DE2148838A1 - NEW N (6) -DISUBSTITUTED ADENOSINE DERIVATIVES AND METHOD FOR MANUFACTURING THE SAME - Google Patents

Description

Novel N (6) -disubstituted adenosine derivatives and processes for making the same

The present invention relates to new N (6) -disubstituted Adenosine derivatives of the general formula I

(D

HO

HO OH

in which

R, a straight or branched alkyl group,

R "is a straight-chain or branched alkyl group with at least 4 carbon atoms, a cycloalkyl, cycloalkyl · alkyl or bicycloalky! group, which optionally may be substituted by alkyl radicals, mean

and their pharmacologically acceptable salts.

It has surprisingly been found that the compounds of the formula I do not have the cardiac properties customary for adenosine derivatives and have circulatory effects, but have an anti-lipolytic,

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antihyperlxpemic and antihypercholesterolemic effect demonstrate. The new compounds cause a strong decrease in concentration of free fatty acids, triglycerides and cholesterol in serum. It will also lower the Blood sugar levels observed.

The process according to the invention for the preparation of the compounds I is characterized in that one purine ribos, ide the general formula II

(II),

HO OH

in which Z is a halogen atom or a reactive mercapto group,

with amines of the general formula III

R.

HN - R,

(IH),

in which R ₁ and R _{p have} the meaning given,

converts, if desired, the hydroxyl groups of the ribose residue is blocked as an intermediate by easily cleavable groups and the compounds I obtained, if appropriate then converted into the corresponding salts with acids.

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To carry out the process according to the invention, the Purine ribosides II with the amines III in an inert solvent (e.g. n-propanol, iso-propanol, butanol, tetrahydrofuran or Dioxane), preferably in the presence of a tertiary amine (e.g. triethylamine) at room temperature or slightly elevated temperature.

The purine ribosides II used as Aungangsprodukte, in where Z is a halogen atom are, for example, in Coil. Czech. Chem. Comm. J30, 1880 (1965). Connections II, in which Z denotes a mercapto group are known from Chem. Pharm. Bull. JL2, 951 (1964).

In the event that the hydroxyl groups of the ribose residue are to be blocked as an intermediate, the protective groups customary in sugar chemistry are used. Acyl groups (preferably acetyl or benzoyl radicals) are suitable for this, or ketals are used, for example the 2 ', 3'-isopropylidene compounds, which after condensation easily convert with acids into the free 2 ¹ , 5'-dihydroxy -Compounds can be transferred, on the other hand, the acyl radicals used as protective groups can be split off under alkaline conditions.

All conventional medicaments can be used as medicaments according to the invention oral and parenteral application forms in question, for example tablets, capsules, coated tablets, syrups, solutions, suspensions, drops, suppositories etc. For this purpose, the active ingredient is mixed with solid or liquid carriers and then added in the desired shape. Examples of solid carriers are lactose, mannitol, starch, talc, Methyl cellulose, silica, calcium phosphate, magnesium stearate and agar-agar, gelatin, to which colorants and flavorings are added if desired. Liquid Carriers for injection solutions must be sterile and are preferably filled into ampoules.

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The pharmacologically acceptable salts are obtained in the customary manner by neutralizing the free base I. with non-toxic inorganic or organic acids; z. B. hydrochloric acid, sulfuric acid, phosphoric acid, Bromic acid, acetic acid, lactic acid, citric acid, Oxalic acid, malic acid, salicylic acid, malonic acid or succinic acid.

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

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example 1 N (6) -Methyl-N (6) -cyclohexyl-adenosine

12.5 g of triacetyl-6-chloro-9- (β-D-ribofuranosyl) -purine, 5 g of N-methylcyclohexylamine and 4.5 ml of triethylamine are refluxed in 100 ml of isopropanol for 2 hours. The solution is then evaporated in vacuo, the residue is dissolved in 100 ml of ammonia-saturated methanol and left at room temperature overnight. After adding 150 ml of water and standing for several hours, the crude compound separates out as a fine, slightly colored crystal pulp. The same is dissolved in hot ethanol, the alcoholic solution is treated with charcoal and, after cooling, 6.9 g (63 % of theory) of N (6) -methyl-N (6) -cyclohexyl-adenosine with a melting point of 143 are obtained -145 C.

Example '2 N (6) -Methyl-N (6) -cyclooctyl-adenosine

8.2 g of triacetyl-6-chloro-9- (ß-D-ribofuranosyl) -purine, 3.1 g of N-methylcyclooctylamine and 4.2 ml of triethylamine are in 100 ml of isopropanol heated under reflux for 5 hours. The solution is evaporated in vacuo, the residue in benzene dissolved and washed 3 times with water. The benzene phase is dried and concentrated. The syrupy residue is in Methanol was added and, after adding 2 ml of sodium methylate, the solution was heated to boiling for 10 minutes. Thereafter When the solution cools, nothing crystallizes, it is evaporated again, the residue is dissolved in ethyl acetate and the ethyl acetate phase then extracted with 1N hydrochloric acid. The hydrochloric acid Hxtict is made alkaline with ammonia and three times shaken out with ether / ess icjes ter. The organic phase is dried vincl evaporated. The back syrup

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-s- 2U8838

is taken up in a little ethyl acetate and the substance is precipitated by dropping in ligroin. After filtering off with suction and drying, 4.5 g (<57 % of theory) of amorphous, chromatographically pure N {6) -methyl-N (6) -cyclooctyl-adenosine are obtained. Sintering at

example N (6) -Methyl-N (6) -cyclopentylmethyl-adenosine

8.2 g of triacetyl-6-chloro-9- (ß-D-ribofuranosyl) -purine, 3.8 g of N-methyl-cyclopentylmethylamine and 5.2 ml of triethylamine are heated to the boil for 1 hour. The solution is evaporated in vacuo, the syrupy residue is taken up in chloroform and the chloroform phase is washed three times with water. After drying over sodium sulfate, the chloroform is distilled off and the remaining syrup is dissolved in methanol. After adding 5 ml of sodium methylate, the solution is refluxed for a few minutes. The precipitate which separates out on cooling is recrystallized from methanol with the addition of Α carbon. Finally, 3.8 g (<* 53 % of theory) of N (6) -methyl-N (6) -cyclopentylmethyl-adenosine with a melting point of 115-116 ° C. are obtained.

In an analogous way, one obtains from

a) Triacetyl-6-chloro-9- (ß-D-ribofuranosyl) -purine and N-methyl-cyclopentylamine

N (6) -Methyl-N (e) -cyclopentyl-adenosine with a melting point of 141-143 ° C (58% of theory)

b) triacetyl-6-chloro-9- (ß-D-ribofuranosyl) -purine and N-methyl-trans-4-methyl-cyclohexylamine

N (G) -Me thy1-M ( G) - (trans-4-me thy Icyc LohexyI) -ademosine of melting point L67-L6B ° C (47 % of theory)

c) Triticety L-6-chLor -9- (ß-D-r.Lbofurnnoay L) -purLn and

ι η ο β u / 1 >. 12th

N-Ethyl-eye lohexy lamin

N (6) -ethyl-N (6) -cyclohexyl-adenosine

from melting point 167-169 ° C (66 % of theory)

d) Triacetyl-6-chloro-9- (β-D-ribofuranosyl) -purine and Nn-propyl-cyclohexylamine N (6) -n-propyl-N (6) -cyclohexyl-adenosine with a melting point of 159-16O ° C (54 % of theory)

e) Triacetyl-6-chloro-9- (β-D-ribofuranosyl) -purine and N-methyl-bicyclo [2.2.1] heptyl-2-amine N (6) -methyl-N (6) - (bicyclo12. 2.ljhepty1-2) -adenosine of melting point 2O4-2O6 ° C (51 % of theory)

f) Triacetyl-6-chloro-9- (ß-D-ribofuranosyl) -purine and N-isobutyl-cyclohexylamine amorphous

N (6) -Isobutyl-N (6) -cyclohexyl-adenosine

(45% of the total)

g) triacetyl-6-chloro-9- (ß-D-ribofuranosyl) -purine and N-I sobuty Icy clopenty lamin amorphes

N (6) -Isobutyl-N (6) -cyclopentyl-adenosine

(24 % of theory)

h) triacetyl-6-chloro-9- (ß-D-ribofuranosyl) -purine and N-methyleyelohepty1-adenosine N (6) -methyl-N (6) -cycJoheptyl-adenosine with a melting point of 120-122 ° C (42 % of theory)

i) Triacety] -6-chloro-9- (ß-D-ribofuranosyl) -purine and Nn-propyl-cycloheptylamine N (6) -nP r opy1-N (6) -cycloheptyl-adenosine of melting point 166-167 ° C (29 % of theory)

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j) Triacetyl-6-chloroT-9- (ß-D-ribofuranosyl) -purine and N-isobutyl-cycloheptylamine amorphous N (6) -isobutyl-N (6) -cycloheptyl-adenosine which sinters from approx. 70 ° C ( 57 % of the total)

k) Triacetyl-6-chloro-9- (ß-D-ribofuranosyl) -purine and N-isobutyl-cyclooctylamine amorphous N (6) -isobutyl-N (6) -cyclooctyl-adenosine which sinters from approx. 60 ° C ( 18 % of the total)

1) Triacetyl ~ 6-chloro-9- (ß-D-ribofuranosyl) -purine and N-methyl-isobutylamine N (6) -methyl-N (6) -isobutyl-adenosine with a melting point of 129-131 ° C (73 % of theory)

m) triacetyl-6-chloro-9- (β-D-ribofuranosyl) -purine and N-methyl-neopentylamine hydrochloride N (6) -methyl-N (6) -neopentyl-adenosine with a melting point of 109-111 ° C (48 % of the total)

n) Triacetyl-6-chloro-9- (ß-D-ribofuranosyl) -purine and N-methyl-n-hexylamine hydrochloride N (6) -methyl-N (6) -n-hexyl-adenosine of melting point 131 -133 ° C (25 % of theory)

o) triacetyl-6-chloro-9- (β-D-ribofuranosyl) -purine and LI-cyclohexyl-2-methylaminopropane N (6) -methyl-N (6) - (Ll-cyclohexyl-propyl-2) -adenosine from melting point 140-141 ° C (38 % of theory)

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Claims (4)

2U8838 claims 1. N (6) -disubstituted adenosine derivatives of the general Formula I. ^Η0 ΤΊ HO OH (I) in which R, a straight or branched alkyl group, R _{2 is} a straight-chain or branched alkyl group with at least 4 carbon atoms, a cycloalkyl, cycloalkylalkyl or bicycloalkyl group, which can optionally be substituted by alkyl radicals as well as their pharmaceutically acceptable salts. 2. Process for the preparation of disubstituted adenosine derivatives of the general formula I. 3098U / 1212 / - 30 - 2U8838 (ι) HO OH in which R, a straight or branched alkyl group, R ^ a straight-chain or branched alkyl group with at least 4 carbon atoms, a cycloalkyl, cycloalkylalkyl or Bxcycloalkylgruppe, which may optionally be substituted by alkyl radicals characterized in that one purine ribosides of the general Formula II (II), HO OH in which Z is a halogen atom or a reactive mercapto group does 309814/121 mean? 2H8838 with amines of the general formula III HN-R ₂ . '(III), in which R, and Rp have the meaning given, uniisetzt, if desired, the hydroxyl groups of the ribose residue is blocked as an intermediate by easily cleavable groups and the compounds I obtained, if appropriate then converted into the corresponding salts with acids. 3. Use of adenosine derivatives of the general formula 1 for the manufacture of drugs with antilipolytic, antihyper lipemic and antihypercholesterolemic as well antihyperglycemic effect. 4. Pharmaceutical preparations, characterized by a content of adenosine derivatives of the general formula I. 309P U / 1212