DE1913816A1 - N (6)-alkyladenosines - Google Patents

Abstract

Adenosines of formula (I):- where R1 is 1-6C alkyl, and R2 is Me or (if R1 Me) H, effect the heart and circulating systems, and influence lipid transfer. Cpds. (I) may be prepd. by reaction of the corresponding 6-halor or mercapto-purineriboside with an amine of formula R1R2 MeCNH2, with appropriate protection of th OH gps.

Description

N (6) -älky1-adenosine derivatives and process for their preparation.

The present invention relates to new N (6) -alkyl-adenosine derivatives of the general formula I. in which R1 is a straight-chain or branched alkyl radical having 2-6 carbon atoms, while R2 is hydrogen or a methyl group, and a process for their preparation.

It has been found that these new derivatives of adenosine have particularly interesting cardiovascular effects and also influence fat metabolism. The process according to the invention for the preparation of compounds I is characterized in that mar. Purine ribosides of the general formula II, in which X denotes a halogen atom or a reactive mercapto group, with amines of the general formula III in which R1 and R2 have the meaning given above, is reacted, if desired, the OH groups of the ribose radical being blocked as an intermediate by easily cleavable protective groups.

As starting compounds II are preferably used the chlorine and bromine derivatives; such substances are e.g. in Coll.Czech.Chem.

Comm. 30, 1880 (1965) or in Biochemical Preparations 10, 148 (1963) described.

To carry out the process according to the invention, the reaction components are expediently in a suitable inert solvent, preferably higher-boiling one Alcohols or ethers (e.g. isopropanol, n-propanol, butanol, tetrahydrofuran or Dioxane) optionally in the presence of an equimolar amount of a tertiary amine (preferably triethylamine? heated or left at room temperature for several days.

But you can also do without a solvent and instead one of the reaction components (preferably the amine component III) in excess insert.

In the event that the hydroxyl groups of the compounds II are intermediate wants to block, one uses the protective groups customary in sugar chemistry. Therefor acyl groups can be used (preferably acetyl or benzoyl radicals), or they are used Ketals, e.g. the 2 ', 3' -isopropylidene compounds, which are formed after condensation can easily be converted into the free 2 ', 3'-dihydroxy compounds with acids.

In contrast, the acyl radicals used as protective groups can be alkaline be split off.

The process according to the invention is detailed in the following examples explained.

Example 1 N (6) -sec-butyladenosine variant a: 20.5 g of triacetyl-6-chloro-9- (B-D-ribofuranosyl) -purine and 11.6 g of sec-butylamine are dissolved in 100 ml of isopropanol and remain for 24 hours.

stand at room temperature. It is then concentrated in vacuo and the residue dissolved in benzene. This solution is washed several times with water, dried and evaporated. The remaining syrup is taken up with 40 ml of methanol and the Solution, after adding 2 ml of in-atrium methylate solution, heated under reflux for 10 min. The precipitate deposited after standing for several hours at room temperature is suctioned off and recrystallized from methanol. 3.8 g (23.6% of theory) of N (6) -sec.-butyladenosine are obtained from melting point 118-120 °.

Variant b: 25.0 g of 6-chloro-9- (ß-D-ribofuranosyl) -purine and 150 ml sec-butylamine are heated to 110 ° in a glass autoclave for 1 hour. After cooling down the precipitated sec-butylamine hydrochloride is filtered off with suction and the filtrate is concentrated. The residue is dissolved in methanol and again concentrated in vacuo. The one left behind Syrup is taken up with ethyl acetate and the solution is 12 hours at room temperature left. Another sec-butylamine hydrochloride also precipitates in the process. Of this is suctioned off and the filtrate is concentrated. Ether is added to the amorphous residue. The product crystallizes out on standing overnight. Receives after suction 20.6 g (73% of theory) of N (6) -sec.-butyladenosine with a melting point of 118-1200.

Example 2 N (6) - (1,3-dimethylbutyl) adenosine 6.15 g of triacetyl-6-chloro-9- (β-dribofuranosyl) -purine, 2.0 g of 2-amino-4-methyl Jentan and 3.0 g of triethylamine are in 50 ml of absolute tetrahydrofuran dissolved and left for 3 days at room temperature. It is then concentrated in vacuo, the residue is taken up in benzene and the solution washed several times with water, then dried and concentrated again. Of the The residue is dissolved in 50 ml of ammonia-saturated methanol and overnight at room temperature left. After driving off the solvent, you get a dark brown, too syrup that does not crystallize when standing for a long time. For further cleaning is dissolved in chloroform and the chloroform phase four times with 50 ml of 0.2N hydrochloric acid each time extracted. The hydrochloric acid extract is brought to pH 8-9 and 3-4 with ammonia times shaken out with ethyl acetate. The ethyl acetate solution is dried with activated charcoal treated, filtered and concentrated. 2.3 g (-44>% 0 of theory) of N (6) - (1,3-dimethylbutyl) adenosine are obtained in the form of a non-crystalline solid foam of m.p. 89-910.

8 egg spie 1 3 In a manner analogous to that described in Examples 1 and 2, the compounds summarized in the following table are obtained: Designation m.p. 0 Yield% (6) - (144ethylbutyl) - 141-143 28.0 adenosine N (6) - (1,2-dimethylbutyl) - 78-82 37.8 adenosine N (6) - (1,3,3-tetramethyl-115-117 butyl) adenosin N (6) - (1,4-Dimethylpentyl) - 98-100 31.5 adenosine Designation m.p. ° C Yield% N (6) - (1,3-dimethylpentyl) - 98-100 47.0 adenosine N (6) - (1,5-dimethylhexyl) - -89-91 21.0 adenosine

Claims (4)

Patent claims 1. N (6) -alkyl-adenosine derivatives of the general formula I in which R1 is a straight-chain or branched alkyl radical with 2-6 carbon atoms, while R2 is hydrogen or a methyl group. 2. Process for the preparation of compounds of the formula 1, characterized in that one purine ribosides of the general formula II (II) in which X represents a halogen atom or a reactive mercapto group. with amines of the general formula III in which R1 and R2 have the meaning given above, is reacted, if desired, the OH groups of the ribose radical being blocked as an intermediate by easily cleavable protective groups. 3. Pharmaceutical preparations with cardiac, circulatory and lipid metabolism, characterized by a content of compounds of formula 1. 4. Use of compounds of formula 1 for the preparation of pharmaceuticals with cardiovascular and lipid metabolism.