DE2230160A1 - ADENOSINE DERIVATIVE - Google Patents

Description

Merck Patent Society June 16, 1972

with "limited liability
Darmstadt

Adenosine derivative

The invention relates to H (6) - (1,2,3,4-tetrahydronaphthyl-2) adenosine.

This compound has been found to have valuable pharmacological properties. It lowers the level of lipoprotein in the blood, and independently has beneficial properties
Effects on the heart and circulation. In particular, the compound according to the invention causes a strong reduction in the concentration of free fatty acids and triglycerides in the
Serum. In animal experiments on anesthetized dogs, even in small doses, the substance causes a strong and sustained increase in the coronary flow while the arterial blood pressure and heart rate remain roughly the same.

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The compound can accordingly .as medicament and can also be used as an intermediate in the manufacture of other pharmaceuticals.

The invention relates to N (6) - (1,2,3,4-tetrahydronaphthyl-2) adenosine and a process for the preparation of this compound, which is characterized in that a compound of the general formula I.

HO-OHg

OH OH

wherein

XP, Cl, Br, J, SR ¹ , SOR ¹ or SO ₀ R ¹ and

R alkyl with up to 6 carbon atoms, phenyl or

Benzyl
mean,

with (1,2,3,4-tetrahydro-naphthyl-2) -amine or that one is a compound that is otherwise the N (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine corresponds, however, instead of Η atoms, solvolytic or hydrogenolytic carries cleavable groups, treated with a solvolytic or hydrogenolytic agent.

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1
per radical R ″ denotes methyl, also ethyl, propyl, isopropyl, the various isomeric butyl, pentyl and hexyl radicals.

In the case of the derivatives of N (6) - (1,2,3,4-tetrahydro-naphthyl-2) -adenosine, which carry groups that can be split off solvolytically instead of Η atoms, come as such z. B. Consider:

a) acyl located on one or more heteroatoms ", ζ. Β; Acetyl, Propionyl, Benzoyl, also IOrmyl, Butyryl, Isobutyryl, valeryl, isovaleryl, caproyl, trifluoroacetyl, trichloroacetyl, toluyl, p-nitrobenzoyl, methanesulfonyl and p-toluenesulfonyl;

"b) ether groups located on the oxygen atoms of the sugar residue, -like Triphenylme thy lather- or cyclic ethers-: or acetal groups ("preferably in the 2 ', 3' position), in particular Isopropylidene and benzylidene groups.

Groups that can be split off by hydrogenolysis are, for example, embossed:

O-aralkyl, e.g. B. O-benzyl groups, S-benzyl or O- (p-Mtrobenzyl) groups, in the 2- and / or 8-position of the purine system

"located Cl, Br, J, SR, SOR ¹ - and / or SO _p R groups.

1
Among the SR residues, the SCH-- and SCpH ^ residues are preferred.

The compound according to the invention can preferably be seen from the Ribofuranosyl purine derivatives I and (1,2,3,4-tetrahydronaphthyl-2) amine produce.

309885/1 35 ^r

This reaction can ζ. B. be carried out in the melt. One works "at temperatures between 70 and 160, the range between 90 and 150 °, in particular between 100 and 140 °, is preferred. The reaction times vary between 2 and 100 hours, preferably between 3 and 12 Hours. To increase the yield, a base such as triethylamine can be added to the reaction mixture. Man works in this case expediently at temperatures below 100 °, preferably between 70 and 85 °. It is also possible, to work under pressure in an autoclave. In this case, the reaction can be over after one hour. For work-up, the cooled melt can be dissolved in a suitable solvent, e.g. B. in dioxane, dimethylformamide or tetrahydrofuran, are largely dissolved, insolubles are filtered off and the solvent is removed. Of the Residue is z. B. in a suitable solvent such as ether, dichloromethane, carbon tetrachloride or preferred taken up in chloroform and extracted with water, which may contain a small amount of acetic acid.

The reaction described can also be carried out in the presence of a solvent such as dimethylformamide, dioxane, tetrahydrofuran, methanol, ethanol, propanol, n-butanol, isobutanol, sec-butanol, tert-butanol and higher alcohols, but in particular in the presence of isopropanol . Mixtures of these solvents are also used, e.g. B. a mixture of dimethylformamide and isopropanol 1: 1. Expediently, with the addition of an inorganic or organic base, e.g. B. pyridine or preferably triethylamine worked. You can also add an excess of the 1,2,3,4-tetrahydro-naphthyl- (2) -amine ". The reaction is carried out at temperatures between

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0 and 180 °, "preferred" at the boiling point of the one used Solvent carried out. The reaction times are approximately between 3 and 30 hours, "preferably between 6 and 12 hours Hours. - It can also z. B. "can be carried out at room temperature; here the reaction times can optionally be extend, e.g. B. on 4 days.

N (6) - (1, 2,3,4-tetrahydro-naphthyl-2) -ad'enosine can also be obtained by adding a compound which, by the way, corresponds to N (6) - (1,2,3,4-Tetrahyäro-haphthyl-2) -adenosine, However, instead of Η atoms, they are solvolytic or hydrogeno-Iytic carries cleavable groups, treated with solvolytic or hydrogenolytic agents.

The usual agents that split off acyl groups are primarily used as solvolytic agents. -As such acidic and alkaline reagents are to be mentioned. Suitable acids are a. B. aqueous hydrochloric or sulfuric acid. Advantageous alkali or alkaline earth metal alcoholates, sodium or potassium hydroxide or carbonate or ammonia are also used used. Among these agents are sodium methylate resp. Ammonia preferred. One works z. B. in inert solvents such as lower alcohols or in hydrocarbons such as benzene, toluene, xylene, preferably in mixtures of these solvents with water. Appropriately, one leads the Reaction at temperatures between 0 and room temperature for one hour and several days, preferably during about 24 - 48 hours. It is also possible to work in the heat, e.g. B. at the boiling point of the used Solvent, the reaction usually taking place in a shorter time, e.g. B. between 1/2 minute and 2 hours, before

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preferably between 30 and 90 minutes. If ammonia is used as the saponification agent, work-up can be carried out by evaporation and taking up in a suitable solvent. If another alkaline deacylating agent is used, the alkaline reaction solution can be neutralized first, e.g. B. by adding equivalent amounts of acetic acid or - in the case of barium methylate - by introducing CO ₀ into the reaction solution.

C.

If cyclic ether or acetal groups are to be split off from the sugar residue, then it is expedient to use acidic solvolysis agents. As such, aqueous mixtures are inorganic or organic acids used, e.g. B. of sulfuric acid, phosphoric acid, hydrochloric acid, hydrofluoric acid, hydrogen bromide, perchloric acid, Formic acid, acetic acid, propionic acid, oxalic acid; Citric acid and others; are preferred under 60-90% formic and acetic acid solutions or very dilute sulfuric or hydrochloric acid. One works usually at temperatures between 0 and 120, expediently at room temperature for longer reaction times, such as about 5 hours to 2 days; however, the reaction can also be carried out at higher temperatures, e.g. B. at 100, perform, the reaction times being between 0.5 and 120 minutes, preferably about 30 minutes. Particularly when using mineral acids, temperatures of 100 ° and reaction times of the order of a few Minutes preferred.

Groups which can be split off hydrogenolytically are expediently removed by means of catalytically excited hydrogen. If the groups to be split off do not contain sulfur, then the usual catalysts, preferably noble

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metal, but also copper-chromium-oxide as well as Ulckel and Cobalt catalysts in embossing. The noble metal catalysts can preferably be used as supported catalysts (e.g. palladium on charcoal), also as oxide catalysts (e.g. platinum oxide) or as finely divided metal catalysts (e.g. platinum black) are present. Jiicke1 and cobalt catalysts are useful used as Raney metals, nickel also on kieselguhr or pumice stone as a carrier. Implementation is at normal pressure and room temperature or under increased pressure (up to about 200 at) and / or increased temperature (up to about 200 °). Inert solvents are preferably used Methanol, ethanol, isopropanol, tert-butanol, ethyl acetate, dioxane, tetrahydrofuran and water or mixtures this solvent.

Groups containing sulfur can also be used as hydrogenolytically cleavable groups Residues (e.g. in, 2- and / or 8-position of the purine system) to be available. Such residues are mainly

1
those of the formula SR in question. Raney catalysts are used for catalysis,

like Raney nickel or Raney cobalt, in lower alcohols (e.g. methanol, ethanol, n-propanol or isopropanol). The reaction times are for this reaction between 20 minutes and 15 hours, preferably 4-12 hours. You work at temperatures between 0 and 120 °, preferably at the boiling point of the solvent used.

The hydrogenolysis with Raney metals in alcohols can also apply to the cleavage of non-sulphurous groups, e.g. B. on the cleavage of 2-bromine and 2-iodine substituents in the purine residue.

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The starting materials for the reaction described above can be obtained in several ways. So you can z. B. ¥ (6) - (1,2,3,4-tetrahydro-naphthyl-2) -adenine, the in 9 digits by an equivalent of a silver or mercury atom or is substituted by trimethylsilyl, with a 1-halogen compound of D-ribose, the rest of them Hydroxy groups are protected, preferably with 2,3 »5-tri-O-acetyl-D-ribofuranosyl chloride, convert and receives the N (6) - (1,2,3,4-tetrahydronaphthyl-2) adenosine, which is provided with protective groups on the sugar.

You can also work according to the so-called fusion method by z. B. the F (6) - (1,2,3,4-tetrahydro-naphthyl-2) -adenine with 1,2,3,5-tetra-O-acetyl-D-ribofuranose in the presence of an acidic catalyst, z. B. of p-toluenesulfonic acid, in the melt. This method is also suitable for the preparation of adenosine derivatives substituted in the 2-position, ζ. Β. Ύοη 2 », 3 ', 5 ^! -Tri-O-acetyl-N (6) - (1,2,3,4-tetrahydro-naphthyl-2) -2-chloro-adenosine, applicable.

Another method for the preparation of N (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine derivatives provided with ßprotecting groups on the sugar is that 2 ^f , 3 ', 5 ^! -Tri-O-acetyl-adenosine or an adenosine derivative, which is provided with other protective groups on the sugar residue, with compounds of the formula II

wherein

Y means Cl or Br

II

3 0 9885/1358

under conditions similar to those given above. In this case, the N (1) -alkyl derivative is initially obtained, the then in the presence of alkaline agents, preferably ammonia or alcoholic sodium hydroxide solution, in the inventive Can rearrange compound (with or without protecting groups).

According to another method, 2 ', 3', 5 ^f -Tri-O-acetyl-N (6) - (1, 2, 3,4 ~ tetrahydro-naphthyl-2) -adenosine can be obtained by adding 1- ( 2 ', 3', 5'-Tri-O-acetyl-D-ribofuranosylJ ^ -cyanimidazol-5-amine with triethyl orthoformate and then a ring closure in the presence of 1,2,3 _} 4-tetrahydro-naphthyl- ( 2) -amine.. ·

One can also use 4- (1> 2,3j4-tetrahydro-naphthyl-2-amino) -6- / 2 ', 3', 5 ^f -tri-0-acetyl-D-ribofuranosyl- (1) -amino7- py £ imiäin-5-amine and reacting with methyl formate to give the desired 2 ^! , 3 ', 5'-Tri-O-aeetyl-N (6) - (1,2,3,4-tetrahydro-naphthyl-2) -adenosine get,

The same reactions can of course also be carried out with compounds in which the hydroxyl groups des Sugar residue by other groups, e.g. B. Isopropylidene groups or benzylidene groups are protected.

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The new compound can be used in admixture with solid, liquid and / or semi-liquid medicament carriers as medicaments in human or veterinary medicine. Those organic or inorganic substances which are suitable for parenteral or enteral (peroral or rectal) administration and which do not react with the new compound are used as carrier substances. Solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants are used in particular for parenteral administration. I ¹ Tablets, coated tablets, capsules, syrups, juices or suppositories are suitable for enteral application. The specified preparations can optionally be sterilized or mixed with auxiliaries.

The active ingredient can be administered orally in humans, preferably in a daily dose between 0.1 and 10 mg, in particular between 0.5 and 5 mg per kg of body weight, can be administered.

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example 1

2.9 g of 6-chloro-9- (ß-D-ribofuranosyl) -purine and 2.9 g of 2-amino- · 1,2,3,4-tetrahydro-naphthalene are heated to 100 for 2 hours, dissolved in methanol, treated with animal charcoal and filtered. F (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine crystallizes out directly from the piltrate. F. 118-120 ° (from methanol).

Example 2

3.0 g of 6-methylmercapto-9- (ß-D-ri'bofuranosyl) -purine and 3.0 g of 2-amino-1,2,3,4-tetrahydro-naphthalene are in the melt to 130 - 140 ° heated. Recrystallized from methanol gives N (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine; i ¹ . 118 - 120 ° (from methanol).

Example 3 ,

2.9 g of 6-chloro-9- (β-D-ri'bofuranosyl) -purine and 1.5 g of 2-amino-1,2,3,4-tetrahydro-naphthalene are boiled in 200 ml of isopropanol with 5 ml of triethylamine for 10 hours. The solvent is evaporated and the residue is treated with chloroform and water. The chloroform solution is dried and evaporated. F (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine is obtained; P. 118 - 120 ° (from methanol).

Example 4

17.3 g of 6-chloro-9- (2 ^!, 3 ', 5 ^! -Tri-0-acetyl-β-D-rilDofuranosy.l) -purine and 9.3 g of 2-amino-1,2,3 , 4-tetrahydro-naphthalene are boiled in 80 ml of isopropanol with 10 ml of triethylamine for 5 hours. Then it is evaporated, taken up with ether and filtered.

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The solution is evaporated, taken up in chloroform and chromatographed on 200 g of silica gel. It -is evaporated and the residue with 200 ml of saturated alcoholic ammonia solution Left for 6 days. It is evaporated again and chromatographed on 250 g of silica gel (elution agent: Chloroform: methanol = 95: 5). N (6) - (1,2,3,4-tetrahydro- naphthyl-2) adenosine; P. 118 - 120 ° (from methanol).

Example 5

23 g of N (6) - (1,2,3,4-tetrahydro-naphthyl-2) -2 «, 3 ', 5 ^l -tri-O-acetyl-adenosine (prepared from 1- (tri-0-acetyl -β-D-ritofuranosyl) -6-chloro-purine and 2-amino-1,2,3,4-tetrahydronaphthalene in isopropanol) are boiled for 90 minutes with a solution of 0.5 g of sodium in 0.5 l of methanol. Then it is neutralized with acetic acid, evaporated and the residue chromatographed on a silica gel column (700 g silica gel; elution with Qhlorbform / methanol = 99/1). N (6) ~ (1,2,3,4-tetrahydro-naphthyl-2) adenosine is obtained; 118-120 ° (from methanol).

Example 6

a) 1 g of N (6) - (1,2,3,4-Ietrahydro-naphthyl-2) -adenine are boiled with 10 ml of hexamethyl-disilazane for 15 hours. It is then evaporated and the residue is left to stand at room temperature for 3 days with 1.6 g of 2,3,5-tri-O- ■ benzyl-D-ribofuranosyl chloride in 50 ml of acetonitrile. The mixture is then boiled for 2 hours. The solvent is evaporated off and the residue is partitioned between water and chloroform, the chloroform layer is dried and evaporated to give 2 ', 3', 5 ^L -Tri-O-benzyl-IT (6) - (1,2,3,4-tetrahydronaphthyl-2 ) -adenosine as an amorphous syrup.

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b) The crude product obtained under a) is taken up in 50 ml of ethanol and 0.5 g of palladium-carbon at room temperature. temperature hydrogenated with shaking. The catalyst is filtered off and evaporated, and the residue is rubbed with water at. N (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine is obtained; 118-120 ° (from methanol).

Example 7. . -

a) 1.0 g of 2,6-bis-benzylthio-9 - (ß-D-ribofuranosyl) -purine and 0.5 g of 2-amino-1,2,3,4-tetrahydro-naphthalene are 12 Heated to 130 ° for hours and the melt dissolved in chloroform. It is washed with sodium carbonate solution and dried over sodium sulfate and evaporate. Crude - (1,2,3,4-tetrahydro-naphthyl-2) -2-benzylthio-adenosine is obtained.

b) The crude product obtained according to a) in 50 ml of ethanol is boiled with 6 g of Raney nickel for 12 hours. The catalyst will Filtrier't and the solution is then concentrated. N (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine is obtained; 118-120 ° (from methanol).

Example 8

1 g of N (6) - (1,2,3,4-tetrahydro-naphthyl-2) -2-chloro-adenosine in 100 ml of ethanol are mixed with 0.8 g of 10% palladium-carbon with the addition of 0.5 g of sodium acetate in a shaking apparatus Hydrogenated for 16 hours. The catalyst is filtered off with suction and the solution is concentrated. The residue is between chloroform / Water distributed and the chloroform solution evaporated after drying. N (6) - (1, .2,3,4-tetrahydro-naphthyl-2) adenosine is obtained; 118-120 ° (from methanol).

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Claims (1)

Claims 1 ^ N (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine. / 2.J Process for the preparation of N (6) - (1,2,3,4-tetrahydro-— naphthyl-2) adenosine, characterized in that a compound of the general formula I HIGH Η OH wherein XF, Cl, Br, J, SR ¹ , SOR ¹ or Alkyl with up to 6 carbon atoms, phenyl or benzyl
mean, with (1,2,3j4-tetrahydro-naphthyl-2) -amine or that one is a compound that is otherwise the N (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine corresponds, however, instead of Η atoms, solvolytic or hydrogenolytic carries cleavable groups, treated with a solvolytic or hydrogenolytic agent. 309885/1358 3. A process for the production of pharmaceutical preparations, characterized in that N (6) - (1,2,3,4-tetrahydronaphthyl-2) adenosine possibly together with at least one solid, liquid or semi-liquid auxiliary or brings the carrier and optionally with at least one other active ingredient into a suitable dosage form. 4. Pharmaceutical preparation containing an effective dose of N (6) - (1,2,3,4-tetrahydro-naphthyl-2) adenosine in addition to at least one solid, liquid or semi-liquid carrier or additive. 5. Pharmaceutical preparation containing 0.1-10 mg of N (6) - (1,2,3,4-tetrahydro-naphthyl-2) -adenosine in addition to at least a solid, liquid or semi-liquid carrier or additive. . 309885/1358