IE914023A1

IE914023A1 - New adenosine derivatives, their production and use

Info

Publication number: IE914023A1
Application number: IE402391A
Authority: IE
Inventors: Fulvio Gadient
Original assignee: Sandoz Ltd
Priority date: 1991-11-19
Filing date: 1991-11-19
Publication date: 1993-05-19

Abstract

Adenosine-2',3'-carbonates of formula are claimed, wherein Rx-R3 and X possess the definitions given in claim 1, processes for their production and their use in the treatment of raised blood pressure, for the protection against cardiac insufficiency, for peripheral and coronary vasodilation, for reducing thrombosis, for protecting the vascular endothelium, for lowering blood lipid, for improving glucose tolerance and lowering the plasma insulin level, as antiarrhythmics, for the treatment of claudicatio intermittens and the Raynaud's disease.

Description

Adenosine-2',3'-carbonates of formula X are claimed, wherein Rx-R3 and X possess the definitions given in claim 1, processes for their production and their use in the treatment of raised blood pressure, for the protection against cardiac insufficiency, for peripheral and coronary vasodilation, for reducing thrombosis, for protecting the vascular endothelium, for lowering blood lipid, for improving glucose tolerance and lowering the plasma insulin level, as antiarrhythmics, for the treatment of claudicatio intermittens and the Raynaud's disease. 6300/ST/RT PATENTS ACT 1964 -I*t-»* - J·** COMPLETE SPECIFICATION SANDOZ LTD., BASLE, Switzerland a Swiss Body Corporate, of Lichtstrasse , CH-4002 5015 CASE 100-7677 NEW ADENOSINE DERIVATIVES, THEIR PRODUCTION AND USE The invention relates to new adenosine-2',3'-carbonates, processes for their production and their use, among other things, for the treatment of raised blood pressure.

The invention relates in particular to compounds of formula R4 wherein Rl· signifies (Ci_6)alkyl, (C3_8)cycloalkyl, phenyl or phenyl(C!_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, (Ci_4)alkyl, (Cx_4)alkoxy and/or CF3, and in the case of phenylalkyl, the - 2 100-7677 alkylene chain is straight-chain or branched, R2 denotes hydrogen, (Ci_4)alkyl, halogen with an atomic number of 9 to 35, or (C3_8)cycloalkyl, R3 denotes groups of formulae -CH20H or -C0NHR4, wherein R4 signifies hydrogen, (Ci_6)alkyl or (C3_8)cycloalkyl, and X is 0 or S with the proviso when R2 signifies hydrogen or halogen with an atomic number of 9 to R3 signifies the group of formula -C0NH (Cx-eJalkyl and X = 0 then R3 does not signify (Cj._e)alkyl Of the compounds of formula I, preferred compounds possess the formula 0 * Ia wherein II X R3a signifies p-methoxyphenyl, p-chlorophenyl R2* signifies hydrogen or methyl and R3* signifies CONH (Ci_4)alkyl, and X signifies 0 or S. - 3 - 100-7677 In formula I, halogen with an atomic number of 9-35 is fluorine, chlorine or bromine, preferably fluorine or chlorine, a (Ci_4)alkyl group is methyl, ethyl, n-propyl, i-propyl, 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, (Ci_4)alkoxy group is methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, tert.-butoxy, especially methoxy, (C3_8)cycloalkyl signifies cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, especially cyclopentyl or cyclohexyl. Substitution of the phenyl ring may be made in ο-, m or p-position, whereby in the case of disubstitution, substitution is preferably made in m- and p-position and in the case of monosubstitution, it 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 carbonates 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 animals including rodents, coyotes and birds.

Production of compounds of formula I, wherein R3 is a group of formula -CH20H, may be effected for example, whereby the protecting group is cleaved from compounds of formula *E 914023 - 4 - 100-7677 wherein Rx, R2 and X are defined as above, and DMT is the 4,4'dimethoxytrityl protecting group.

Cleavage of the 4,4'-dimethoxytrityl protecting group conveniently takes place in an acidic medium, for example in 80X 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 aqueous formic acid.

Production of compounds of formula I, wherein R3 is the group -C0NHR4, is effected by introducing the group \ C = X wherein X is defined as above, into compound of formula / - 5 100-7677 III HO OH wherein Rx, R2 and R4 are defined as above.

\ Introduction of the C = X / group into compounds of formula III conveniently takes place by reacting them with for example 1,1'-carbonyl- resp. l,l'-thiocarbonyl-diimidazole in a solvent such as dimethylformamide whilst stirring for 5 hours at room temperature.

The compounds of formula III are known, for example from German published application 3810551.

Production of the compounds of formula II may be effected for example whereby the 4,4'-dimethoxytrityl protecting group is introduced into compounds of formula HO oh IV - 6 100-7677 wherein R2 is defined as above. This is effected by means of a reaction with 4,4'-dimethoxytrityl chloride in dimethylformamide at room temperature. The compounds of formula thereby formed, wherein R2 and DMT are defined as above, are reacted with a compound of formula Rx-NH2, wherein R3 is defined as above, in a solvent such as dioxane at boiling temperature of \ the reaction mixture, and then the group C = X, wherein X is / defined as above, is introduced into the compounds of formula - Ί - 100-7677 thereby formed, wherein Rx , R2 and DMT are defined as above.

\ Introduction of the C = X group into compound / of formula VI conveniently takes place by means of a reaction with for example 1,1'-carbonyl- resp. 1,1'-thiocarbonyldiimidazole in a solvent such as dimethylformamide whilst stirring for 5 hours at room temperature.

Insofar as the production of the required starting materials 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. - 8 100-7677 Example 1 1'-desoxy-1'-(6-p-methoxyphenylamino-2-methyl-9-purinyl)-g-Dribofuranuronic acid-N-ethylamide-2',3'-carbonate 2.14 g of l'-desoxy-l'-(6-p-methoxyphenylamino-2-methyl-9purinyl)-fJ-D-ribofuranuronic acid-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 between 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°.

Example 2 6-cyclohexyladenosine-2',3'-carbonate 4.2 g of 6-cyclohexyl-5'-(4,4'-dimethoxytrityl)-adenosine-2',3'carbonate are dissolved in 21 ml of 802 acetic acid and stirred for 6 hours at room temperature. The solution is subsequently concentrated at 40° in a high vacuum, the residue is taken up in ethyl acetate and adjusted to pH 8 with a 102 sodium hydrogen carbonate solution whilst cooling. The aqueous phase is shaken out three times with ethyl acetate, and the combined organic extracts are dried over sodium sulphate. The product is purified by elution on silica gel with 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-cyclohexyl-5'-(4,4'-dimethoxytrityl)-adenosine-2',3'carbonate used as starting material may be produced e.g. as follows: - 9 - 100-7677 a) To a solution of 9.17 g of 6-chloropurine-9-fJ-ribofuranoside and 5.6 ml of triethylamine in 96 ml of dimethylformamide is added in drops at room temperature a solution of 14 g of 4,4'-dimethoxytrityl chloride in 96 ml of dimethylformamide, and the mixture 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 acetate 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-value of 0.6. b) 5 g of 6-chloro-5'-(4,4'-dimethoxytrityl)-adenosine and 2.95 ml of cyclohexylamine in 30 ml of dioxane are stirred for hours in an oil bath of 105°. It is subsequently cooled, filtered, and the filtrate is concentrated at reduced pressure. The residue is dissolved in ethyl acetate and shaken out with cold 0.1 N hydrochloric acid. After washing with water and drying over sodium sulphate, the organic phase is concentrated and eluted on silica gel with ethyl acetate/hexane 8:2. The resulting 6-cyclohexyl-5'-(4,4'-dimethoxytrityl)-adenosine is a foam, and in ethyl acetate has a RF-value of 0.5. c) 4.6 g of 6-cyclohexyl-5'-(4,4'-dimethoxytrityl)-adenosine and 4.46 g of 1,1'-carbonyldiimidazole in 30 ml of dimethylformamide 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 between ethyl acetate and ice water. The aqueous phase is extracted three times with ethyl acetate and the organic extracts are dried over sodium sulphate. After concentration, the residue is - 10 - 100-7677 chromatographed on silica gel with a mixture of ethyl acetate/hexane 8:2. The 6-cyclohexyl-5'-(4,4'-dimethoxytrityl)-adenosine-2',3'-carbonate is a foam, and in ethyl acetate has a Rf-value of 0.8.

The following compounds of formula I may be produced using the process described in examples 1 (R3 = C0NHR4) or 2 (R3 = CH2-0H): Example Ri R2 r3 X M.p. 3 cyclopentyl Me CONHEt 0 amorph. 4 cyclopentyl H CONHEt 0 106-110° 5 cyclohexyl H CONHEt 0 112-115° 6 p-methoxyphenyl H CONHEt 0 120-124° 7 phenyl H CONHEt 0 126-130° 8 p-fluorophenyl H CONHEt 0 122-126° 9 p-chlorophenyl H CONHEt 0 130-135° 10 cyclohexyl Me CONHEt 0 185-187° 11 phenyl Me CONHEt 0 116-121° 12 p-fluorophenyl Me CONHEt 0 115-118’ 13 p-chlorophenyl Me CONHEt 0 119-124° 14 p-methoxyphenyl Me CONHEt s 149-151’ 15 p-methoxyphenyl H CONHEt s 125-128’ 16 p-chlorophenyl Me CONHEt s 131-136° 17 p-fluorophenyl Me CONHEt s 126-130’ 18 p-methoxyphenyl H CH20H 0 121-123° 19 p-chlorophenyl H CH2OH 0 110-114° 20 3-pentyl H ch2oh 0 156-159° - 11 - 100-7677 The 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 Al and A2 receptors 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.H. LU and T.A. PUGSLEY, which is described in MOLEC. PHARMACOL. 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-stimulation of the renal nerves according to the method of H.J. Schurek, J.P. Brecht, H. Lohfert and K. Hierholzer, described in COMMUNICATION a la REUNION de 1'ASSOCIATION DBS PHARMACOLOGISTES LOUVAIN UCL 4th June 1977, as well as P.M. Vanhoutte, D. Browning, E. Coen, T.J. Verbeuren, L. Zonnekeyen and M.G. Collins described in HYPERTENSION 4, 251-256 (1982).

Measurement of blood pressure, heart rate, urine production and renin activity in plasma of wake, NaCl-depleted and repleted, normotensive or spontaneously hypertensive rats with catheters implanted in the abdominal aorta and in the vena cava, following i.v. administration or administration of - 12 - 100-7677 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 secretion and release of noradrenaline from nerve endings, and the direct vasodilation, take part in the anti-hypertensive activity of the compounds according to the invention. It results from this that the compounds according to the invention can not only be used as antihypertensive agents but they also possess protective effect against cardiac insufficiency. They are reducing 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. Both 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 ischaemic skeleton muscle. For the compounds of the invention there is a potential for the treatment of peripheral vascular diseases like claudicatio intermittens and the Raynaud's disease. Further the coronary vasodilation leads to the suppression or improvement of myocardial ischaemia and consequently of angina pectoris. The compounds of the invention have activity in the treatment of arrhythmia.

Being adenosine Αχ-receptor agonists they lead to a normal sinus rhythm at supraventricular and β-adrenergic stimulated ventricular tachycardias. The compounds of the invention possess further a neuroprotective activity. Accordingly they can be used for the prophylaxis of peripheral vascular diseases which are accompanied by neuronal degeneration. They reduce further the - 13 - 100-7677 formation of thrombi by inhibition of the aggregation of thrombocytes and protect the vascular endothelium by inhibition of the activation of leucocytes. The compounds of the invention are lowering the plasma insulin level without influencing the glucose tolerance. They are potentiating the uptake of glucose in the fatty tissue. This insulin saving activity 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 of many cardiovascular diseases.

For the above indications, of the compounds 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 administration 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 in the range of approximately 1 to 500 mg; suitable dosage forms for e.g. oral or non-oral administration generally contain about 5 to 250 mg of a compound of formula I together 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.

IE 9*14023 - 14 - 100-7677 The invention therefore also relates to medicaments which contain the compounds according to the invention in free form or in the form of their 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. 100-7677

Claims

1. PATENT CLAIMS;

1. Adenosine-2',3'-carbonates of formula wherein y R x signifies (C!_ 6 )alkyl, (C 3 _ 8 )cycloalkyl, phenyl or phenylCCi-g)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, (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy and/or CF 3 , and in the case of phenylalkyl, the alkylene chain is straight-chain or branched, R 2 denotes hydrogen, (Ci_ 4 )alkyl, halogen with an atomic number of 9 to 35, or (C 3 _ 8 )cycloalkyl, R 3 denotes groups of formulae -CHjOH or -C0NHR 4 , wherein R 4 signifies hydrogen, (Ci_ 8 )alkyl or (C 3 _ 8 )cycloalkyl, and X is 0 or S with the proviso when R 2 signifies hydrogen or halogen with an atomic number of 9 to 35 R 3 signifies the group of formula -CONH (Ci_e)alkyl and X = 0 then - 16 100-7677 Rx does not signify (Cx_ 6 )alkyl

2. Adenosine-2',3'-carbonates according to claim 1 of formula R, wherein Rx a signifies R 2 a signifies Rj a signifies X signifies A/ II X p-methoxyphenyl, p-chlorophenyl, hydrogen or methyl and CONH (Cx_ 4 )alkyl, and 0 or S Ia

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)-H-Dribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclopentylamino-2-methyl-9-purinyl)-|3-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclopentylamino-9-purinyl)-P-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate - 17 - 100-7677 1'-desoxy-1'-(6-cyclohexylamino-9-purinyl)-fJ-D-ribofuranuronic acid-N-ethylamide-2', 3'-carbonate 1'-desoxy-1'-(6-p-methoxyphenylamino-9-purinyl)-P-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-phenylamino-9-purinyl)-|3-D-ribofuranuronic acidN-ethylamide-2' ,3'-carbonate 1'-desoxy-1' — (6—p— fluorophenylamino-9-purinyl)-β-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-chlorophenylamino-9-purinyl)-β-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-cyclohexylamino-2-methyl-9-purinyl)-fJ-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-phenylamino-2-methyl-9-purinyl)-3-D-ribofuranuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-fluorophenylamino-2-methyl-9-purinyl)-3-D-ribo furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-chlorophenylamino-2-methyl-9-purinyl)-3-D-ribo furanuronic acid-N-ethylamide-2',3'-carbonate 1'-desoxy-1'-(6-p-methoxyphenylamino-2-methyl-9-purinyl)- $-Dribofuranuronic acid-N-ethylamide-2',3'-thiocarbonate 1'-desoxy-1'-(6-p-methoxyphenylamino-9-purinyl)-(J-D-ribofuranuronic acid-N-ethylamide-2',3'-thiocarbonate - 18 - 100-7677 1'-desoxy-1'-(6-p-chlorophenylamino-2-methyl-9-purinyl)-3-D-ribo furanuronic acid-N-ethylamide-2',3'-thiocarbonate 1'-desoxy-1'-(6-p-fluorophenylamino-2-methyl-9-purinyl)-f5-D-ribo furanuronic acid-N-ethylamide-2',3'-thiocarbonate 6-cyclohexyladenosine-2',3'-carbonate 6-p-me thoxyphenyladenosine-2', 3'-carbona te 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 R 3 is the group of formula -C0NHR 4 , characterised in that \ the group C = X / wherein X possesses the definition given in claim 1, is introduced into compounds of formula HO OH II 19 100-7677 wherein Ri, R 2 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 -CH 2 0H, characterised in that the protecting group is cleaved from compounds of formula HM II wherein Rx, R 2 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 - 20 100-7677 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.

9. Process according to Claim 4 or 5, substantially as described herein by way of Example.

10. Product of a process according to Claim 4, 5 or 9.

11. Compounds according to any of Claims 1-3, substantially as described herein by way of Example.

12. Therapeutical compositions according to Claim 6, substantially as described herein by way of Example. DATED THIS 19th day of November, 1991