HUT60504A - Process for producing new adenosine derivatives and pharmaceutical compositions comprising such compounds - Google Patents

Abstract

The invention relates to adenosine-2',3'-carbonates of the formula (I) in which R1-R3 and X have the significance explained in claim (1), process for producing them and their use in the treatment of increased blood pressure, to protect against cardiac insufficiency, for peripheral and coronary vasodilation, to reduce thrombus formation, to protect the blood vessel endothel, reduce blood lipids, improve glucose tolerance and reduce the plasma insulin level, as an anti-arrhythmic in supraventricular tachycardia and also to treat claudicatio intermitens and Reynaud's disease.

Description

The present invention relates to novel adenosine derivatives having antihypertensive activity, to pharmaceutical compositions containing them as active ingredients, and to processes for their preparation. More particularly, the present invention relates to novel adenosine-2 ¹ , 3 · 3-carbonate derivatives and their preparation, which are the compounds of formula (I) 74348-2703-PT.

R 1 is C 1-6 alkyl; C3-C8 cycloalkyl; phenyl or phenyl (C 1 -C 6) alkyl, wherein the benzene rings are optionally mono- or mono-substituted with 9 to 35 halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and / or trifluoromethyl; they may be substituted; and the alkylene chain of the phenylalkyl group may be straight or branched;

R2 is hydrogen; C 1-4 alkyl;

A halogen atomic number 9-35; or C3-C8 cycloalkyl;

R 3 is -CH 2 OH or -CONHR ^{4 in} which

R4 is hydrogen; C 1-6 alkyl; or C3-C8 cycloalkyl; and X is oxygen or sulfur, with the proviso that when

R2 represents a halogen atom or a hydrogen atom numbered from 9 to 35,

R3 is -CONH- (C1-C6 alkyl), and

X represents an oxygen atom, then

R 1 is other than C 1-6 alkyl.

A preferred group of compounds of formula I are those compounds of formula Ia.

- 3 where p is methoxyphenyl or p-chlorophenyl; R ₂ ^is hydrogen or methyl;

R ₃ ^represents -C0NH- (Cl-C6) alkyl; and X is oxygen or sulfur.

In the formula (I), the halogen atomic numbers 9-35 are fluorine, chlorine or bromine, preferably fluorine or chlorine; C 1-4 alkyl is methyl, ethyl, npropyl, isopropyl, η-butyl, isobutyl or tert-butyl; when the alkyl number of the alkyl group is up to 6, it may also be, for example, η-pentyl, isopentyl, 3-pentyl, n-hexyl, isohexyl; alkyl is especially methyl, ethyl, isopropyl or 3-pentyl; C 1-4 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, η-butoxy, isobutoxy, tert-butoxy, especially methoxy; C3-C8 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, especially cyclopentyl or cyclohexyl. The phenyl group may be substituted at the 0, m or p position; in the case of disubstitution, the substituent groups are preferably attached at the m and p positions, and in the case of monosubstitution, they are attached at the m or p position, preferably at the p position. The substitution of the alkylene chain and the phenyl group in the phenylalkyl group is detailed above.

Some adenosine carbonate derivatives have already been disclosed in U.S. Patent No. 4,167,565. Our current announcement is separated by 4 needles. These known adenosine carbonates can be used for other purposes, such as to control unwanted animals such as rodents, coyotes and birds.

Compounds of formula (I) wherein R3 is -CH2OH may be prepared, for example, from a compound of formula (II) wherein R1, R2 and X are as defined above and DMT is 4,4'- dimethoxytrityl protecting group - deprotection.

The 4,4'-dimethoxytrityl protecting group may conveniently be removed by stirring in acidic medium, for example, with 80% acetic acid at room temperature for 6 hours. For example, aqueous hydrochloric acid or aqueous formic acid may be used instead of acetic acid.

Compounds of formula (I) wherein R3 is -CONHR4 - wherein R4 is as defined above - can be prepared by reacting a compound of formula (III) wherein R1, R2 and R4 are as defined above with C A group of the formula X is introduced wherein X is as defined above.

The group X is conveniently introduced into the compound of formula (III) by stirring the compound of formula (III) in a solvent such as dimethylformamide for 5 hours at room temperature, for example 1,1'-carbonyl or With 1,1 '- (thiocarbonyl) diimidazole.

Examples of compounds of formula (III) are: a

No. 810,551 German Patent Application.

For example, compounds of formula II may be prepared by introducing a 4,4-dimethoxytrityl protecting group into a compound of formula IV wherein R2 is as defined above; this is accomplished by reacting a compound of formula (IV) with 4,4'-dimethoxytrityl chloride in dimethylformamide at room temperature. Thus, a compound of formula (V), wherein R2 and DMT are as defined above, is reacted with a compound of formula R1-NH2, wherein Rp is as defined above, in a solvent, such as dioxane, at the boiling point of the reaction mixture; and introducing into the compounds of formula (VI) thus obtained, wherein R1, R2 and DMT are as defined above, a group of formula C = X, wherein X is as defined above. The C = X group of the compound of formula (VI) is conveniently introduced by stirring a compound of formula (VI) in a solvent such as dimethylformamide, for example, with 1,1'-carbonyl, for 5 hours at room temperature. and 1,1 '- (thiocarbonyl) diimidazole.

If the preparation of the required starting materials is not disclosed, they are known or may be prepared by known methods or in a manner analogous to the methods or methods described below.

The invention will now be described in more detail by the following non-limiting examples. In these examples, temperature values are given in degrees Celsius and are not corrected.

Example 1

Preparation of 1'-Deoxy-1 '- [6- (p-methoxyphenyl) amino-2-methyl-9-pururin] -β-D-ribofuranuronic acid N-ethylamide-2', 3 · carbonate

2.14 g of 1'-deoxy-1 '- [6- (p-methoxyphenyl) amino-2-methyl-9-purinyl] -β-D-ribofuranuronic acid N-ethylamide and 3.0 g of 1, A solution of 1'-carbonyldiimidazole in dimethylformamide (15 mL) was stirred at room temperature for 5 hours, then the reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and purified by chromatography on silica gel. The product was recrystallized from ethyl acetate and diethyl ether to give the title compound, m.p. 168-170 ° C.

Example 2

Preparation of 6-Cyclohexyl-adenosine-2, 3'-carbonate

A solution of 4.2 g of 6-cyclohexyl-5 '- (4,4'-dimethoxytrityl) adenosine-2', 3'-carbonate and 21 ml of 80% acetic acid was stirred at room temperature for 6 hours and then under high vacuum Concentrate at 40 ° C. The residue was taken up in ethyl acetate and adjusted to pH 8 with 10% sodium bicarbonate with cooling. The aqueous phase is extracted three times with ethyl acetate, the organic extracts are combined, dried over sodium sulfate and purified by chromatography on silica gel. Elution was carried out with a mixture of ethyl acetate and n-hexane (8: 2) and the title compound was recrystallized from ethyl acetate / diethyl ether. M.p. 152-154 ° C.

The starting material 6-cyclohexyl-5 '(4,4'-dimethoxytrityl) adenosine-2', 3'-carbonate can be prepared, for example, as follows:

a) To a solution of 9.17 g of 6-chloropurine-9-B-ribofuranoside, 5.6 ml of triethylamine and 96 ml of dimethylformamide at room temperature in 14 g of 4,4'-dimethoxytrityl chloride in 96 ml of dimethylformamide After stirring at room temperature for 1 hour, the solvent was distilled off under high vacuum at 35 ° C and the residue was partitioned between ethyl acetate and water. The organic extract was dried over anhydrous sodium sulfate, evaporated and the residue was chromatographed on silica gel. Elution with ethyl acetate / hexane (8: 2) gave 6-chloro-5 '- (4,4'-dimethoxytrityl) -purine-9-B-ribofuranoside as an foam which had an Rf value of ethyl acetate as the foam. developed with propellant 0.6.

b) A solution of 5 g of 6-chloro-5 '- (4,4'-dimethoxytrityl) purine-9-ribofuranoside, 2.95 ml of cyclohexylamine and 30 ml of dioxane is stirred in an oil bath at 105 ° C for 2 hours, it was then cooled, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and extracted with ice-cold 0.1 N hydrochloric acid. The organic layer was washed with water, dried over anhydrous sodium sulfate, evaporated and the residue chromatographed on silica gel. Elution with 8: 2 ethyl acetate / hexane gave 6-cyclohexyl-5 '- (4,4'-dimethoxytrityl) adenosine as a foam which had an Rf value of 0.5 when developed with ethyl acetate.

c) A solution of 4.6 g of 6-cyclohexyl-5- (4,4'-dimethoxytrityl) adenosine, 4.46 g of 1,1-carbonyldiimidazole and 30 ml of dimethylformamide was stirred at room temperature for 1 hour and the solvent was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo at very good vacuum and partitioned between ethyl acetate and ice water. The aqueous phase was extracted three times with ethyl acetate and the combined organic extracts were dried over anhydrous sodium sulfate. After evaporation, the residue is chromatographed on silica gel, eluting with ethyl acetate: hexane (8: 2), to give 6-cyclohexyl-5 '- (4,4'-dimethoxytrityl) -adenosine-2' m 3 'carbonate as a foam. having an Rf value of 0.8 when developed with ethyl acetate.

The following formula (I) compounds can be prepared képleetű procedure described in Example 1 (wherein R3 represents a group of formula -CONHR 4) or Example 2 (where R ₃ CH 2 OH group).

The example is R1

X Op. ° C line number

3. cyclopentyl

Me CONHEt 0 amorphous

4. cyclopentyl

H CONHEt 0

106-110

5th cyclopentyl H CONHEt 0 112-115 6th p-methoxyphenyl H CONHEt 0 120-124 7th phenyl H CONHEt 0 126-130 8th p-fluorophenyl H CONHEt 0 122-126 9th p-chlorophenyl H CONHEt 0 130-135 10th cyclohexyl Me CONHEt 0 185-187 11th phenyl Me CONHEt 0 116-121 12th p-fluorophenyl Me CONHEt 0 115-118 13th p-chlorophenyl Me CONHEt 0 119-124 14th p-methoxyphenyl Me CONHEt S 149-151 15th p-methoxyphenyl H CONHEt s 125-128 16th p-chlorophenyl Me CONHEt s 131-136 17th p-fluorophenyl Me CONHEt s 126-130 18th p-methoxyphenyl H ch ₂ oh 0 121-123 19th p-chlorophenyl H ch ₂ oh 0 110-114 20th 3-pentyl H ch ₂ oh 0 156-159

The compounds of the present invention are distinguished by their interesting pharmacological properties and are therefore useful as medicaments.

In particular, the compounds of the present invention have antihypertensive activity, which results from the results of the following assays.

RF Bruns et al., Molec. Pharmacol. 29, 331 (1986)] measured the binding of the compounds of the invention to membranes derived from rat cortex or guinea pig cortex or striatum. and A ₂ adenosine receptors. We also examined the

- the effect of the compounds of the invention on isolated perfusion-treated kidneys of rats with respect to the following parameters:

- renin separation,

- renal haemodynamics,

inhibition of noradrenaline release from nerve endings following electrical stimulation of renal nerves [H. J. Schurek et al., Communication: La Réunion de l'Association des Pharmacologistes Louvain UCL, June 4, 1977; and Ρ. M. Vanhoutte et al., Hypertension 4, 251 (1982) 1;

- blood pressure, heart rate, urinary output, and plasma renin activity of normal blood pressure and spontaneous hypertensive rats, awake, desalted and re-treated with saline, were measured in the abdominal aorta and intravascular cavaeter infusion. or bolus or intravenous administration by the method of JFM Smits and JM Brody [Am. J. Phvsiol. 247, RI 003 - RI 008 (1984)].

From our results, it can be concluded that both the inhibition of renin secretion and the release of norepinephrine from nerve endings play a role in the antihypertensive effect of the compounds of the invention, as well as the direct vasodilatory effect. As a result, the compounds of the present invention are not only useful as antihypertensive agents, but also have a protective effect against heart failure. The workload of the heart is reduced by reducing the post-workload of the heart by inhibiting renin secretion and release of neurotransmitters; they also improve cardiac metabolism by dilating the coronary arteries. By treating with the compounds of the present invention, the patient's quality of life and life expectancy are both improved and prolonged. By virtue of their peripheral vasodilator activity, the compounds of the present invention directly dilate blood vessels and improve the blood supply of tissues, i.e. oxygen. The deficient blood supply (ischemic) skeletal muscle is mainly affected by the improvement of oxygen supply. Thus, there is a possibility that the compounds of the invention may be used to treat peripheral vascular diseases such as intermittent stroke and Raynaud's disease. In addition, by dilating the coronary arteries, elimination or improvement of myocardial inadequate blood supply (ischemia) can be achieved, and thus healing or improvement of angina pectoris. The compounds of the invention are also useful in the treatment of arrhythmia.

Due to their adenosine A1 receptor agonist activity, the compounds of the present invention normalize sinus rhythm in supraventricular and B-adrenergic-induced ventricular tachycardias. In addition, the compounds of the present invention also have neuroprotective effects and may accordingly be used for the prevention of peripheral vascular disease with nerve degeneration.

They also reduce the formation of blood clots (thrombi) by inhibiting platelet aggregation. The compounds of the present invention reduce plasma insulin concentrations without affecting glucose tolerance; and potentiate glucose uptake into adipose tissue. This insulin-sparing effect is shown in Table II. can be used to treat type 2 diabetes. In addition, the compounds of the present invention lower blood lipid levels and may have a positive effect on the development of atherosclerosis, a cause of many cardiovascular diseases.

The above indications are advantageous for the 1st, 6th,

The compounds of the invention described in Examples 9, 12 and 14, in particular Example 1.

For the above applications, the appropriate dosage will vary with the active ingredient employed, the mode of administration and the treatment desired; however, satisfactory results can generally be obtained using about 0.01 to 10 mg / kg body weight of the compound of the invention per day; if desired, the dosage may be administered in divided doses of 2 to 4 parts or in a sustained release form. For larger mammals, the daily dose is approximately 1 to 500 mg. For example, dosage forms suitable for oral or non-oral administration will generally contain from about 5 mg to about 250 mg of a compound of Formula I together with solid or liquid vehicles.

The compounds of the invention may be used alone or in suitable dosage forms. Dosage forms, such as solutions or tablets, are known in the art

- 13 can be produced similarly.

Accordingly, the present invention also provides pharmaceutical compositions comprising the compounds of the invention in free form or in the form of their physiologically acceptable salts; the invention also relates to the preparation of these medicaments in a known manner. Excipients and additives commonly used in the pharmaceutical art can be used for their preparation.

Claims (8)

Claims A process for the preparation of the adenosine 2 ', 3'carbonate derivatives of the formula I: wherein: R 1 is C 1 -C 6 alkyl; C3-C8 cycloalkyl; phenyl or phenyl (C 1 -C 6) alkyl, wherein the benzene rings are optionally mono- or mono- to 9-35-halo, C 14 -alkyl, C 1 -C 4 -alkoxy and / or trifluoromethyl; they may be substituted; and the alkylene chain of the phenylalkyl group may be straight or branched; R2 is hydrogen; C 1-4 alkyl; A halogen atomic number 9-35; or C3-C8 alkyl; r _{3 is} -CH 2 OH or -CONHR ^{4 in} which R4 is hydrogen; C 1-6 alkyl; or C3-C8 cycloalkyl; and X is oxygen or sulfur, with the proviso that when R2 represents a halogen atom or a hydrogen atom numbered from 9 to 35, R ₃ is -CONH- (C 1-6 alkyl), and X represents an oxygen atom, then R 1 is other than C 1-6 -alkyl, and is selected from the group consisting of C 1-6 -alkyl and C 1 -C 6 -alkyl. »· ·· - 15 characterized in that a) Preparation of a compound (I) wherein R3 is -CONH4 group of the formula wherein R4 is as defined above, with a compound (III) - wherein Rl, _R2 and R4 the meanings given above \ defined in these terms - C = X. introducing a generic group wherein X is as defined above; obsession b) (I) Compounds of formula wherein R 3 is -CH ₂ OH, (II) a compound of formula - wherein Rl, _R2 and X are as defined above, DMT and 4,4-dimethoxy- trityl protecting group is deprotected. 2. A process for the preparation of an adenosine A1 receptor agonist for use in the prevention of peripheral vascular disease with antihypertensive activity, which method comprises the preparation of a compound of formula (I) prepared according to claim 1 in a conventional diluent, carrier and / or or mixed with excipients to form a pharmaceutical composition. Adenosine 2 ', 3'-carbonate derivatives of the general formula (I) - wherein R 1 is C 1-6 alkyl; C3-C8 cycloalkyl; phenyl or phenyl (C 1 -C 6) alkyl, wherein the benzene rings are optionally substituted with 4 to 4 carbon atoms, 9 to 35 halogen atoms, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and / or may be mono- or disubstituted with trifluoromethyl; and the alkylene chain of the phenylalkyl group may be straight or branched; r ₂ is hydrogen; C 1-4 alkyl; A halogen atomic number 9-35; or C3-C8 cycloalkyl; R 3 is -CH 2 OH or -CONHR ^{4 in} which R4 is hydrogen; C 1-6 alkyl; or C3-C8 cycloalkyl; and X is oxygen or sulfur, with the proviso that when Denotes a halogen atom or a hydrogen atom of the order of 9-35, represents -CONH- (C1-C6 alkyl), and represents an oxygen atom, it does not mean a C1-C6 alkyl radical. Compounds of formula (Ia) which are a narrow class of compounds of formula I according to claim 3, wherein R ^a is p-methoxyphenyl or p-chlorophenyl group; R2 ^a is hydrogen or methyl; R3 represents ^a -CONH- (Cl-C6) alkyl; and X is oxygen or sulfur. * 2 R3 X Rí • 9 · ·· ♦ · · · * • · »♦ * <···· ··« »9 · ♦ · · * · The 1'-deoxy-1 '- [6- (pmethoxyphenyl) amino-2-methyl-9-purinyl] -β-D-ribofuranuronic acid N-ethylamide-2' according to claim 3 or 4. , 3'-carbonate, 1'-deoxy-1 '- [6- (cyclopentylamino) -2-methyl-9-yl] -βD ribofuranuronsav-N-ethylamide, 2', 3'-carbonate, 1'-deoxy-1 '- [6- (cyclopentylamino) -9-purinyl] -β-Dribofuranuronsav-N-ethylamide-2', 3'-carbonate, 1'-deoxy-1 '- [6- (cyclohexylamino) -9-purinyl] -β-Dribofuranuronsav-N-ethylamide-2', 3'-carbonate, 1'-deoxy-1 ¹ - [6- (p-methoxyphenyl) amino-9-yl] -β-Dribofuranuronsav-N-ethylamide-2 ', 3'-carbonate, 1'-deoxy-1 ¹ - [6- (phenylamino) -9-purinyl] -β-D-ribofuranuronsav-N-ethylamide-2 ', 3'-carbonate, 1'-deoxy-1 '- [6- (p-fluorophenyl) amino-9-purinyl] -β-Dribofuranuronic acid N-ethylamide-2', 3'-carbonate, 1'-deoxy-1 '- [6- (p-chlorophenyl) amino-9-purinyl] -β-Dribofuranuronic acid N-ethylamide-2', 3'-carbonate, 1'-deoxy-1 '- [6- (cyclohexylamino) -2-methyl-9-purinyl] -? - D-ribofuranuronic acid N-ethylamide-2', 3'-carbonate, 1'-deoxy-1 '- [6- (phenylamino) -2-methyl-9-yl] ribofuranuronsav-β-D-N-ethylamide, 2', 3'-carbonate, 1'-deoxy-1 '- [6- (p-fluorophenyl) amino-2-methyl-9-yl] ribofuranuronsav-B-D-N-ethylamide, 2', 3'-carbonate, 1'-deoxy-1 '- [6- (p-chlorophenyl) amino-2-methyl-9-yl] ribofuranuronsav-β-D-N-ethylamide, 2', 3'-carbonate, 1'-deoxy-1 '- [6- (p-methoxyphenyl) amino-2-methyl-9-yl] ribofuranuronsav-β-D-N-ethyl-2-amide ^1, 3'-carbonate, 1'-deoxy-1 '- [6- (p-methoxyphenyl) amino-9-purinyl] 18 • ···· ** · · ♦ · ·· * ··. • · · ·· * · · · »4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · D-ribofuranuronic acid-N-ethylamide-2 ′, 3′-carbonate. , 1'-deoxy-1 '- (6- (p-chlorophenyl) amino-2-methyl-9-purinyl) -Bd-ribofuranuronic acid N-ethylamide-2', 3'-carbonate, 1'-Deoxy-1 '- [6- (p-fluorophenyl) amino-2-methyl-9-purinyl] BD-ribofuranuronic acid N-ethylamide-2', 3'-carbonate, 6-cyclohexyl adenosine-2 ', 3'-carbonate, 6- (p-methoxyphenyl) adenosine-2 ', 3'-carbonate, 6- (p-chlorophenyl) adenosine-2 ', 3'-carbonate and 6- (3-pentyl) adenosine-2 ', 3'-carbonate. 6. A pharmaceutical composition for the prevention of peripheral vascular disease with an anti-hypertensive effect, an adenosine β receptor agonist, characterized in that the active ingredient is a compound of claims 3-5. A compound of formula (I) as claimed in any one of claims 1 to 6 in admixture with diluents, carriers and / or excipients customary in the pharmaceutical formulation. 7. Use of compounds according to any one of claims 1 to 6 for the treatment of hypertension, protection against heart failure, dilation of peripheral and coronary arteries, reduction of thrombosis, protection of vascular endothelium, reduction of blood lipid levels, improvement of glucose tolerance, reduction of plasma insulin levels and antiarrhythmics. treatment. 8. The procedure of 3-5. The use of a compound according to any one of claims 1 to 4 for lowering hypertension, protecting against heart failure, peripheral and coronary vasodilating, reducing thrombosis, protecting endothelium of blood, lipid-4 blood. 4ΒΒΒΒ • • 4 4 4 4 4 4 4 4 4őőőőőőőΒΒőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőőő csökkentő csökkentőőő csökkent csökkentőőőő csökkentőőő antiarrhythmic drugs for the treatment of periodic limbs and Raynaud's disease.