DE1814711A1 - Adenosine derivatives and processes for making the same - Google Patents

Description

in which R- hydrogen, halogen, an amino or Hydroxyl groups

R ₂ halogen, alkyl, haloalkyl, alkoxy, carboxy, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl or alkylmercapto groups,

R ^ denote hydrogen, halogen, alkyl or alkoxy groups, in the event that R. is halogen or an amino and / or. Is hydroxyl group, R _{2 can} also be hydrogen, - ■. -

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and methods of making the same.

It has been found that the inventive aderiosin derivatives I have particularly interesting cardiovascular effects.

The process according to the invention for the preparation of the compounds I is characterized in that in a known V / eise Purlnriboside of the general formula II

(II),

in which R _{1 has} the meaning given above and

X is a halogen atom or a reactive mercapto group

is,

with amines of the general formula III

^R 2

(III),

in which R ₂ and. JR, have the meaning given above,

converts, where, if desired, the hydroxyl groups of the ribose residue are intermediate by easily cleavable protection «

9? A

BATH ORIGINAL

groups blocked and the radicals R ₂ and R-, subsequently released or converted.

The starting compounds II used are, in particular, purine ribosides in which R. and X are chlorine or bromine atoms * as described, for example, in J. Heterocyclic Chem. I _- , p. 215 (1964) or J.Org.Chem. ^, S, 5262 (1966). Compounds II in which R, hydrogen or an amino group and X are chlorine or bromine atoms are also very suitable; such connections are, for example, described in Coll.Czech. Chem. Comm. J50, p. 1880 (1965) or in J.Org.Chem. 28, p. 945 (1963). Compounds II can also be used in which R, is a hydroxyl group and X is a methyl or benzyl mercapto group * these substances are obtained, for example, by diagoting the in Chem.ihaiin.iBull. (jap *) 12, S * 951 (1964) described thioguanosine derivatives *

To carry out the process according to the invention, the reaction components are expediently in a suitable inert chemical, preferably in higher alcohols or ethers (e.g. n-propanol, isopropanol, butanol, tetrahydrofuran, dioxane), if appropriate in the presence of an equimolar amount of a tertiary left amine (preferably triethylamine) is heated or more {days at room temperature. But you can also do without a * solvent and instead use one of the reaction components, preferably the amine component III, in excess. '' ■ .- '

If you want to block the hydroxyl groups of the compounds II in a luterine way, use the protective groups customary in sugar chemistry. Acyl groups (preferably acetyl or benzyl radicals) are suitable for this, or ketals are used, e.g. the ^ ', ^' - isopropylidene compounds, which after condensation are easily converted into the free with acids

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2 ', J5 ^T -dihydroxy compounds can be converted; the acyl radicals used as protective groups, on the other hand, can be split off under alkaline conditions. In the case of some of the substituents Rp and PU listed above, it is advisable to release them only after condensation has taken place; for example, carboxy-substituted compounds are advantageously prepared by saponification of the corresponding alkoxycarbonyl compounds.

In the examples below, that is according to the invention Procedure explained in more detail.

009827/1878 ^BAD

.. Example 1

N. (6) - · (^ -A * th oxy carbonyl-phenyl) -adeno sin

4.3 g of 6-chloro-9- (beta-JD-ribofuranosyl) -purln, 2 _a 7 g of 3-Aminobenzoesäureäthylester and 4.8 ml of tri ~ n ~ bütylamin be ΪΤι. 40 ml of n-butanol refluxed for 9.5 hours. The reaction solution is then concentrated in vacuo and the residue is triturated with ethyl acetate and water. The insoluble part is filtered off with suction and recrystallized from alcohol. 1.6 g (26 % of theory) of N (6) - (3-ethoxyoarbonyl-phenyl) adenosine with a mp. 201-203 ° C. are obtained.

Those in the following table are obtained in an analogous manner listed connections:

Table 1

description
N (6) -0-Carbamoy1-phenyl) -
. adenosine Fp. ( ⁰ C)
220-230 Yield {%)
14th N (6) - (3-methylcarbamoyl-
pheny1) -adenos in 217-219 46 N (6) - (4-ethoxycarbonyl-
phenyl) adenosine 239-241 30th N (6) - (4-carbamoyl-phenyl) -
adenosine 267-269 52 N (6 -) - (4-methylcarbamoyl '>'
phenyl) adenosine 240-242 20th

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Example2 N (6) - (3-Carboxy-phenyl) -adenosine

3.0 g N (6) - (3-ethoxycarbonyl-phenyl) -adenosine are heated in a mixture of 180 ml of alcohol, 120 ml of water and 1.5 g of sodium hydroxide for 15 minutes on a water bath. The solution
is clarified with activated charcoal, weakly acidified with dilute hydrochloric acid and then concentrated to 80 ml. The precipitate which separates out on cooling is filtered off with suction and washed with water, acetone and ether. After recrystallizing from
Alcohol with the addition of a little water gives 1.4 g
(50 % of theory) N (6) - (3-carboxy-phenyl) -adenosine with a p. 237 ° C.

The following compounds are obtained in an analogous manner:

Table '2

description
• N (6) - (2-carboxy-phenyl) -
adenosine Pp. (° c)
251-253 Yield {%)
17th N (6) - (4-carboxy-phenyl) -
adenosine 273 32

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Example 5

N (6) - (2, ^ - Dimethoxyphenyl) adenosine

A mixture of 6.2 g of triacetyl-6-chloro-9- (beta-D-ribofuranosyl) -purine and 6.9 g of 2,5-dimethoxy-aniline is heated one hour at 110 ⁰ C. Partial crystallization of the flask contents occurs after just 20 minutes. After cooling, the reaction mixture is taken up in 250 ml of ethyl acetate, washed twice with water, dried and concentrated in vacuo. The residue is dissolved in 40 ml of ammonia-saturated methanol and left at room temperature overnight. The deposited precipitate is filtered off with suction and recrystallized from alcohol / water. This gives 5.1 g (51% of theory) of N (6) - (2,5-dimethoxy-phenyl) -adenosine, melting at 205-207 ⁰ C..

The compounds summarized in the following table are obtained in an analogous manner:

'"■■'". table 3

Description . :. ·, ·; ft Yield (%) Κ (β) - (5 * 4-dimethyl-phenyl) -
adenosine 174-176 40 '' _: phenyl) adenosine 198-200 55 N (6) - (2,6-dimethyl-phenyl) - 265 (ZeTB.) 54 N (6) - (5.4 * diinethoxy «phenyl) -
adenosine ' 48 phenyl) adenosine 59 M (6) - O-Hydroxy-4-methy 1-
iiiarbamoyl-pheny 1) -aaefiosin 58

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INSPECTED

example N (6) - (4-methyl-phenyl) adenosine

8.2 g of triacetyl-6-chloro-9- (β ~ D - ribofuranosyl) -purine and 6.4 g of p-toluidine are refluxed in 100 ml of dioxane for 1 hour. It is then concentrated in vacuo and the residue is dissolved in benzene. The benzene phase is washed three times with water, dried and concentrated. The residue is taken up in 50 ml of methanol, 2 ml of sodium methylate solution are added to the solution and the mixture is refluxed for 10 minutes. The precipitated after cooling, precipitate is filtered off and recrystallized from methanol .. This gives 6.0 g (85% of theory) of N (6) -. (4-methyl-phenyl) '-adenosine, melting at 204-206 ⁰ C. .

Similarly, those in the table below Get the listed connections

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Table 4

Description ·
N (6) - (2-methyl-phenyl) adenosine ■ pp. (° c)
167-168 Yield {%)
58 N (6) - (3-Me thy1-phenyl) -adenos in 188-190 64 N (6) - (3-trifluoromethyl-phenyl) -
adenosine 20-205 50 N (6) - (2-methoxyphenyl) adenosine 227-228 74 N (6) - (3-methoxypheny1) adenosine 197-198 69 N (6) - (4-methoxyphenyl) adenosine 207-209 85 N (6) - (2-chloro-phenyl) -adenos in 206-207 38 N (6) - (3-ChloE.phenyl) adenosine 208-209 19th N (6) - (4-chloro-phenyl) -adenosine 204-206 76 N (6) - (2-fluorophenyl) adenosine 186-188 39 · N. (6) - (3-Fluoro-phenyl) -adenosine 205-206 6.5 N (6) - (4-fluoro-pheny1) -adenosine 230-232 43 N (6) - (2,3-Dimethyl-pheny1) -
adenosine 156-157 46 N (6) - (2,4-dimethyl-phenyl) -
adenosine 181-182 30th N (6) - (- 2-methyl-4-methoxyphenyl) -
adenosine I87-I88 47 • N (6) - (3-riethoxy-4-methyl-phenyl) -
adenosine I87-I88 36 N (6) - (2-methyl-4-chlorophenyl) -
■ adenosine 184-185 19th

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Example 5

N (6) - (4-methyl-phenyl) -2-chloro-adenosine .

The solution of 6.8 g of triacetyl-2,6-dichloro-9- (ß-D-ribofuranosyl) -purine, 2.4 g of 4-methyl-aniline and 4.2 ml of triethylamine in 50 ml of tetrahydrofuran is at 24 hours Room temperature stirred. The precipitated triethylammonium hydrochloride is filtered off with suction and the piltrate is concentrated. The residue is taken up in benzene, washed with water, dried and concentrated in vacuo. It is then dissolved in 50 ml of ammonia-saturated methanol and left at room temperature overnight. The deposited precipitate is filtered off with suction and recrystallized from methanol. 5 * 5 g (60 % of theory) of N (6) - (4-methylphenyl) -2-chloro-adenosine with a melting point of ° are obtained

The following compounds are obtained in an analogous manner:

Table 5

description
N (6) -phenyl-2-chloroadenosine Fp. ( ⁰ C)
138-140 Yield {%)
° i- N (6) - (3-methoxyphenyl) -2-chloro-
adenosine 126-128 33 N (6) - (4-methoxyphenyl) -2-chloro-
adenosine 196-198 46 N (6) - (4-chloro-phenyl) -2-chloro-
adenosine 226-228 34 N (6) - (3-fluorophenyl) -2-chloro-
adenosine 240-242 17th N (6) ~ (4-fluorophenyl) -2-chloro-
adenosine 210-212 22nd N (6) - (3 _J 4-Dimethoxyphenyl) -2 ~
chlorine adenosine I6O-I63 46 N (6) - {> Chior »4-methoxy-phenyl) -
S-ohlor-adenosine I9O-I92 18th

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■ Example6

N (6) "(4-methylphenyl) -2-bromoadene.osine

5.0 g of triacetyl-2-bromo-6-chloro-9- (β-D-ribofuranosyl) -purine, 2.0 g of 4-methyl-aniline and 1.5 g of triethylamine are dissolved in 60 ml of n-butanol 2 Boiled under reflux for hours. After cooling, 200 ml of ether are added and the precipitated triethylamine hydrochloride is filtered off with suction. The filtrate is washed with water, dried and concentrated in vacuo. The residue is taken up with 75 ml of ammonia-saturated methanol and the solution is stored overnight at 3-4 ° C. * The precipitate which has separated out is filtered off with suction * and recrystallized from methanol with the addition of water. This gives 3.1 g (71% ä * Th.) N (6) - (4-methyl-phenyl) -2- b ^ om-adenosine by Pp, i ⁰

The triacetyl-2-bromo-6-chloro-9- (ß-D-rilaofuranosyl) -purine used as starting material is prepared in the following way:

4.3 g of 2 ¹ , 3 *, s'-ribofur4nosyl) purine are dissolved in 30 ml of absolute methylene solder and a 20% solution of nitrosyl bromide in absolute is added dropwise at room temperature while stirring. Methylenohlorid to, until oils immediately onset of vigorous nitrogen development comes to a standstill. It is then heated to the boil for 5 minutes and left at room temperature for another 50 minutes. The solution is washed once with 5 # sodium sulfite solution and once with water, then dried and concentrated in vacuo. The yellow oily residue crystallizes after a short time. After recrystallization from isopropanol gives 3 * 45 β (70 # ä.Th ") Trlacetyl-S-bromo-e-g-chloro - ^^ D-ribofuranosyl) purine, mp 150-152 ⁰ C. ·

the following compounds are obtained in an analogous manner *

. . SAD ORIGINAL

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Table 6

description
N (6) - (2-methyl-phenyl) -2-bromo-
adenosine Fp. ( ⁰ C)
201-202 Yield {%)
57 N (6) - (4-methoxyphenyl) -2-bromo-
adenosine 188-189 66 N (6) - (4-chloro-phenyl) -2-bromo-
adenosine 221-222 65 N (6) - (2,> dimethyl-phenyl) -2-
bromo-adenosine 145-147 60 N (6) - (3-chloro-4-methoxy-
phenyl) -2-bromo-adenosine I75-I76 60

Example 7

N (6) -phenyl-2-amino-adenosjn

5.2 g of 2-amino-6-bromo-9- (ß-D-ribofuranosyl) -purine, 1.6 g of aniline and 4.2 ml of triethylamine are refluxed for 1½ hours in 40 ml of isopropanol. The solvent is removed in vacuo and the residue is triturated with ethyl acetate and water. The sparingly soluble product is sucked off. By extracting the aqueous phase with ethyl acetate, further quantities can be obtained, so that a total of 2.2 g of crude product is obtained. After recrystallization from alcohol with addition of small amount of water 1.6 g (20% of theory) of N (6) -phenyl-2-amino-adenosine resulting from Pp. 219-221 ⁰ C.

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Example 8

N (6) - (4-Methoxyphenyl) -2-hydrQxy-adenosine

3 * 9 g of 2-hydroxy-6-benzylmercapto-9- (ß-D-ribofuranosyl) -purine and 3/7 g of 4-methoxyaniline are refluxed in 50 ml of isopropanol for 8 hours. The precipitate which has separated out after cooling is filtered off with suction and recrystallized twice from h-propanol with the addition of a little methanol. 2.2 g (55 % of theory ) of N (6) - (4-methoxyphenyl) -2-hydroxy-adenosine of pp. 204-206 ° C. are obtained.

The following connections are established in an analogous manner:

Table 7

description
N (6) -phenyl-2-hydroxy-adenosine Pp. ( ⁰ C)
I7O-I72 Yield (#)
54 N (β) - (2f.-methylphenyl) -2-hydroxy-
adenosine I98-2OO 56 N (6) - (3-Methy 1-phenyl) -2-hydroxy-
adehosin 226-229 42 N (6) - (> methoxyphenyl) -2-
hydroxy adenosine 2OI-2O3 56 N (6) - (4-chloro-phenyl) -2-
hydroxy adenosine 221-223 64 N (6) - (2-methyl-phenyl) -2-hydroxy-
adenosine I58-I6I 86 N (.6) - 0, 4-Dimethoxyphenyl) -2-
hydroxy adenosine 213-215 11th N (6) - (3-chloro-4-methoxyphenyl) -
2-hydroxy-adenosine 23O-232 56

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Claims (1)

Claims in which R. is hydrogen, halogen, an amino or hydroxyl group, Rg halogen, alkyl, haloalkyl, alkoxy, carboxy, Alkyloxycarbonyl, carbamoyl, alkylcarbamoyl or alkylmercapto groups, R ^ denote hydrogen, halogen, alkyl or alkoxy groups, where, in the event that R. is halogen or an amino or hydroxyl group, Rg can also be hydrogen _f 00 9 8 27/1978 ORIGINAL INSPECTED 18U711 2.) Process for the preparation of adenosInderivaten of the general formula I, characterized in that one in known V / ice purine ribosides of the general formula II HO OH in which R. has the meaning given above and X is a halogen atom or a reactive mercapto grouping is with amines of the general formula III R, (III), in which R _g and R * have the meaning given above «. is reacted, if desired, the hydroxyl groups 4es ribose radicals intermediately blocked by easily cleavable SchUtiSgruppen and the radicals R ₂ and ft * subsequently liberated or converted. 009827/1978 _0RialNAL msPEOTED 18H711 j5.) Use of adenosine derivatives of the general formula I. for the production of drugs with cardiovascular effects. 4.) Pharmaceutical preparations, characterized by a content of adenosine derivatives of the general formula I. 0 09827/1978