DK145825B - ANALOGY PROCEDURE FOR THE PREPARATION OF RIBOFURANOSYLIMIDAZOLD DERIVATIVES - Google Patents

Description

145825 i

The present invention relates to an analogous process for the preparation of novel imidazole derivatives, namely ribofuranosylimidazole derivatives of the general formula I

CONH „5 / B1 Η N- (2 / Njj ′ C0NHN02

R T

0.0. 1 09N0-Y New

TJ

02N0 ono2 1 2 wherein R and R each represent hydrogen or methyl.

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The process of the present invention is characterized in that a compound of the general formula 11 conh2 in H N- (/ Ni x CONH

/ o I

H0- ^ ° NJ

25 \ -

HO OH

1 2 where R and R are as defined above are nitrated.

The nitration of the compounds of the general formula II can be carried out in a manner known per se. Thus, the nitration, e.g. carried out with nitric acid. Conveniently, hydrolysis of the water formed by the reaction can be suppressed by the addition of a water-binding agent such as concentrated sulfuric acid or oleum. The nitration is conveniently carried out at low temperatures, preferably in the range of from ca. -40 to approx. -10 ° C.

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The starting compounds of general formula II are also novel and can be prepared by analogy with the preparation of known compounds. A method of preparation is outlined in Scheme I below. With reference to the exact reaction conditions, reference is made to the Examples.

Scheme I.

COOCEL · 10 -L - // Vv R2 “

15 ^ B, Y4C

rMJ1l + W

/ \ Ν ./^ οοεΗ3 R2 I IV BzO OBz

20 Si ία * 3> 3 V

X GOOCH-1 H N- {

Nil -X Nil / ^ COOCH., 25 R ^ 3

BzO-1/2 Xj T /

BzO OBz

30 I

* CONH- i H N - / ΪΤ C0NH9

35 R A

HO jX Xj II

HO OH

In Scheme I above, Bz represents the benzoyl group and the Ac 1 2 acetyl group and R and R have the meaning given above.

The compounds of the above general formulas IV

and VI are also novel.

The compounds of the general formula III are known or can be prepared by analogy with the preparation of known compounds. The compound of general formula V is known.

The compounds prepared by the process of the present invention possess valuable cardiac 15 (e.g., coronary dilating) and circulatory dynamic properties and can therefore be used as drugs, i. for the treatment of angina pectoris. As a dosage guideline, an amount of from 0.01 to 30 mg / kg body weight per day applies. per day, and it can be administered as a single dose or, more preferably, in multiple sub-doses.

The present compounds can be used as pharmaceutical compositions with direct or retarded release of the active substance in admixture with an organic or inorganic inert carrier suitable for enteral, percutaneous or parenteral administration. The pharmaceutical compositions may be in solid form, e.g. such as tablets, dragees, suppositories or capsules, in semi-solid form, e.g. as ointments, or in liquid form, e.g. as solutions, suspensions or emulsions. The pharmaceutical compositions may be prepared in a manner known to those skilled in the art.

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The coronary dilating effect can be measured by the following method:

In the study, bastard dogs weighing between 20 and 35 kg are used. The test animals are anesthetized with pentobarbital administered intravenously in an amount of 35 mg / kg, tracheal-intubated and artificially ventilated with atmospheric air. After the opening of the thorax, the heart is released and on the left coro-artery ramus circumflexus, a pre-calibrated flow sample is placed from an electromagnetic flowmeter to measure the flow of blood. The arterial blood pressure is measured via a catheter in the aortic ascendence with pressure transducer. The heartbeat drives a tachograph to measure the heart rate. The detection of a nitroglycerin-like mode of action is performed by the coronary segment analysis after Winbury (Winbury, M. et al., J. Pharmacol. Exp.

Ther. 165 (1), 70-95, 1969).

The compounds are dissolved in propylene glycol and administered intravenously. The maximum effect of a substance is calculated after each dosing as a percentage of the starting value and the duration of action is determined each time. The table below summarizes pharmacological data for NOx Xe of the compounds of this invention.

5 145825 'ti

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Si I I I

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H O O O

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fi o o o

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fe '~~ w dP 00 m <] + 1 +

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p | o o o S

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g A A H 4J

fe 3 ffl - g p o

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1> 1 m ro co

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H P

Φ »Cji tit tn 44 • rt \ ro H o tn to tr> H ti oe g ------- g 44 3 m ro cm> i V)

-P

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44 -P

S P

P 0 P -P ιϋ> i τ3 tn ^ | U 03 o c

p; Η <ϋ -P

0) II CO IH Λ> S fi +1 τι a · cd 44 O (U tn IH CM O -P QJ i — I * rl Ό.

OH fe + J Η P fel Ό β (D || II O) (U <W P d 0) g H ··· Η Η (1) Id H l> 0) cm rocM Η P -P β t n d

And fe fi fe d 0) P O 44 P

MP U -P -P O P> i -P

HO tT> tn CjpT-iOPC

dJH-l O II O Id Id Λ O -P P

pj (1) H i — 1 H II 11 II II II II

• ri PJ fe fe fe Λ (U fe pg t) TI 'd „> oh o o o) fe fe rf! Pi · fetd g g g fi fl fe O fe -ri 6 145825

Example 1.

15.0 g of 2-methyl-1-f} -D-ribofuranosylimidazole-4,5-dicarboxamide are dissolved at -40 ° C in 120 ml of smoking nitric acid (D = 5 1.50). In addition, a pre-cooled mixture of 50 ml of oleum and 50 ml of nitromethane is dripped so that the reaction temperature does not exceed -30 ° C. The reaction mixture is then stirred for 45 minutes at -30 to -25 ° C and then dripped with vigorous stirring on 1 liter of an ice-water mixture. The precipitated product is filtered off, washed with cold water and dried in a potassium hydroxide desiccator. After recrystallization from ethanol, 12.0 g of 2-methyl-N-nitro-1- (2,3,5-tri-O-nitro-ES-D-ribofuranosyl) imidazole-4,5-dicarboxamide, m.p. ° C (decomposition). This compound's structure is confirmed by X-ray structure analysis.

By analogy, the following compounds are prepared by nitration: 2-Ethyl-N 2 (or N 2) -nitro-1- (2,3,5-O-nitro - & - D

ranosyl) imidazole-4,5-dicarboxamide, mp 126 - 127 ° C

(decomposition), 5 4 2-isopropyl-N (or N) -nitro-1- (2,3,5-tri-O-nitro-pD-ribo-furanosyl) imidazole-4,5-dicarboxamide, m.p. 102 ° C.

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For the two above-mentioned compounds, no X-ray structure analysis is performed to confirm the structure. Therefore, the possibility of an isomeric structure is also taken into account.

The starting nucleosides can be prepared as follows: a) 19.8 g of 2-methylimidazole-4,5-dicarboxylic acid dimethyl ester are dissolved in 120 ml of benzene, 16.7 ml of triethylamine is added and then at 5 ° C 18 ml of trifluoromethanesulfonic acid trimethylsilyl ester and stir for 3 hours at room temperature. The phases are then separated and the benzene extract evaporated to dryness. The crude 2-methyl-1- (trimethylsilyl) imine thus obtained is dazole-4,5-dicarboxylic acid dimethyl ester and 50.5 g of 1-O-acetyl-2,3,5-tri-O-benzoyl-3 -D-ribofuranose is dissolved in 500 ml of ethylene chloride. To this, 18 ml of trifluoromethanesulfonic acid trimethylsilyl ester is added dropwise under an argon atmosphere and the reaction mixture is stirred for 18 hours at room temperature. The solution is poured into 500 ml of a saturated sodium hydrogen carbonate solution with stirring and the reaction mixture is stirred for an additional 1 hour. The phases are then separated and the aqueous phase is extracted with 250 ml of methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed over silica gel with a mixture of hexane and ethyl acetate. After recrystallization from ethanol, 30.8 g of 2-methyl-1- (2,3,5-tri-O-benzoyl-3-D-ribofuranosyl) imidazole-4,5-dicarboxylic acid dimethyl ester, m.p. C.

By analogy, the following compounds are prepared by reaction of 1-O-acetyl-2,3,5-tri-O-benzoyl-5-D-ribofuranose with the silylated 2-ethyl or 2-isopropylimidazole-4,5-dicarboxylic acid dimethyl esters .

2-Ethyl-1- (2,3,5-tri-O-benzoyl-3-D-ribofuranosyl) imidazole - 4,5-dicarboxylic acid dimethyl ester, m.p. 147 ° C, 2-isopropyl-1- (2.3, 5-Tri-O-benzoyl-f} -D-ribofuranosyl) imidazole-4,5-dicarboxylic acid dimethyl ester, m.p. 147-148 ° C.

The imidazole-4,5-dicarboxylic acid esters used in the above step can be prepared as follows: Dry hydrogen chloride gas is refluxed into a suspension of 14.6 g of 2-ethylimidazole-4,5-dicarboxylic acid in 150 ml of methanol so long that no starting material is present (thin layer chromatography control). The obtained solution is then evaporated to dryness and the residue is evaporated twice with 100 ml of methanol each time. The residue is dissolved in 250 ml of ice water, neutralized with a saturated sodium bicarbonate solution and extracted three times with 250 ml of ethyl acetate each time. The ethyl acetate extracts are dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from benzene to give 9.6 g of 2-ethylimidazole-4,5-dicarboxylic acid dimethyl ester, m.p. 111 ° C.

By analogy, 2-isopropylimidazole-4,5-dicarboxylic acid dimethyl ester, melting point 150 ° C, is prepared by reacting 2-isopropylimidazole-4,5-dicarboxylic acid with methanol.

b) A solution of 26.0 g of 2-methyl-1- (2,3,5-tri-O-benzoyl- .beta.-D-ribofuranosyl) imidazole-4,5-dicarboxylic acid dimethyl ester in 500 ml of methanol, which at 0 ° C has been saturated with anhydrous ammonia, left to stand for 7 days at room temperature in a closed pressure flask. The reaction mixture is then evaporated to dryness and the residue is recrystallized from methanol.

9.5 g of 2-methyl-1-3-D-ribofuranosylimidazole-4,5-dicarboxamide, m.p. 167 ° C is obtained.

By analogy, the following compounds are prepared by ammonolysis:

2-Ethyl-1- [3-D-ribofuranosylimidazole-4/5-dicarboxamide, [a] D

= + 59.4 ° (c = 1.00 in dimethylsulfoxide), 2-isopropyl-1- [3-D-ribofuranosylimidazole-4,5-dicarboxamide, [a] p5. = + 43.3 ° (c = 1 , 00 in dimethyl sulfoxide).

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