoxytrityl chloride in 96 ml of dimethylformamide, and the mixeure is stirred for 1 hour at room temperature.
The solvent is then distilled off in a high vacuum at 35 and the residue is partitioned between ethyl aceeate and ice water. The organic extracts are dried over sodium sulphate, concentrated and the residue is eluted on silica gel with a mixture of ethyl acetate~hexane 8:2.
The purified 6-chloro-5'-(4,4'-dimethoxytrityl)-adenosine is obtained as a foam and in ethyl acetate has a Rf-valu2 of 0.6.
b) 5 g of 6-chloro-5'-(4,4'-dlmethoxytrityl)-adenosine and 2.95 ml of cyclohexylamine in 30 ml of dioxane are stirred for 2 hours in an oil bath o~ 105. It is subsequently cooled, filtered, and the filtrate i9 concentrated at reduced pressure. The residue is dissolved in ethyl acetate and shaken out with cold 0.1 N hydrochloric acid. Afeer washing with water and drying over sodium sulphate, the organic phase is concentrated and eluted on silica gel with ethyl acet~te/-; hexane 8:2. The resultlng 6-cyclohexyl-5'-(4,4'-dimethoxy-trityl)-adenosine is a foam, and in ethyl acetate ha~ a RF-value of 0.5.
c) 4.6 g of 6-cyclohexy1-5'-(4,4'-dimethoxytrityl)-adenosine and 4.46 g of 1,1'-carbonyldiimidazole in 30 ml of dimethyl-formamide are stirred for 1 hour at room temperature. The solvent is subsequently distilled off at 35 in a high vacuum, and the residue is partitioned bet~een ethyl acetate and ice water. The aqueou~ phase is extracted three times with ethyl acetate a~d the organic extracts are dried over sodium sulphate. After concentration, the residue is ., :
':
~.
'-., : , -:' ~ 3 chromatographed on silica gel with a m~xture of e~hyl ac~tate/hexane 8:2. The 6-cyclohexyl-5'-~4,4'-dimethoxy-trityl)-adenosine-2',3'-carbonate is a foam, and in ethyl acetate has a R~-value of 0.8.
The following compounds of formula I may be produced using the process described in examples 1 (R3 _ CONHR4 ) or 2 (R3 =
CH2-OH):
Exa~ple R~ R2 R3 ~ ~.p.
- :, 3 cyclopentyl Me CON~B~ O amorph.
4 cyclopentyl H CON~Bt O 106-110 ; 5 cyclohexyl H CON~Et O 112-115 6 p-methoxyphenyl ~ CONHBt O 120-124 7 phenyl H CON~E~ O 126-130 8 p-fluorophenyl H CON~Et O 122-126 9 p-chlorophenyl 8 CONHEt O 130-135 cyclohexyl Me CON~Bt O 185-187 :
11 phenyl Me CON~Xt O 116-121 12 p-fluorophenyl Me CON B t O 115-118 13 p-chlorophenyl Me CON~t O 119-124 14 p-meeho~yphenyl Me CON~t S 149-151 `
p-methoxyphenyl H CONH~t S 125-128 16 p-chlorophenyl Me CONHRt S 131-136 17 p-fluorophenyl Me CON~t S 12S-130 18 p-methoxyphenyl ~ CH20H 0 121-123 19 p-chlorophenyl H CH20H 0 110-114 20 3-pentyl H CH20~ 0 156-159 . ~. .
:
2 ~
~ 100-7677 Th~ compounds according to the invention are notable for their interesting pharamacological properties. They may therefore be used as medicaments.
In particular, the compounds according to the invention possess anti-hypertensive activity, as can be deduced from the results of the following trials:
Measurement of the binding to adenosine A1 and A2 receptor~ in membranes from the rat's cortex or from the cortex or striatum of the pig's brain, using the method of R.F. BRUNS, G.~. LU and T.A. PUGSL~Y, which is described in MOL~C. PHAR~ACQL. 29, 331-346 (1986). Further testing of the activity of the compounds according to the invention on the isolated, perfused rat's kidneys for the following parmeters:
- renin secretion, - renal haemodynamics - Inhibition of the release of noradrenaline from the nerve endings following electro-stimulatioln of the renal nerves accordin to the method of ~.J. Schurek, J.P. ~recht~
H. Lohfert and K. ~ierholzer, described in CO~MUNICATION a la R~UNION de l'ASSOCIATION DES P~ARMACOLOGISTES LO W AI~ UCL 4th June 1977, as well as P.M. Vanhoutte, D. Browning, ~. Coen, T.J. Verbeuren, L. Zonnekeyen and M.G. Collins described in ~YPERTENSION 4, 251-256 (1982).
- Measurement of blood pr~ssure, heart rate, urine production ; and renin activity in plasma of wake, NaCl-depleted and repleted, normotensive or spontaneously hyperten~ive rats with catheters implanted in the abdominal aorta and in the vena cava, followlng i.v. administration or administration of :
~, ' ' ' ~
~ ~ ;
the compounds according to the invention as an infusion or bolus according to the method of J.F.M. Smits and J.M. Brody described in Am. J. Physiol. 247, Rl 003-R1 008 (1984).
It can be deduced from the results of the examinations that both the inhibition of renin s~cr~tion and release of noradrenaline from nerve endings, and the direct vasodilation, take part in the anti-hypertensive activity of the compound~ according to the invention. It results from this that the compounds according to the invention can not only bc used as antihypertensive agents but they also possess protective effect against cardiac insufficiency. They are reducin~ the work load of the heart by reduction of the afterload due to inhibition of renin secretion and release of neurotransmitters. Further the cardiac metabolism ~
is improved by coronary vasodilation. ~oth the quality and the -duration of life are increased by treatment with compounds of the invention. Being peripheral vasodilators the compounds of the invention are widening the blood vessels directly,they are increasing the supply of blood and consequently the oxygen supply of the tissue. Especially this increase of the nutrive blood supply has consequences on the lschaemic skeleton muscle. For the compounds of the invention there is a potential for the treatmen~
of peripheral vaseular diseases like claudicatio intermittens and the Raynaud's disease. Further the coronary vasodilation leads to the suppression or improvement of myocardial lschae~ia and consequently of angina pectoris. The compounds of the invention have activity in the treatment of arrhythmia.
Being adenosine A1-receptor agonists they lead to a normal sinus rhythm at supraventricular and ~-adrenergic stimulated ventricular tachycardias. The co~pounds of the invention possess fureher a neuroprotective activity. Accordingly they can be used for the prophylaxis of peripheral vascular diseases ~hich are accompanied by neuronal degeneration. They reduce further the .... .
:
formation of thrombi by inhibition of the aggre ation of thrombocytes and protect the vascular endo~helium by inhibition of the activation of leucocytes. The compounds of the invention are lowering the plasma insulin level ~1thout influencing the glucose tolerance. They are potentiating the uptake of glucose in the fatty tlssue. This insulin saving ~ctivity can be used for the treatment of typ II diabetes. They further reduce the blood lipid level, an activity that may influence positively arteriosclerosis, the reason o~ many cardiovascular diseases.
For the above indications, of the compoundc according to the invention, the compounds of examples 1, 6, 9, 12 and 14, especially the compound of example 1, are preferred.
For the above application, the dosage to be used varies according to the substance used, the type of admini9tration and the desired treatment. In general, however, satisfactory results are obtained with a daily dosage of approximately 0.01 to 10 mg per kg body weight; if necessary, administration may be effected in 2 to 4 portions or even in sustained release form. For larger mammals, the daily dosage lies ln the range of approximately 1 to 500 mg;
suitable dosage forms for e.g. oral or non-oral administration generally ~ontain about 5 to 2S0 mg of a compound of formula I
toge~her with solid or liquid carrier substances.
The compounds according to the invention may be administered alone or in suitable dosaging forms. The medicinal form, e.g. a solution or a tablet, can be produced analogously to known methods.
- .
, ~ ' , . .:
.
~ 53 The invention therefore also relates to medicaments which contain the compounds according to the invention in free form or in the form of ~heir physiologically acceptable salts, as well as the production of these medicaments in known manner. The assistants and carrier substances which are usual in pharmacy may be used for their preparation.
. . '' ..' i . , ,~
', ' ' :
The invention relates to new adenosine-2',3'-carbonates, processes for their production and their use, among other thing~, for ~he treatment of raised blood pressure.
The invention relates in particular to compounds of formula ~R,~
HtJ
R3 ~ \J
/
~1 o o c wherein Rl signifies (C1_6)alkyl, (C3_8)cycloalkyl, phenyl or phenyl(C1_6)alkyl? whereby the phenyl rings, independe~tly of one another, may be optionally mono- or di-substituted by halogen with an atomic number of 9 to 35, (Cl_4)alkyl, (Cl_4)alkoxy and/or CF3, and in the case of phenylalkyl, the . ` , ' :
.`: ; ' ' '. ' . -`` 2 ~
alkylene ch~in is straight-chain or branched, Rz denotes hydrogen, (C1_4)alkyl, halogen with an ato~ic number of 9 to 35, or (C3_8)cycloalkyl, R3 denotes groups of formulae -C~zO~ or -CONHR4, wherein R4 signifies hydrogen, (C1_6)alkyl or (C3_8)cycloalkyl, and X is O or S
,with the proviso when R2 signifies hydrogen or halogen with an atomic number of 9 to R3 signifies the group of formula -CON~ (Cl_6)alkyl and X - O
then R1 doe~ not signify (C1_6)alkyl Of the compounds of formula I, preferred compounds possess the formula ~ R~ `
~N
N ~ I~
~ ;' O O
wherein X
R1~ signifies p-methoxyphenyl, p-chlorophenyl, R2R signifies hydrogen or methyl and R3a signifies CONH (Cl_4)alkyl, and X signifies O or S.
.: - - ~ : . . .
: ` , - . , ~ 1 0 ~ 9 In formula I~ halogen with an atomic number of 9-35 is fluorine, chlorine or bromine, preferably fluorine or chlorine, a (Cl_4)-alkyl group is methyl, ethyl, n propyl, i-propyl9 n-butyl, i-butyl, tert.-butyl, and where the alkyl group has up to 6 carbon atoms, it is also n-pentyl, i-pentyl, 3-pentyl, n-hexyl, i-hexyl, etc., especially methyl, ethyl, isopropyl or 3-pentyl, a (Cl_4)alkoxy group i3 methoxy, ethoxy, n-propoxy, i-propoxy, n-buto~y, i-butoxy, tert.-butoxy, especially methoxy, (C3_a)-cycloalkyl signifies cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, especially cyclopsntyl or cyclohexyl. Substitution of the phenyl ring may be made in o-, m-or p-position, ~hereby in the case of disubstitution, substitution is preferably made in m- and p-position and in the case of monosubstitution, ~t is made in m- or p-position, but preferably in p-position. In phenylalkyl~ the alkylene chain and the phenyl substitution are as discussed above.
Certain adenosine carbonatec are already disclosed in US-Patent 4167565. The instant application is limited therefrom. The known adenosine carbonates are of a different use however they serve for controlling undesired ani~als including rodents, coyotes and birds.
Production of compounds of formula I, wherein R3 is a group of formula -C~20H, may be effected for example, whereby the protecting group is cleaved from compounds of formula 2 ~
_ 4 _ 100-7677 . HN
y ~ N~
R~L N N
D~0 ~ II
O O :~:
y ~.
wherein Rl, R2 and X are defined as above, and D~T is the 4,4'-dimethoxytrityl protecting group.
Cleavage of the 4,4'-dimethoxytrityl protectin~ group conveniently takes place in an acidic medium, for example in 80% ~.
acetic acid, at room temperature for 6 hours whilst stirring. ~`! `
Further agents which can be used instead of acetic acid are aqueous hydrochloric acid or aqueou9 for~ic acid.
Production of compound~ of ~ormula I9 wherein R3 is the group ;
-CONHR4 ~ iS effected by introducing the group C ~ X uherein X is defined as above, into compound of formula , .1 .
.~ '' . .
; ' `: ' . -- .
~,:
.
2 ~
hN
N~
o ~/ III
H0 o~
wherein Rl, R2 and R4 are defined as aboYe.
\
Introduction of ~he C - X
group into compounds of formula III conveniently takes place by reacting them with for example 1,1'-carbonyl- resp. 1,1'-thio-carbonyl-diimidazole in a solvent such a~ dimethylformamide whilst stirring for 5 hours at room temperature.
The compounds of formula III are known, i.or example irom German published application 3810551.
Production of the compounds of formula II may be effected for example whereby the 4,4'-dimethoxytrityl protectin~ group i9 introduced into compounds of formula a R~ N~) IV
HO--~
. . . ~ . . .. . .
'. ' ~ : ' ~ - ' :
. ~' ,' . . ' ...
-, . ': , , : :.
' ' ' ' . , 2 ~
wherein R~ is defined a~ above. This is effected by means of a reaction with 4,4'-dimethoxytrityl chloride in dimethylforma~ide at room temperaeure. The compounds of formula Cl R~
thereby formed, wherein R~ and DMT are defined as above, are reacted with a compound of formula Rl-N~29 wherein Rl is defined as above, in a solvent such as dioxane at: boiling temperature of the reaction mixture, and then the group C Y X, wherein X is defined as above, is introduced into the compounds of formula ~aO
R~J~N ~ N~ VI
~<~ y ~:
\~ " ~
: H O ~ ~ ~
' ~ . . ! . .
''`'''~. ' ~ "' ' ~' ' ,' '' --: . , . ~ , ' ': ' ' ~
' . ' ~, . , , . " . ' ' 2 ~
thereby formed, wherein R1, R2 and DMT are defined as above.
Introduction of the C = X group into compound of formula VI conveniently takes place by m2ans of a reaction with for example 1,1'-carbonyl- resp. 1~1'-thiocarbonyl-diimidazole in a solvent such as dimethylformamide whilst stirring for 5 hours at room temperature.
Insofar as the production of the required ~tarting materialQ is not described, these are known or may be produced by known processes resp. analogously to the processes described here or analogously to known processes.
In the following examples, all temperatures are given in degrees celsius and are uncorrected.
~ .
:
. ~ ~ . , .: .
~.. . ..
2 ~ g ~
~xample 1 1'-de~oxy-1'-(6-p-methoxyphenylamino-2-meth~l-9-~rinyl)-~-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 2.14 g of 1'-desoxy-1'-(6-p-methoxyphenylamino-2-methyl-9-purinyl~ D-ribofuranuronic acld-N-ethylamide and 3.0 g of 1,1'-carbonyldiimidazole are dissolved in 15 ml of dimethylformamide and stirred for 5 hours at room temperature. The solution is subsequently concentrated at reduced pressure and the residue is partitioned ~etween ethyl acetate and water. After drying over sodium sulphate, the organic phase is purified on silica gel. The compound named in the title is crystallized from ethyl acetate and diethyl ether. M.p. 168-170~.
Examplc 2 6-cyclohexy~adenosine-2',3'-carbonate 4.2 g of 6-cyclohexyl-5'-(4,4'-dimethoxy~rityl)-adenosine-2',3'-carbonate are dissolved in 21 ml of 80% acetic acid and stirred for 6 hours at room temperature. The solution is subsequently concentrated at 40 in a high vacuum, the residue i9 taken up in ethyl acetate and ad~usted to pa 8 with a~ lOX sodlum hydrogen carbonate solution whilst cooling. The aqueous phase i shaken out three times with ethyl acetate, and the combined organic `
extracts are dried over sodium sulphate. The product i9 purified by elution on silica gel wlth a mixture of ethyl acetate/n-hexane 8:2.
The compound named in the title is crystallized from ethyl acetate~diethyl ester. M.p. 152-154~.
The 6-cyclohexy1-5'-(4,4'-dimethoxytrityl)-adenosine-2'93'-carbonate used as starting material may be produced e.g. as ~ollows:
:` .
, ::; ' '' ' . :. :
: ~
_ 9 _ 105-7677 a) To a solution of 9.17 e of 6-chloropurine-9-~-ribofuranoside and 5.6 ml of triethylamine in 96 ml of dimethylformamide i~
added in drops at room tempe~aeure a solution of 14 g of 4,4'-dimethoxytrityl chloride in 96 ml of dimethylformamide, and the mixeure is stirred for 1 hour at room temperature.
The solvent is then distilled off in a high vacuum at 35 and the residue is partitioned between ethyl aceeate and ice water. The organic extracts are dried over sodium sulphate, concentrated and the residue is eluted on silica gel with a mixture of ethyl acetate~hexane 8:2.
The purified 6-chloro-5'-(4,4'-dimethoxytrityl)-adenosine is obtained as a foam and in ethyl acetate has a Rf-valu2 of 0.6.
b) 5 g of 6-chloro-5'-(4,4'-dlmethoxytrityl)-adenosine and 2.95 ml of cyclohexylamine in 30 ml of dioxane are stirred for 2 hours in an oil bath o~ 105. It is subsequently cooled, filtered, and the filtrate i9 concentrated at reduced pressure. The residue is dissolved in ethyl acetate and shaken out with cold 0.1 N hydrochloric acid. Afeer washing with water and drying over sodium sulphate, the organic phase is concentrated and eluted on silica gel with ethyl acet~te/-; hexane 8:2. The resultlng 6-cyclohexyl-5'-(4,4'-dimethoxy-trityl)-adenosine is a foam, and in ethyl acetate ha~ a RF-value of 0.5.
c) 4.6 g of 6-cyclohexy1-5'-(4,4'-dimethoxytrityl)-adenosine and 4.46 g of 1,1'-carbonyldiimidazole in 30 ml of dimethyl-formamide are stirred for 1 hour at room temperature. The solvent is subsequently distilled off at 35 in a high vacuum, and the residue is partitioned bet~een ethyl acetate and ice water. The aqueou~ phase is extracted three times with ethyl acetate a~d the organic extracts are dried over sodium sulphate. After concentration, the residue is ., :
':
~.
'-., : , -:' ~ 3 chromatographed on silica gel with a m~xture of e~hyl ac~tate/hexane 8:2. The 6-cyclohexyl-5'-~4,4'-dimethoxy-trityl)-adenosine-2',3'-carbonate is a foam, and in ethyl acetate has a R~-value of 0.8.
The following compounds of formula I may be produced using the process described in examples 1 (R3 _ CONHR4 ) or 2 (R3 =
CH2-OH):
Exa~ple R~ R2 R3 ~ ~.p.
- :, 3 cyclopentyl Me CON~B~ O amorph.
4 cyclopentyl H CON~Bt O 106-110 ; 5 cyclohexyl H CON~Et O 112-115 6 p-methoxyphenyl ~ CONHBt O 120-124 7 phenyl H CON~E~ O 126-130 8 p-fluorophenyl H CON~Et O 122-126 9 p-chlorophenyl 8 CONHEt O 130-135 cyclohexyl Me CON~Bt O 185-187 :
11 phenyl Me CON~Xt O 116-121 12 p-fluorophenyl Me CON B t O 115-118 13 p-chlorophenyl Me CON~t O 119-124 14 p-meeho~yphenyl Me CON~t S 149-151 `
p-methoxyphenyl H CONH~t S 125-128 16 p-chlorophenyl Me CONHRt S 131-136 17 p-fluorophenyl Me CON~t S 12S-130 18 p-methoxyphenyl ~ CH20H 0 121-123 19 p-chlorophenyl H CH20H 0 110-114 20 3-pentyl H CH20~ 0 156-159 . ~. .
:
2 ~
~ 100-7677 Th~ compounds according to the invention are notable for their interesting pharamacological properties. They may therefore be used as medicaments.
In particular, the compounds according to the invention possess anti-hypertensive activity, as can be deduced from the results of the following trials:
Measurement of the binding to adenosine A1 and A2 receptor~ in membranes from the rat's cortex or from the cortex or striatum of the pig's brain, using the method of R.F. BRUNS, G.~. LU and T.A. PUGSL~Y, which is described in MOL~C. PHAR~ACQL. 29, 331-346 (1986). Further testing of the activity of the compounds according to the invention on the isolated, perfused rat's kidneys for the following parmeters:
- renin secretion, - renal haemodynamics - Inhibition of the release of noradrenaline from the nerve endings following electro-stimulatioln of the renal nerves accordin to the method of ~.J. Schurek, J.P. ~recht~
H. Lohfert and K. ~ierholzer, described in CO~MUNICATION a la R~UNION de l'ASSOCIATION DES P~ARMACOLOGISTES LO W AI~ UCL 4th June 1977, as well as P.M. Vanhoutte, D. Browning, ~. Coen, T.J. Verbeuren, L. Zonnekeyen and M.G. Collins described in ~YPERTENSION 4, 251-256 (1982).
- Measurement of blood pr~ssure, heart rate, urine production ; and renin activity in plasma of wake, NaCl-depleted and repleted, normotensive or spontaneously hyperten~ive rats with catheters implanted in the abdominal aorta and in the vena cava, followlng i.v. administration or administration of :
~, ' ' ' ~
~ ~ ;
the compounds according to the invention as an infusion or bolus according to the method of J.F.M. Smits and J.M. Brody described in Am. J. Physiol. 247, Rl 003-R1 008 (1984).
It can be deduced from the results of the examinations that both the inhibition of renin s~cr~tion and release of noradrenaline from nerve endings, and the direct vasodilation, take part in the anti-hypertensive activity of the compound~ according to the invention. It results from this that the compounds according to the invention can not only bc used as antihypertensive agents but they also possess protective effect against cardiac insufficiency. They are reducin~ the work load of the heart by reduction of the afterload due to inhibition of renin secretion and release of neurotransmitters. Further the cardiac metabolism ~
is improved by coronary vasodilation. ~oth the quality and the -duration of life are increased by treatment with compounds of the invention. Being peripheral vasodilators the compounds of the invention are widening the blood vessels directly,they are increasing the supply of blood and consequently the oxygen supply of the tissue. Especially this increase of the nutrive blood supply has consequences on the lschaemic skeleton muscle. For the compounds of the invention there is a potential for the treatmen~
of peripheral vaseular diseases like claudicatio intermittens and the Raynaud's disease. Further the coronary vasodilation leads to the suppression or improvement of myocardial lschae~ia and consequently of angina pectoris. The compounds of the invention have activity in the treatment of arrhythmia.
Being adenosine A1-receptor agonists they lead to a normal sinus rhythm at supraventricular and ~-adrenergic stimulated ventricular tachycardias. The co~pounds of the invention possess fureher a neuroprotective activity. Accordingly they can be used for the prophylaxis of peripheral vascular diseases ~hich are accompanied by neuronal degeneration. They reduce further the .... .
:
formation of thrombi by inhibition of the aggre ation of thrombocytes and protect the vascular endo~helium by inhibition of the activation of leucocytes. The compounds of the invention are lowering the plasma insulin level ~1thout influencing the glucose tolerance. They are potentiating the uptake of glucose in the fatty tlssue. This insulin saving ~ctivity can be used for the treatment of typ II diabetes. They further reduce the blood lipid level, an activity that may influence positively arteriosclerosis, the reason o~ many cardiovascular diseases.
For the above indications, of the compoundc according to the invention, the compounds of examples 1, 6, 9, 12 and 14, especially the compound of example 1, are preferred.
For the above application, the dosage to be used varies according to the substance used, the type of admini9tration and the desired treatment. In general, however, satisfactory results are obtained with a daily dosage of approximately 0.01 to 10 mg per kg body weight; if necessary, administration may be effected in 2 to 4 portions or even in sustained release form. For larger mammals, the daily dosage lies ln the range of approximately 1 to 500 mg;
suitable dosage forms for e.g. oral or non-oral administration generally ~ontain about 5 to 2S0 mg of a compound of formula I
toge~her with solid or liquid carrier substances.
The compounds according to the invention may be administered alone or in suitable dosaging forms. The medicinal form, e.g. a solution or a tablet, can be produced analogously to known methods.
- .
, ~ ' , . .:
.
~ 53 The invention therefore also relates to medicaments which contain the compounds according to the invention in free form or in the form of ~heir physiologically acceptable salts, as well as the production of these medicaments in known manner. The assistants and carrier substances which are usual in pharmacy may be used for their preparation.
. . '' ..' i . , ,~
', ' ' :
Claims (8)
1. Adenosine-2',3'-carbonates of formula I
wherein R1 signifies (C1-6) alkyl, (C3-8)cycloalkyl, phenyl or phenyl(C1-6)alkyl, whereby the phenyl rings, independently of one another, may be optionally mono- or di-substituted by halogen with an atomic number of 9 to 35, (C1-4)alkyl, (C1-4)alkoxy and/or CF3, and in the case of phenylalkyl, the alkylene chain is straight-chain or branched, R2 denotes hydrogen, (C1-4)alkyl, haloglen with an atomic number of 9 to 35, or (C3-8)cycloalkyl, R3 denotes groups of formulae -CH2OH or -CONHR4, wherein R4 signifies hydrogen, (C1-6)alkyl or (C3-8cycloalkyl, and X is O or S
with the proviso when R2 signifies hydrogen or halogen with an atomic number of 9 to R3 signifies the group of formula -CONH (C1-6)alkyl and X = O
then R1 does not signify (C1-6)alkyl
wherein R1 signifies (C1-6) alkyl, (C3-8)cycloalkyl, phenyl or phenyl(C1-6)alkyl, whereby the phenyl rings, independently of one another, may be optionally mono- or di-substituted by halogen with an atomic number of 9 to 35, (C1-4)alkyl, (C1-4)alkoxy and/or CF3, and in the case of phenylalkyl, the alkylene chain is straight-chain or branched, R2 denotes hydrogen, (C1-4)alkyl, haloglen with an atomic number of 9 to 35, or (C3-8)cycloalkyl, R3 denotes groups of formulae -CH2OH or -CONHR4, wherein R4 signifies hydrogen, (C1-6)alkyl or (C3-8cycloalkyl, and X is O or S
with the proviso when R2 signifies hydrogen or halogen with an atomic number of 9 to R3 signifies the group of formula -CONH (C1-6)alkyl and X = O
then R1 does not signify (C1-6)alkyl
2. Adenosine-2',3'-carbonates according to claim 1 of formula Ia wherein R1a signifies p-methoxyphenyl, p-chlorophenyl, R2a signifies hydrogen or methyl and R3a signifies CONH (C1-4)alkyl, and X signifies O or S
3. Adenosine-2',3'-carbonates according to patent claims 1 or 2, selected from compounds:
1'-desoxy-1'-(6-p-methoxyphenylamino-2-methyl-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclopentylamino-2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclopentylamino-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclohexylamino-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-methoxyphenylamino-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-phenylamino-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-fluorophenylamino-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-chlorophenylamino-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclohexylamino-2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-phenylamino-2-methyl-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-fluorophenylamino 2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-chlorophenylamino-2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-methoxyphenylamino-2-methyl-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-thiocarbonate 1'-desoxy-1'-(6-p-methoxyphenylamino-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-thiocarbonate 1'-desoxy-1'-(6-p-chlorophenylamino-2-methyl-g-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-thiocarbonate 1'-desoxy-1' (6-p-fluorophenylamino-2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-thiocarbonate 6-cyclohexyladenosine-2',3'-carbonate 6-p-methoxyphenyladenosine-2',3'-carbonate 6-p-chlorophenyladenosine-2',3'-carbonate 6-(3-pentyl)adenosine-2',3'-carbonate
1'-desoxy-1'-(6-p-methoxyphenylamino-2-methyl-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclopentylamino-2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclopentylamino-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclohexylamino-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-methoxyphenylamino-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-phenylamino-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-fluorophenylamino-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-chlorophenylamino-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclohexylamino-2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-phenylamino-2-methyl-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-fluorophenylamino 2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-chlorophenylamino-2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-methoxyphenylamino-2-methyl-9-purinyl)-.beta.-D-ribofuranuronic acid-N-ethylamide-2',3'-thiocarbonate 1'-desoxy-1'-(6-p-methoxyphenylamino-9-purinyl)-.beta.-D-ribofuran-uronic acid-N-ethylamide-2',3'-thiocarbonate 1'-desoxy-1'-(6-p-chlorophenylamino-2-methyl-g-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-thiocarbonate 1'-desoxy-1' (6-p-fluorophenylamino-2-methyl-9-purinyl)-.beta.-D-ribo-furanuronic acid-N-ethylamide-2',3'-thiocarbonate 6-cyclohexyladenosine-2',3'-carbonate 6-p-methoxyphenyladenosine-2',3'-carbonate 6-p-chlorophenyladenosine-2',3'-carbonate 6-(3-pentyl)adenosine-2',3'-carbonate
4. Process for the production of adenosine-2',3'-carbonates of formula I according to claim 1, wherein R3 is the group of formula -CONHR4, characterised in that the group wherein X possesses the definition given in claim 1, is introduced into compounds of formula III
wherein R1, R2 and R4 possess the definitions given in claim 1.
wherein R1, R2 and R4 possess the definitions given in claim 1.
5. Process for the production of adenosine-2',3' carbonates of formula I according to claim 1, wherein R3 is the group of formula -CH20H, characterised in that the protecting group is cleaved from compounds of formula II
wherein R1, R2 and X possess the definitions given in claim 1, and DMT is the 4,4'-dimethoxytrityl protecting group.
wherein R1, R2 and X possess the definitions given in claim 1, and DMT is the 4,4'-dimethoxytrityl protecting group.
6. Therapeutical composition containing as active substances adenosine-2',3'-carbonates according to patent claims 1 to 3, optionally together with pharmacologically acceptable assistants and/or diluents.
7. Use of adenosine-2',3'-carbonates according to patent claims 1 to 3 in the treatment of raised blood pressure, for protection against cardiac insufficiency, for peripheral and coronary vasodilation, for reducing thrombosis, for protecting the vascular endothelium, for lowering the blood lipid level, for improving glucose tolerance and lowering the plasma insulin level, as antiarrhythmics, for the treatment of claudicatio intermittens and the Raynaud's disease.
8. Use of adenosine-2',3'-carbonates according to patent claims 1 to 3 for the production of medicaments having activity against raised blood pressure, for protection against cardiac insufficiency, against peripheral and coronary vasodilation, for reducing thrombosis, for protection of the vascular endothelium, for lowering blood lipid level, for improving glucose tolerance and lowering the plasma insulin level, as antiarrhythmics, for treatment of claudicatio intermittens and the Raynaud's disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4025879A DE4025879A1 (en) | 1990-08-16 | 1990-08-16 | NEW ADENOSINE DERIVATIVES, THEIR PRODUCTION AND USE |
| DEP4025879.3 | 1990-08-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2064869A1 true CA2064869A1 (en) | 1992-02-17 |
Family
ID=6412310
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002064869A Abandoned CA2064869A1 (en) | 1990-08-16 | 1991-08-13 | Adenosine derivatives, their production and use |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0496852A1 (en) |
| JP (1) | JPH05502889A (en) |
| AU (1) | AU638600B2 (en) |
| CA (1) | CA2064869A1 (en) |
| CS (1) | CS97892A3 (en) |
| DE (1) | DE4025879A1 (en) |
| FI (1) | FI921691A0 (en) |
| HU (1) | HUT60504A (en) |
| PL (1) | PL294368A1 (en) |
| TW (1) | TW197448B (en) |
| WO (1) | WO1992003463A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU5165793A (en) * | 1992-10-01 | 1994-04-26 | Mcneilab, Inc. | Derivatives of 7,8-disubstituted guanosines |
| GB9301000D0 (en) * | 1993-01-20 | 1993-03-10 | Glaxo Group Ltd | Chemical compounds |
| CN114437159B (en) * | 2022-04-11 | 2022-06-28 | 佛山市晨康生物科技有限公司 | Cyclic carbonate nucleoside compound and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4167565A (en) * | 1976-11-08 | 1979-09-11 | Abbott Laboratories | Adenosine-5'-carboxamides and method of use |
| US4514405A (en) * | 1981-09-17 | 1985-04-30 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Use of adenosine derivatives as anticonvulsants |
| DE3406533A1 (en) * | 1984-02-23 | 1985-08-29 | Boehringer Mannheim Gmbh, 6800 Mannheim | USE OF ADENOSINE DERIVATIVES AS ANTIALLERGICA AND MEDICINAL PRODUCTS CONTAINING THEM |
| AU579412B2 (en) * | 1984-10-26 | 1988-11-24 | Warner-Lambert Company | N` - substituted adenosines |
-
1990
- 1990-08-16 DE DE4025879A patent/DE4025879A1/en not_active Withdrawn
-
1991
- 1991-08-13 JP JP3513113A patent/JPH05502889A/en active Pending
- 1991-08-13 HU HU921080A patent/HUT60504A/en unknown
- 1991-08-13 PL PL29436891A patent/PL294368A1/en unknown
- 1991-08-13 AU AU83032/91A patent/AU638600B2/en not_active Ceased
- 1991-08-13 WO PCT/CH1991/000170 patent/WO1992003463A1/en not_active Application Discontinuation
- 1991-08-13 EP EP91913964A patent/EP0496852A1/en not_active Withdrawn
- 1991-08-13 CA CA002064869A patent/CA2064869A1/en not_active Abandoned
- 1991-11-26 TW TW080109279A patent/TW197448B/zh active
-
1992
- 1992-04-01 CS CS92978A patent/CS97892A3/en unknown
- 1992-04-15 FI FI921691A patent/FI921691A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU8303291A (en) | 1992-03-17 |
| JPH05502889A (en) | 1993-05-20 |
| AU638600B2 (en) | 1993-07-01 |
| FI921691A0 (en) | 1992-04-15 |
| HU9201080D0 (en) | 1992-06-29 |
| TW197448B (en) | 1993-01-01 |
| DE4025879A1 (en) | 1992-02-20 |
| EP0496852A1 (en) | 1992-08-05 |
| CS97892A3 (en) | 1992-08-12 |
| WO1992003463A1 (en) | 1992-03-05 |
| PL294368A1 (en) | 1993-06-28 |
| HUT60504A (en) | 1992-09-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9351970B2 (en) | Anti-viral pyrimidine nucleoside analogues | |
| CA2147893C (en) | Enantiomerically pure .beta.-d-dioxolane nucleosides with selective anti-hepatitis .beta. virus activity | |
| NZ250414A (en) | Substituted 5'-deoxy-5-fluorocytidines and pharmaceutical compositions | |
| WO2001025192A1 (en) | Guanidine derivatives and their use in the production of a medicament for blocking xanthine oxidase/dehydrogenase | |
| US5219840A (en) | Antihypertensive 9-(2,N6 -disubstituted adenyl) ribofuranuronic acid derivatives | |
| NO173653B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 6-BENZOCSAZINYL AND 6-BENZOTIAZINYL-2,3,4,5-TETRAHYDROPYRIDAZINE-3-ONER | |
| GB2203149A (en) | 1-(6-amino-9-purinyl)- beta -D-ribofuranuronic acid amides and thioamides | |
| AU2002246956B2 (en) | Inhibitors of ADP-ribosyl transferases, cyclases, and hydrolases, and uses thereof | |
| EP3476854B1 (en) | Antiviral precursor drug nucleoside cyclophosphate compound and use thereof | |
| US5534503A (en) | 2'-O, N6 -disubstituted and 2'-O, N6, 2-trisubstituted adenosines and their medicinal uses | |
| US4855288A (en) | Furanuronic acid derivatives, process for their production and their use | |
| CA2064869A1 (en) | Adenosine derivatives, their production and use | |
| EP0539442B1 (en) | Enzyme inactivators | |
| US4849423A (en) | Purine derivatives, medicaments containing them and methods of treating cardiac insufficiencies and irregularities with them. | |
| EP1265871B1 (en) | Pyridazinyl phenyl hydrazones useful against congestive heart failure | |
| NZ240719A (en) | Adenosine-2',3'-carbonates, process for their preparation and use thereof. | |
| IE914023A1 (en) | New adenosine derivatives, their production and use | |
| EP0831092B1 (en) | Hydroquinone derivative and pharmaceutical use thereof | |
| US4980351A (en) | 3-aminopropoxyaryl derivatives having cardiotonic and antihypertensive use and compositions thereof | |
| US5179084A (en) | Antiviral phosphoric acid esters of oxetanocins | |
| SK146096A3 (en) | Adenosine derivatives, processes for their preparation, their use for the preparation of drugs, their use in therapy and pharmaceutical compositions containing them | |
| PT99600A (en) | Process for the preparation of new adenosine derivatives and of pharmaceutical compositions that contain them | |
| IE54121B1 (en) | Pharmaceutically active imidazolecarboxylic acid derivatives | |
| JPH0588709B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |