DE2139107A1 - N(6)-subst adenosine derivs - with coronary circulatory etc activity - Google Patents

Abstract

Title derivs. of formula (I): and their therapeutically acceptable salts (where A is -NH(CH2)nR1, 1,2,3,6,7,11b-hexahydro-4H-pyrazino- 2,1-a -isoquinolyl or (4-methylthiazolyl)-piperazinyl; R1 is (a) an opt. unsatd. N-contg. 6-membered ring which is opt. substd. by not >6C alkyl, is not >10C aralkyl, OH, keto, Cl, OCH3, methylenedioxy, is not >3C hydroxyalkyl or is not >6C alkylmercaptoalkyl, on to which a benzene ring may be used, and which 2 ring atoms may additionally be linked by a -CH2CH2- bridge, or (b) a 2-indolyl, benzofuryl, benzodioxanyl or benzothienyl residue; R2 is H, F, Cl, Br, NR3R4, OR3, SR3, NHNH2 or N3; R3 and R4 are H or is not >7C alkyl; and n is 0-4) are new cpds. which increases coronary flow and/or increase the oxygen partial pressure in coronary venous blood. They also have circulatory, antilipolytic and/or hypocholesterolaemic activity, and may be used as inters. for other pharmaceuticals.

Description

Heterocyclically substituted adenosine compounds The invention relates to the new adenosine derivatives of the general formula I, wherein A is a R1 - (CH2) n -NH, 1,2,3,6,7,11b-hexahydro-4H-pyraainoLT, i-α7isoquinolyl or (4-methylthiazolyl) piperazinyl radical, R1 optionally substituted, saturated or substituted by alkyl with up to 6 carbon atoms, aralkyl with up to 10 carbon atoms, hydroxyl, keto oxygen, chlorine, methoxy, methylenedioxy, hydroxyalkyl with up to 3 carbon atoms or alkylmercaptoalkyl with up to 6 carbon atoms unsaturated six-membered nitrogen-containing ring to which a benzene ring can also be attached, or to which two ring atoms can also be linked by an additional -CH2-CH2 bridge, or an indolyl- (2) -, benzofuranyl, Benzodioxanyl or benzothienyl radical, R² H, F, Cl, Br, NR³R4, OR², SR², NHNH2, N3, R³ and R4 independently of one another are hydrogen or alkyl with up to 7 carbon atoms and n 0, 1, 2 , 3 or 4 mean, as well as their therapeutically safe salts.

It has been found that these compounds are valuable pharmacological Possess properties. They increase the Coronax flow and / or enlarge it Partial pressure of oxygen in the coronary venous blood. You also have circulatory effects, lipolysis-inhibiting and / or cholesterol-lowering effects. The connections can accordingly be used as pharmaceuticals and also as intermediate products for manufacture other medicines are used.

The invention accordingly relates to adenosine derivatives of the general formula I and their therapeutically acceptable salts. Among the compounds I, those of the formulas Ia-Id are particularly preferred: wherein B is R6- (CH2) n1-NH-, 1,2,3,6,7,11b-hexahydro-4H -pyrazino [2,1-a] isoquinolyl- or (4-methyl-thiazolyl) -piperazinyl -Rest, R6 a pyridyl, isoquinolyl, tetrahydroisoquinolyl, tetrahydroquinolyl, indolyl (2), quinuclidinyl, benzotbienyl, optionally substituted by alkyl with 1-2 carbon atoms, benzyl, hydroxyl, keto oxygen, 2-hydroxyethyl or methyl mercaptomethyl -, benzofuranyl or benzodioxanyl radical, R7 is H, Cl, NH2, NH-NH2 and n1 is 0 or 1 where B has the meaning given where D is a R8- (CH2) n1-NH2-, 1,2,3,6,7, 1b-hexahydro-4H-pyrazino [2,1-a] isoquinolyl- or (4- Methylthiazolyl) piperazinyl radical and R8 is a saturated or unsaturated six-membered nitrogen-containing ring, optionally substituted by methyl, benzyl, hydroxyl, keto oxygen, 2-hydroxyethyl or methyl mercaptomethyl, to which a benzene ring can also be fused, or in which two ring atoms can also be fused can be connected to one another by an additional -CH2-CH2 bridge, and n1 and R7 have the meaning given, in which D has the meaning given.

The invention also relates to a process for the preparation of these compounds, which is characterized in that a compound of the general formula II, in which XF, Cl, Br, J, SR5, SOR5 or SO 2R5 and R5 are alkyl with up to 6 carbon atoms, phenyl or benzyl, and in which R2 has the meaning given, with an amine of the general formula III, A-NH2 wherein A has the meaning given, III is reacted or that a compound which otherwise corresponds to the general formula I, but which instead of H atoms carries solvolytically or hydrogenolytically cleavable groups, treated with a solvolytic or hydrogenolytic agent or that one Adenine derivative of the general formula IV, in which A and R2 have the meaning given, in the presence of a condensing agent, reacted with D-ribose or a D-ribose-yielding compound or that an adenosine derivative of the general formula V, wherein R¹, R² and n have the meaning given and An # is the equivalent of an anion, treated with an alkaline agent, and / or optionally then in the compound obtained d »r general formula I a substituent R2 by treatment with a nucleophilic agent in converts another substituent R2; and / or the adenosine derivative of the general formula I obtained is converted into its therapeutically acceptable salt with a corresponding acid.

The radical R1 primarily denotes an optionally substituted one Pyridyl, isoquinolyl, tetrahydroisoquinolyl, indolyl (2), quinuclidinyl, benzothienyl ' Benzofuranyl or benzodioxanyl radical. Among these residues are the optional substituted nitrogen-containing ring systems, especially the optionally substituted one Tetrahydroquinolyl, isoquinolyl or letrahydroisoquinolyl radicals are preferred.

* Tetrahydroquinolyl, As substituents there are e.g. in question: alkyl with up to 6 carbon atoms, e.g. methyl, ethyl, also propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-amyl, isoamyl, pentyl- (2), pentyl- (3), Neopentyl, 3-methyl-butyl- (2), 2-methyl-butyl- (1), tert-amyl, n-hexyl, isohexyl and / or hexyl- (2); Aralkyl with up to 10 carbon atoms, e.g. benzyl, also 2-phenylethyl, 3-phenyl-propyl, o-, m- and p-tolyl methyl, the dimethyl and trimethylbenzyl groups; Hydroxyethyl, also hydromethyl, hydroxy-n-propyl or hydroxy-isopropyl; Alkyl-mercapto-alkyl, e.g. methyl-mercapto-methyl, also ethyl-mercapto-ethyl, n-propyl-mercapto-n-propyl, methyl-mercapto-ethyl, methyl-mercapto-propyl, methylmercapto-butyl, ethyl-mercapto-methyl, Ethyl-mercapto-propyl, ethyl-mercapto-butyl, propyl-mercapto-methyl, propyl-mercapto-ethyl, Butyl-mercapto-methyl and butyl-mercapto-ethyl.

The radical R2 preferably denotes H; however, it can also contain chlorine, amino, Hydrazino, also fluorine, bromine, Ng3R4 (where R3 and / or R4 are not K), OX3 or N3.

The radicals R3 and R4 are preferably H.

n preferably denotes 0 or 1, but in particular 1.

Among the compounds of the formula II are those with X = Cl, SCH3 or S-CH2-C6H5 preferred.

The radical R5 means methyl, also e.g. ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl, isoamyl, pentyl- (2), pentyl- (3), Neopentyl, 3-methyl-butyl- (2), 2-methyl-butyl- (1), tert-amyl, n-hexyl, isohexyl or hexyl- (2).

In the case of the compounds I, which can be split off solvolytiscl instead of H atoms Wear groups come as such z. B. contemplated: on one or more heteroatoms Acetyl, propionyl, benzoyl or an R¹- (CH2) m-CO contained in the compound I Group (m = 0, 1, 2 or 3), also formyl, butyryl, isobutyryl, valeryl, isovaleryl, Caproyl, trifluoroacetyl, trichloroacetyl, toluoyl, p-nitrobenzoyl, methanesulfonyl and p-toluenesulfonyl; ether groups on the oxygen atoms of the sugar residue, such as triphenylmethyl ether or cyclic ether or acetal groups (the latter preferred in the 2 ', 3t-position), in particular isopropylidene or benzylidene groups.

As groups which can be split off by hydrogenolysis, for. B. in question: 0-aralkyl, z. B. O-benzyl groups or O- (p-nitro-benzyl) groups, in the 2- and / or 8-position Cl, Br, J, S-benzyl, SR5, SOR5 and / or S02R5 groups, one at an —NH group bonded amino or carbobenzoxy (benzyloxycarbonyl) or tert-butyloxycarbonyl group. Among the residues in the 2- and / or 8-position are the SCH3-, SC2H5- and S-benzyl residues are preferred.

In the compounds V, the An # radical can be an equivalent of an anion represent any inorganic or organic acid, e.g. B. the the Hydrochloric, bromic or hydroiodic acid. It preferably means Cl # The adenosine derivatives of the formula I can preferably be derived from the ribofuranosyl purine derivatives II and the Prepare amines III.

This reaction can e.g. B. be carried out without a solvent. You work at temperatures between 70 and 1600, the range between 100 and 1500, in particular between 120 and 1400, is preferred. The response times range between 1 and 100 hours, preferably between 2 and 24 hours. To the A base such as triethylamine can be added to the reaction mixture to increase the yield attached.

In this case, it is advisable to work at temperatures below 1000, preferably between 70 and 850. It is also possible under pressure in an autoclave to work. In this case, the reaction can end after one hour be. For work-up, the cooled reaction mixture can be dissolved in a suitable solvent, z. B. in dioxane, dimethylformamide or tetrahydrofuran, largely dissolved, insolubles are filtered off and the solvent is removed. The residue is z. B. in a suitable solvent such as ether, dichloromethane, carbon tetrachloride or preferably taken up in chloroform and with water, which optionally also may contain a small amount of acetic acid, shaken out. The products can by melting point (as far as can be determined), optical rotation, molecular weight, 1R spectrum and R-wer-t are characterized.

The Uiusezung the compounds II and III can also in the presence of a Solvents such as dimethylformamide, dioxane, tetrahydrofuran, methanol, ethanol, Propanol, n-butanol, isobutanol, sec-butanol, tert-butanol and higher alcohols, in particular, however, be carried out in the presence of isopropanol. One uses also mixtures of these solvents, e.g. B. a mixture of dimethylformamide and isopropanol 1: 1.

It is expedient with the addition of an inorganic or organic Base, e.g. B. pyridine or preferably triethylamine worked. You can do one too Add excess of the amine III. The reaction is carried out at temperatures between 0 and 1800, preferably carried out at the boiling point of the solvent used. The reaction times are approximately between 3 and 60 hours, preferably between 12 and 50 hours. - It can also z. B. can be worked at room temperature; here the reaction times can optionally be extended, e.g. B. on 4 days.

The compounds of formula I can also be obtained by a compound which otherwise corresponds to the formula I, but which instead of Carries H atoms solvolytically or hydrogenolytically cleavable groups, with solvolytically or hydrogenolytically acting agents.

The usual solvolytic agents are primarily used acyl group-releasing agents in question. As such, there are acidic and alkaline reagents Examples of suitable acids are aqueous hydrochloric or sulfuric acid. Advantageous alkali or alkaline earth metal alcoholates (e.g. sodium, potassium, calcium, Strontium or barium methylate, sodium or potassium ethylate), sodium or Potassium hydroxide or carbonate or ammonia is used. Among these agents are sodium methylate or ammonia preferred.

One works e.g. in inert solvents such as lower alcohols, e.g. methanol, ethanol or isopropanol, or in hydrocarbons such as benzene, Toluene, xylene, preferably in mixtures of these solvents with water. Appropriately if the reaction is carried out under mild conditions, e.g. P.

at temperatures between 0 ° and room temperature for one hour and several days, preferably for about 24-72 hours. However, it can work can also be carried out in the heat, e.g. at the boiling point of the solvent used, the reaction usually takes less time, e.g. between 1/2 minute and 2 hours, preferably between 30 and 90 minutes. The work-up can when using ammonia as a saponification agent by evaporation and absorption in a suitable solvent. When using another alkaline Deacylating agent, the alkaline reaction solution can be neutralized first, z. B. by adding equivalent amounts of acetic acid or - in the case of Bariu-mmethylat -, by introducing CO2 into the reaction solution The subsequent work-up can e.g. B. be made as indicated above.

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 become more 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; Of these acids, 60 - 90 goat aneisen- or acetic acid solutions or very dilute sulfuric or hydrochloric acid. One works in the Fagel at temperatures between 0 and 120 °, expediently at room temperature during longer reaction times, such as about 5 hours to 2 days; however can the reaction also at higher temperatures, e.g. at 100 °, carry out the Reali'i'i ': -' times between 0.5 and 120 minutes, preferably at about 30 minutes, lie. Temperatures of 1000 and reaction times on the order of a few minutes are preferred.

The removal of groups which can be split off hydrogenolytically is expedient made by catalytically excited hydrogen. Are the groups to be split off does not contain sulfur, then the usual catalysts, preferably noble metal, but also copper-chromium-oxide and nickel and cobalt catalysts are possible. 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. Nickel and Cobalt Catalysts are useful as Raney metals, nickel also on kieselguhr or pumice stone as Carrier used. The reaction is carried out at normal pressure and room temperature or under increased pressure (up to about 200 at) and / or increased temperature (up to about 2000) carried out. Inert solvents are used, preferably methanol, ethanol, Isopropanol, tert. -Butanol, ethyl acetate, dioxane, tetrahydrofuran or water or Mixtures of these solvents.

Groups containing sulfur can also be used as hydrogenolytically cleavable groups Groups (@@@@) in the starting compounds, which otherwise correspond to formula I, are available be. In this case, Rancy catalysts, such as Raney nickel, are used for splitting off or Raney cobalt, in lower alcohols (e.g.

Methanol, ethanol, n-propanol or isopropanol). The response times are in this reaction between 20 minutes and 15 hours, preferably at 48 hours. One works at temperatures between 0 and 120 °, preferably at the boiling point of the solvent used.

The hydrogenolysis with Raney metals in alcohols can also be apply the cleavage of non-sulfurous groups, e.g. to the cleavage of 2- or 8-bromo or joe-substituted in the purine residue. Also the conversion of Hydrazines or azido groups in amino groups are used with this reduction method performed.

The starting materials for the reaction described above can can be obtained in various ways. So you can z. B. heterocyclic in the N (6) position substituted adenine derivatives which are in the 9-position an X equivalent of a silver or Carrying mercury atoms or the trimethylsilyl group with a 1-halogen compound the D-ribose, the remaining hydroxyl groups of which are protected, preferably with 2,3, 5-tri-0-acetyl- or benzyl-D-rtbofuranosylchlcrid, convert and get that on the sugar adenosine of formula 1 provided with protective groups.

One can also work according to the so-called fusion method by using for example, an adenine which is heterocyclically substituted in the N (6) position is substituted with 1,2,3,5-tetra-O-acetyl-D ribofuranose in the presence of an acidic catalyst, e.g.

of p-toluenesulfonic acid, converts in the melt. This method is; also for the preparation of adenosine derivatives substituted in the 2-position, e.g. of 2-chloro-2 ', 3', 5'-tri-O-acetyl-adenosines of the general formula I, applicable.

Another method of making am sugars with protecting groups provided adenosine derivatives of the formula I consists in that 2 ', 3', 5'-tri-O-acetyl-adenosine or an adenosine derivative, which is provided with other protective groups on the sugar residue is, with compounds of the formula VI, R¹- (CH3) 2-X in which R1, n and X are as indicated Be-VI have meaning under similar conditions as above for the implementation of Compound II indicated with compound III, converts. There are initially the N (1) -alkyl derivatives are obtained, which are then, as described below, in Presence of alkaline agents, preferably ammonia or alcoholic Sodium hydroxide solution, into which compounds I (with or without a protective group) can be rearranged. This method can be carried out primarily with compounds VI in which R is an oxygen or sulfur-containing heterocycle.

A variant of this method is based on the same adenosine derivatives and sets them with compounds of WOrmel VII, where R1 - CO-- Hal R1 is the specified VII has meaning and Hal has Ci, 13r or J means to. The N (6) acyl derivatives obtained are in inclusion with a complex hydride, e.g. B. with lithium aluminum hydride, reduced. You can also use free adenosine with 4 moles of compound VII (Hal = Cl) react and treat the product obtained with lithium aluminum hydride. It will the CO group adjacent to the N (6) group on the adenosine residue is reduced to a CH2 group and at the same time the acyl radicals located at the sugar distillate are split off reductively.

Another method can be heterocyclic in the N (6) position substituted 2 ', 3', 5'-tri-O-acetyladenosine derivatives are obtained by adding 1- (2 ', 3', 5'-tri-O-acetyl-D-ribofuranosyl) -4-cyano-imidazole-5 -amin with orthoformic acid triäthyiester reacts and then a ring closure in Presence of an amine of formula III makes.

One can also use 6- [2 ', 3', 5'-tri-O-acetylamino7-pyrimidin-5-amines which are heterocyclically substituted in the 4-position go out and react with, methyl formate to the desired in N (6) position heterocyclically substituted 2 ', 3', 5'-tri-O-acetyl-adenosine derivatives reach.

The same reactions can of course also be carried out with compounds perform, in which the hydroxyl groups of the sugar residue are replaced by other groups, e.g. isopropylidene groups or benzylidene groups are protected.

I also leave the adenosine derivatives 1 by reacting compounds of the formula IV with D-ribose or a D-ribose-yielding compound in the presence obtained a condensing agent. ilbn uses microbiologicals appropriately or organic condensation agents containing phosphate As microbiological condensation agents are suitable e.g.

Submerged cultures of Bacillus subtilis, in particular the ATCC strain 13952. It is expedient to work with nutrient solutions, all of which are used for the growth of the Microorganism and carbon and nitrogen sources suitable for enzymatic conversion Contained in appropriate quantities and proportions and which also contain the common salts (phosphates, sulfates, trace elements) and active ingredients (vitamins) or complex substrates (yeast extract, meat extract) are added. The pH of the Reaction broth can vary between 5 and 9 and is preferably between pH 6.5 and 7.5.

One works at temperatures between 20 and 400, preferably between 25 and 35 °. During the reaction it is possible to aerate the reaction broth. The starting substance can be added to the reaction broth at the time of inoculation or preferably also later, e.g. B. after 20 hours, are added. As D-ribose-producing compounds are all commonly used in the cultivation of microorganisms Carbon and / or nitrogen sources, e.g. 13. as carbon sources: Glucose, Galactose, mannose, fructose, sucrose glycerine, potato starch, corn steep liquor, Malt extract (maltose), molasses, peptones, pectins, yeast extracts, beet pulp; as nitrogen sources: amino acids, peptones, yeast extracts, albumin or soy meal. The reaction can also be carried out with a suspension of grown, but then centrifuged or filtered and optionally washed organisms in water or buffer solution carried out under the conditions specified above (pH value, air, temperature) will. For isolation, extraction is preferably carried out with a suitable solvent, z. B. dichloromethane, chloroform or ether.

The attachment of D-ribose to an adenine derivative of the formula IV can also in the presence of a phosphate-containing organic condensing agent, e.g. of phenyl polyphosphate. One works z. B. with the addition of a acidic catalyst, preferably an inorganic mineral acid, e.g. B. of hydrochloric acid, in an organic, inert solvent, such as. B. dimethyl sulfoxide or preferred Dimethylformamide. In the reaction, the adenine derivative IV initially becomes a short time heated with the polyphosphate to temperatures between 30 and 700, preferably to 500, the dissolved sugar is added, the solvent removed and the residue a few minutes, preferably about 10 minutes, to 50 - 1200, preferably to 70 - 900, heated. The work-up is carried out by neutralization, preferably with ion exchangers, performed.

The adenosine derivatives I can also be converted into the 1 position substituted adenos inderivate V obtained with alkaline agents. As alkaline Means come inorganic or organic bases, such as (possibly diluted) aqueous solutions of altali, alkaline earth or heavy metal hydroxides (e.g. 13th of Sodium or potassium hydroxide), sodium or potassium carbonate or preferably of Ammonia, also organic bases such as aniline, triethylamine and others in question. The reaction is carried out in a suitable solvent, e.g. B. water, lower alcohols (such as methanol, ethanol, isopropanol), tetrahydrofuran or dioxane, or in Mixtures of these solvents at temperatures between 0 and about 1,000, preferably at 65-900, and takes 1/2 to 5 hours, preferably about 2 hours.

The starting compounds V can be converted into adenosine or its derivatives (which can be provided with a protective group as an intermediary) with alkylating agents of the formula VI.

A preferred variant of this process is that one on the isolation of the compounds V dispensed with, and - starting from adenosine and Compounds VI - the intermediate solution of the compounds V is alkaline adjusts and warms up for a short time. In this way, the connections are obtained immediately I.

In the compounds of the formula I obtained, if desired, the R² substituent by treating one nucleophilic agent against another Substituents R² are exchanged. This can preferably be done in the case of compounds I. done with R2 = Cl. One treats z. B. with a nucleophilic compound of the Formula VIII, wherein Me -Q Me H or an equivalent of an VIII alkali, alkaline earth or heavy metal atom and Q denotes NR³R4, OR³, SR³, NH-NH2 or N3, in one suitable solvent. - The compounds I with R2 = RH-NH2 or 4% are z. B. accessible by adding the corresponding chlorine compound in an inert solvent, such as dimethylformamide, tetrahydrofuran or dioxane, with hydrazine hydrate or with sodium azide, optionally reacted in the autoclave; the reaction is usually after 12 hours completed.

The more basic among the compounds I can optionally by treatment with acids into their therapeutically safe acid addition salts be transferred. For salt formation one uses z. B. inorganic acids or organic carboxylic or sulfonic acids, for example hydrochloric acid, hydrobromic acid, Sulfuric acid, malonic acid, succinic acid, maleic acid, citric acid, methanesulfonic acid.

The new compounds can be mixed with solid, flü's and / or semi-liquid pharmaceutical carriers as pharmaceuticals in human or veterinary medicine The carrier substances used are organic or inorganic Substances in question which are for parenteral or enteralc (peroral or rectal) application are suitable and do not react with the new compounds, such as for example water, glycerine, vegetable oils, natural or synthetic triglycerides (e.g. cocoa butter), benzyl alcohols, polyethylene glycols, suitable higher fatty alcohols, Gelatine, cellulose derivatives, lactose, starch, such as potato starch, corn starch, Amylopectin, sucrose, sorbitol, mannitol, laminaria powder, citrus pulp powder, Magnesium stearate, talc, gum arabic, titanium dioxide, petrolatum, cholesterol. To the Solutions, preferably oily or aqueous, are used in particular for parenteral administration Solutions, as well as suspensions, emulsions or implants; this will be liquids conveniently packed in ampoules. Suitable for enteral application Tablets, coated tablets, capsules, syrups, juices or suppositories. The specified preparations can optionally be sterilized or with auxiliaries such as varnishes, lubricants, preservatives, Stabilizers or wetting agents, solubilizers, emulsifiers, plasticizers, Salts to influence the osmotic pressure, buffer substances, sweet, colored, Flavors and / or aromas are added.

The active ingredients are preferably used in a dosage of 0.05 to 200 mg administered per dosage unit.

Example 1 2.86 g of 6-chloro-9- (β-D-ribofuranosyl) purine and 2.2 g of 2-methyl 3-hydroxy-4-aminomethyl-5-methylmercaptomethyl-pyridine are dissolved in 200 ml of isopropanol heated to 800 with 6 ml of triethylamine for 2 days. It is then evaporated and made with chloroform and water added. After a short time, N (6) - [2-methyl-3-hydroxy-5-methylmercaptomethyl-pyridyl- (4) -methyl] adenosine crystallizes the end. Mp 252 ° (from methanol).

Analogously with 2-benzyl-3-amino-quinuclidine 2-aminomethyl-pyridine 1-aminomethyl-3-methyl-isoquinoline 1-aminomethyl-3-methyl-6-methoxy 1-aminomethyl-3-methyl-6,7-dimethoxy-isoquinoline 1-aminomethyl-3-methyl-6-isoquinoline 1-aminomethyl-3-methyl-6,7-dichloro-isoquinoline and 1-aminomethyl-3-methyl-6,7-methylenedioxy-isoquinoline the following compounds obtained: N (6) - [2-benzyl-quinuclidine- (3)] - adenosine, m.p. 103-105 ° (from isopropanol) N (6) - [pyridyl- (2) -methyl] -adenosine, mp 148-150 ° (from methanol) N (6) - [3-methyl-isoquinolyl- (1) -methyl] -adenosine, F. 230-2320 (from the reaction mixture) N (6) - [3-methyl-6-methoxy-isoquinolyl- (1) -methyl] adenosine N (6) -Z3-methyl-6,7-dimethoxy-isoquinolyl- (1) -methy g -adenosine N (6) - [3-Methyl-6-chloro-isoquinolyl- (1) -methyl] adenosine N (6) - [3-methyl-6,7-dichloro-isoquinolyl- (1) -methyl] -adenosine N (6) - [3-methyl-6,7-methylenedioxy-isoquinolyl- (1) -methyl] adenosine.

Example 2 4.3 g of 6-chloro-9- (β-d-ribofuranosyl) -purine and 2.7 g of 3-amino-2-oxo-1,2,3,4-tetrahydroquinoline are heated to 500 in 30 ml of dimethylformamide with 6 ml of triethylamine for 2 days. It is cooled, filtered and evaporated. N (6) - [1,2,3,4-tetrahydro-2-oxo-quinolyl- (3)] - adenosine is obtained, F. 241-2420 (from isopropanol).

3-Amino-1,2,3,4-tetrahydroquinoline is used analogously to make 2-aminomethyl-benzodioxane and 3-aminomethyl-benzothiophene, 2-aminomethyl-benzofuran, the following compounds obtained: N (6) - [1,2,3,4-tetrahydroquinolyl- (3)] adenosine, F. 195 - 1970 (from isopropanol) N (6) - [Benzodioxanyl- (2) -methyl] -adenosine, mp 170-173 ° (from Xthanol / ether) and N (6) - [Benzothienyl- (3) -methyl] -adenosine, F. 264-2670 (from methanol).

N (6) - [Benzofuranosyl- (2) -methyl] adenosine, mp 174-177 ° (from isopropanol).

Example 3 2.5 g of 6-chloro-9- (β-D-ribofuranosyl) -purine and 3.5 g of 2-aminomethyl-indole are heated to 100 ° for 2 hours, dissolved in methanol, treated with animal charcoal and filtered, N (6) - [indolyl (2) methyl] adenosine crystallizes directly from the filtrate the end.

B. 140-1420 (from methanol).

Analogously with 1-Qminomethyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline 1-aminomethyl-2- (2-hydroxyethyl) -1,2,3,4-tetrahydroisoquinoline 1-aminomethylisoquinoline 1-aminomethyl-3-methyl-1,2,3,4-tetrahydroisoquinoline, 1-aminomethyl-3-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline 1-aminomethyl-3-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 1-aminomethyl-3-methyl-6-chloro-1,2,3,4-tetrahydroisoquinoline 1-aminomethyl-3-methyl-6,7-dichloro-1,2,3,4-tetrahydroisoquinoline 1-aminomethyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline 1-aminomethyl-2-methyl-1> 2,3,4-tetrahydroisoquinoline 1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline and 1- (4-methyl-thiazolyl-2) -piperazine the following connections obtained: N (6) - [2-Benzyl-1,2,3,4-tetrahydro-isoquinolyl- (1) -methyadenosine, dihydrochloride F. 154 - 1550 (from ethereal hydrochloric acid) InJ (6) -L2- (2-hydroxyethyl) -1,2,3,4-tetrahydroFisoquinolyl- (1) -methyl7-adenosine, Dihydrochloride 237-2390 (from methanol) N (6) - [Isoquinolyl- (1) -methyl] -adenosine, F. 225- (from dioxane) N (6) - [3-methyl-1,2,3,4-tetrahydroisoquinolylmethyl] adenosine, M.p. 138-140 ° (from ethane N (6) - g -methyl-6-methoxy-1,2,3,4-tetrahydro-isoquinolyl- (1) -methyl7-adenosine N (6) - [3-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroquinolyl- (1) -methyl] -adenosine N (6) -L) -Methyl 1-6-chloro-1, 2,3,4-tetrahydroisoquinolyl (1) methyl] adene N (6) -L3-methyl-6,7-dichloro-1h2,3,4-tetrahydroisoquinolyl- (1) -methyl7-adenosine N (6) - [3-methyl-6,7-methylenedioxy-1, 2,3,4-tetrahydroquinolyl (1) methyl] adenosine N (6) -g -Methyl-1,2,3,4-tetrahydroisoquinolyl- (1) -methyl7-adenosine, amorphous (from Ethanol) N (6) - [1,2,3,6,7,11b-Hexahydro-4H-pyrazino [2,1-a] quinolyl-7-adenosine, B. 230-232 ° (from ethanol) and N (6) - [4- (4-methyl-thiazolyl- (2)) - piperazinyl] -adeno B. 190 - 1910 (made from ethanol).

Example 4 2.5 g of 6-methylmercapto-9- (β-D-ribofuranosyl) -purine and 3.8 g of 1-aminomethyl-3-methyl-isoquinoline are heated to 130-1400 for 10 hours. The cooled residue is taken up in chlorine form and triturated with ether. N (6) - (3-methylisoquinolyl (1) methyl) adenosine, mp 230-2320 (from isopropanol) is obtained.

The others given in Examples 1-3 are obtained analogously Amines the adenosine derivatives listed there.

Example 5 13 g of crude N (6) - [benzofuranyl- (2) -methyl - [- 9- [2 ', 3', 5'-tri-O-acetyl-β-D-ribofuranosyl] -purine (Can be prepared from 8 g of 6-chloro-9- (2 ', 5r, 5t-tri-0-acetyl-ß-D-ribofuranosyl) -purine and 3 g of 2-aminomethyl-benzofuran by 3-day heating to 600 in the presence of 25 ml of dimethylformamide and 10 ml of triethylamine) are mixed with 200 ml of alcoholic ammonia solution Left to stand at room temperature for 3 days. Then it is evaporated. You get N (6) - [Benzofuranyl- (2) -methyl] -adenosine, m.p. 174-177 ° - (from isopropanol).

Analogously, the corresponding compounds are acetylated on the sugar residue obtained by deacylation the following compounds: N (6) -1ethyl-3-hydroxy-5-methylmercaptomethyl-pyridyl- (4) -methyl7-adenosine, F. 252O (from methanol) N (6) - [2-Benzyl-quinuclidinyl- (3)] - adenosine, M.p. 103-105 ° (from isopropanol) N (6) - [pyridyl- (2) -methyl] adenosine, B. 148-150 ° (from Methanol) -N (6) - [3-methyl-isoquinolyl- (1) -methyl] -adenosine, m.p. 230-2320 N (6) - / 3-methyl-6-methoxy-isoquinolyl- (1) -methyl 7 -adenosine N (6) -r-methyl-6,7-dimethoxy-isoquinolyl- (1) -methyl7-aenosine N (6) - [3-methyl-6-chloro-isoquinolyl- (1) -methyl-adenosine N (6) - [3-methyl-6,7-dichloro-isoquinolyl- (1) -methyl] -adenosine N (6) - / 3-methyl-6,7-methylenedioxy-isoquinolyl- (1) -methyl7- adenosine N (6) - [1,2,3,4-tetrahydro-2-oxo-quinolyl- (3)] - adenosine, F. 241 - 2420 (from isopropanol,) N (6) - [1,2,3,4-tetrahydroquinolyl- (3)] - adenosine, mp 195-197 ° (from isopropanol) 0 N (6) - [Benzodioxanyl- (2) -methyl] -adenosine, mp 170-173 ° (from ethanol / ether) N (6) - [Benzothienyl- (3) -methyl] -adenosine, M.p. 264-267 ° (from methanol) N (6) - [indolyl- (2) -methyl] adenosine, M.p. 140-142 ° (from Methanol) N (6) - / 2-benzyl-1,2,3,4-tetrahydro-isoquinolyl- (1) -methyl7-adenosine, dihydrochloride, F. 154 - 155 (from ethereal hydrochloric acid) N (6) -2 / 2- (2-hydroxyethyl) -1,2,3,4-tetrahydro-isoquinolyl- (1) -methyl7-adenosine, D'ihydrochloride 237 - 2390 (from methanol) N (6) - [Isoquinolyl- (1) -methyl] -adenosine, 225-228 ° (from dioxane) N (6) -Z3-methyl-1,2,3,4- »tetrahydro-isoquinolyl- (1) -methyl7-adenosine, M.p. 138-140 ° (from ethanol) N (6) - [3-methyl-6-methyl-1,2,3,4-tetrahydro-isoquinolyl- (1 ) -methyl7-adenosine N (6) - / D-methyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolyl- (1) -methyl7-adenosine N (6) - / 3-methyl-6-chloro-1,2,3,4-tetrahydroisoquinolyl- (1) -methyl] adenosine N (6) - [3-methyl-6-dichloro-1,2,3,4-tetrahydroisoquinolyl- (1) -methyl7-adenosine N (6) - [3-methyl-6,7-methylenedioxy-1 , 2,3,4-tetrahydro-isoquinolyl- (1) -methyl7-adenosine N (6) - g methyl-1,2,3,4-tetrahydroisoquinolyl- (1) -methyl7-adenosine, amorphous (from ethanol) N (6) - [1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinolinyl] adenosine, B. 230-2320 (from ethanol) and N (6) -14- (4-methyl-thiazolyl- (2) -piperazinyl7-adenosine, F. 190 - 1910 (from ethanol).

Example 6 13 g of crude N (6) - [benzofuranyl- (2) -methyl] -9- (2 ', 3', 5'-tri-O-acetyl-β-D-ribofuranosyl) -purine (prepared as in Example 5) are mixed with a solution of 0.2 g of sodium in 200 ml of methanol boiled for 90 minutes. It is then neutralized with acetic acid and evaporated and the residue is chromatographed on a silica gel column (150 g of silica gel; elution with chloroform: methanol = 99.1). N (6) - [Benzofuranyl- (2) -methyl7-adenosine, F. 174-177O (from isopropanol).

Example 7 a) 0.9 g of N (6) - (3-methyl-isoquinolyl (1) -methyl) adenine are boiled with 10 ml of hexamethyl disilazane for 15 hours. Then it is injected and the residue with 1.6 g of 2,3,5-tri-O-benzyl-D-ribofuranosyl chloride in 50 ml Acetonitrile left to stand at room temperature for 3 days.

It is then boiled for 2 hours. The solvent is evaporated and the residue partitioned between water and chloroform. The chloroform layer is dried and evaporated. 2 ', 3', 5'-tri-O-benzyl-N (6) - [3-methyl-isoquinolyl- ( 1 methyl7-adenosine as an amorphous syrup.

b) The crude product obtained under a) is taken up in 50 ml of ethanol and hydrogenated on 0.5 g of palladium-carbon at room temperature with shaking. Man the catalyst is filtered off, evaporated and the residue is rubbed with water. N (6) - [3-methyl-isoquinolyl- (1) -methyl] adenosine, mp 230-2320 (from isopropanol) is obtained.

The other compounds mentioned in Example 5 are made analogously obtain.

Example 8 a) 1.0 g of 2,6-bis-benzylthio-9- (β-D-ribofuranosyl) -purine and 0.5 g of 1-aminomethyl-3-methyl-isoquinoline are heated to 1300 for 12 hours and the melt dissolved in chloroform.

It is washed with sodium carbonate solution and dried over sodium sulfate and evaporates. Crude N (6) - / 3-methylisoquinolyl (1) methyl] -2-benzylthio-adenosine is obtained.

b) The crude product obtained according to a) in 50 ml of ethanol is mixed with 6 g Raney nickel cooked for 12 hours. The catalyst is filtered off and the solution then concentrated. Ma 'receives N (6) - [3-methyl-isoquinolyl- (1) -methyl] adenosine; F. 230-2320 (from isopropanol).

Example 9 1.0 g of N (6) -13-methyl-isoquinolyl- (1) -methyl7-2-chloro-adenosine in 100 ml of ethanol with 0.8 g of 10 point palladium-carbon with the addition of 0.5 g of sodium acetate hydrogenated in a shaker for 16 hours. The catalyst is suctioned off and the solution is concentrated. The residue is between chloroform / water distributed and the chloroform solution evaporated after drying. Amorphous is obtained N (6) - [3-methyl-isoquinolyl- (1) -methyl] adenosine; 230-232 ° (from isopropanol).

Example 10 250 mg of 2-amino-6-chloro-9- (ß-D-ribofuranosyl) -arin and 180 mg of 1-aminomethyl-3-methyl-1,2,3,4-tetrahydroisoquinoline are used in 15 ml of isopropanol boiled with 1 ml of triethylamine for 15 hours'. Then it is evaporated. You get N (6) - [3-methyl-isoquinolyl- (1) -methyl] -2-amino. @osin as an amorphous product with a R12 value of 0.72 (mobile phase methanol: triethylamine = 9: 1).

Example 11 10 1 of a sterile nutrient solution are used in a small fermenter from 1.0% glucose, 0.5% peptone, 0.2% yeast extract, 0.1% ammonium primary phosphate, 0.05% magnesium sulfate and 0.001% Iron (II) sulfate (pH 6.8) with inoculated into a submerged culture of Bacillus subtilis. The culture grows with aeration and stirring at 28 ° and, after 20 hours, 1 g of N (6) - (3-methyl-isoquinolyl- (1) -methyl) -adenine is added. The reaction has ended after 48 hours (control by thin layer chromatography). It is then extracted with chloroform, washed with water, over sodium sulfate dried, mixed with animal charcoal and shaken thoroughly, filtered and evaporated. With ether, N (6) - (3-methyl-isoquinolyl- (1) -methyl) adenosine is obtained; B. 230-2320 (from isopropanol).

The other compounds mentioned in Example 5 are obtained analogously.

Example 12 2 g of N (6) - [3-methyl-isoquinolyl- (1) -methyl] adenine in 100 ml of dimethylformamide are mixed with 0.6 ml of concentrated hydrochloric acid and 3 g of phenyl polyphosphate offset. The mixture is heated to 500 for 10 minutes and 0.2 g of ribose in 50 ml of dimethylformamide is added to. The solvent is removed, the residue is heated to 1000 and for 3 minutes dissolves in 5 ml of a water-methanol mixture (1: 1). It is neutralized with 2N NaOH, cools, filtered and evaporated. N (6) - [3-methylisoquinolyl- (1) -methyl7-adenosine is obtained, F. 230-2320 (from isopropanol).

Example 13 2.67 g of adenosine in 70 ml of dimethylformamide are added 291 g of 2-chloromethyl-benzodioxane 24 heated to 800 for 5 tunds-n. The solvent is evaporated and the residue is taken up in water. It is then concentrated with 20 ml Ammonia heated to 80-900 for 2 hours. It is evaporated and between chloroform and water distributed. The chloroform solution is dried and evaporated. You get N (6) - [Benzodioxanyl- (2) methyl] adenosine; B. 170 - 1730 (from ÄthanoVÄther).

The other compounds mentioned in Example 5 are analogously converted from adenosine obtain.

Example 14 1 g of N (6) - / 1,2,3,4-detrallydro-3-methyl-isoquinolyl- (1) -methyl7-2-chloro-adenosine (prepared according to Example 15) in 20 ml of dioxane is added with 2 ml of 85% hydrazine hydrate for 24 hours cooked. the solution is evaporated and chromatographed on a silica gel column (Mobile phase: chloroform: methanol = 1: 1). N (6) - [1,2,3,4-tetrahydro-3-methyl-isoquinolyl- (1) -methyl] -2-hydrazino-adenosine is obtained.

Example 15 2 g of 2,6-dichloro-9- (2 ', 3', 5'-tri-0-acetyl-β-D-ribofuranosyl) -purine and 1.4 g of 1-aminomethyl-3-methyl-1,2,3,4-tetrahydroisoquinoline in 100 ml of isopropanol are boiled in the presence of 10 ml of triethylamine for 20 hours. The mix will afterward evaporated. There is an advantage between a mixture of chloroform and water, the a few drops of glacial acetic acid have been added beforehand, shake and separate the chloroform layer then off. After drying, it is evaporated.

The residue is mixed with 100 ml of an IN methanolic barium methylate solution cooked. One then passes in carbon dioxide for 0 minutes, evaporates and takes in Methanol on.

After filtration, it is evaporated in a mixture of chloroform: methanol = 9: 1 added and purified by means of silica gel chromatography. N (6) - [1,2,3,4-tetrahydro-3-methyl-isoquinolyl- (1) -methyl] -2-chloro-adenosine is obtained, Example 16 4.9 g of N (6) - [2- (2-hydroxyethyl) -1,2,3,4-tetrahydroisoquinolyl- (1) methyl] adenosine in 25 ml of isopropanol are treated with 20 ml of ethereal hydrochloric acid. This crystallizes N (6) - [2- (2-hydroxyethyl) -1,2,3,4-tetrahydroisoquinolyl- (1) methyl] adenosine dihydrochloride the end. B. 237-2390 (from methanol).

Claims (22)

Claims 1. Adenosine derivatives of the general formula I, wherein A is R¹- (CH2) n -NH-, 1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinolyl- or (4-methyl-thiazolyl) -piperazinyl- Radical, R1 is optionally substituted by alkyl with up to 6 carbon atoms, aralkyl with up to 10 carbon atoms, 1-hydroxyl, keto oxygen, chlorine, methoxy, methylenedioxy, hydroxyalkyl with up to 5 carbon atoms or alkyl mercaptoalkyl with up to 6 C-atoms substituted, saturated or unsaturated six-membered nitrogen-containing ring, to which a benzene ring can also be fused, or in which two ring atoms can be linked by an additional -CH2-CH2 bridge, or an indolyl- (2) -, Benzofuranyl, benzodioxanyl or renæothienyl radical 5 R2 H, F, Cl, Br, NR³R4, oR3, SR3, NHNH2, N3 R3 and R4 independently of one another hydrogen or alkyl with up to 7 carbon atoms and n 0, 1, 2 , 3 or 4 mean, as well as their therapeutically safe salts. 2. N (6) - [pyridyl- (2) methyl] adenosine. 3. N (6) - [2-methyl-3-hydroxy-5-methylmercapromethyl-pyridyl- (4) -methyl] adenosine. 4. N (6) - [4- (4-Methyl-thiazolyl-2) -piperazinyl] -adenosine. 5. N (6) - [Isoquinolyl- (1) -methyl] adenosine. 6. N (6) - [3-methyl-isoquinolyl- (1) -methyl] adenosine. 7. N (6) - [1,2,3,4-tetrahydroquinolyl- (3)] adenosine. 8. N (6) - [2-methyl-1,2,3,4-tetrahydroisoquinolyl- (1) -methyl] adenosine. 9. R (6) 5-methyl-1,2,3,4-tetrahydroisoquinolyl (1) methyl] adenosine. 10. N (6) - [2-Benzyl-1,2,3,4-tetrahydroisoquinolyl- (1) methyl] adenosine. 11. N (6) - [2- (2-hydroxyethyl) -1,2,3,4-tetrahydroisoquinolyl- (1) methyl] adenosine. 12. N (6) - [1,2,3,4-tetrahydro-2-oxo-quinolyl- (3)] adenosine. 13. N (6) - [1,2,3,6,7,11b-Hexahydro-4H -pyrazino [2,1-a] isoquinolyl] adenosine. 14. N (6) - (Indolyl-2-methyl) adenosine. 15. N (6) - [2-Benzyl-quinuclidinyl- (3)] - adenosine. 16. N (6) - [Benzothienyl- (3) -methyl] adenosine. 17. N (6) - [Benzofuranyl- (2) -methyl] adenosine. 18. N (6) - [benzodioxanyl- (2) -methyl] adenosine. 19. A process for hexagonal formation of adenosine derivatives of the general formula I and, if appropriate, their therapeutically acceptable salts, characterized in that a compound of the general formula II, where XF, Cl, Br, J, SR5, SOR5 or SO2R5 and RS are alkyl with up to 6 carbon atoms, phenyl or benzyl, and where R has the meaning given, with an amine of the general formula III, A- NH2, where A has the meaning given. III is reacted or that a compound which otherwise corresponds to the general formula I, but which, instead of hydrogen atoms, carries groups that can be split off solvolytically or hydrogenolytically, is treated with an agent having a solvolytic or hydrogenolytic action, or an adenine derivative of the general formula IV, wherein A and R² have the meaning given, in the presence of a condensing agent with D-ribose or a D-ribose-providing compound, or that an adenosine derivative of the general formula V, where R1, R2 and n have the given meaning and An # denotes the equivalent of an anion, treated with an alkaline agent, and / or optionally then a substituent R2 in the compound of the general formula I obtained by treatment with a nucleophilic J: converts ttCl to another substituent R²; and / or the adenosine derivative of the general formula I obtained is converted into its therapeutically acceptable salt with a corresponding acid 20. A method for the manufacture of pharmaceutical preparations, thereby characterized in that at least one compound of formula 1 may optionally be combined with at least one solid, liquid or semi-liquid Hilis or Dräger substance and optionally with at least one further active ingredient in a suitable dosage form brings 21. A pharmaceutical preparation containing an effective dose of a compound of formula I in addition to at least one solid, liquid or semi-liquid carrier or additive. 22. A pharmaceutical preparation containing 0.05-200 mg of a compound of formula I in addition to at least one solid, liquid or semi-liquid carrier or additive.