FI61194C - ADJUSTMENT OF THERAPEUTIC ADHESIVE TREATMENT - Google Patents

Description

ΓαΙ / 11λ ADVERTISING PUBLICATION s * aqa [b] (11) utlägoningsskript 1 94 C Patent Now issued 10 06 1932

Patent raeddelat ^ ^ (51) Kv.lk?/lnt.Ci.3 C 07 H 19/16

FINLAND-FINLAND (H) PMMttitWkMIMI * - PatanOMekning 760l8U

(22) Hakamltptlvt —Anaeknlngadag 27.01. "j6 'r' (23) Aikupliv · —Giklghatadag 27.01.76 (41) Tullut julkbaksl - Bltvlt offamllg 19.0 8.76 j · * (44) NihttvUulpunon ji ki» ul. | ullutou «pvm. -

Patent · och ragisterstyrelsen '7 AmMcm uttagd och utl. * Kr »ft * n publfeond 26.02.82 * (32) (33) (31) Requested atuolkau» —Bagird prior * · Switzerland-Switzerland (CH) 2032/75, 87 ^ 8/75, 1609 ^ / 75 (71) F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel, Switzerland-Switzerland (CH) (72) Ulf Fischer, Frenkendorf, Gunther Häusler, Reinach, Switzerland-Switzerland (CH) (7 ^) Oy Kolster Ab (5I +) Method for the preparation of adenosine nitrates for therapeutic use - Förfarande för framställning av terapeut användbara adeno-sinnitrater

The invention relates to a process for the preparation of therapeutically useful adenosine nitrates of the formula I and their physiologically tolerable acid addition salts, * V \ (I)

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OR 1 OR 2 2,611 94 1 2 wherein R and R are hydrogen atoms or nitro groups, at least one of which is a nitro group, and R 5 is hydroxy, lower alkoxy, amino, lower alkylamino. di-lower alkylamino, aryl-lower alkylamino, cycloalkylamino, piperidino, [2- (dimethylamino) ethyl] amino or [2- (nitrooxy) ethyl] amino.

The terms "lower alkyl" and "lower alkoxy" include straight or branched chain groups having 1 to 6 carbon atoms, such as methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, sec-butyl, sec-butoxy or tert-butyl or tert. -butoxy. Examples of lower alkylamino or di-lower alkylamino groups include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino and diisopropylamino. Examples of aryl-lower-alkylamino groups, which include in particular phenyl-lower-alkylamino, are benzylamino and 1- or 2-phenethylamino. Cycloalkylamino groups are especially-! ti are those having up to 7 carbon atoms, such as cyclopentyl or cyclohexylamino.

By "physiologically acceptable acid addition salts" is meant salts of the compounds of formula I with suitable organic or inorganic acids, such as hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, acetates, lactates, oleates, nitrates, mesylates, mesylates, tosylates, tosylates, tosylates, tosylates, tosylates, tosylates, tosylates, tosylates, tosylates, tosylates, tosylates, tosylates, roads, etc.

The process according to the invention is characterized in that the compound of the formula II NH2 &> r5-co 0 lII) sTp h /

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3,61194, which has the same meaning as above, is nitrated and, if desired, converted into a physiologically acceptable acid addition salt.

The nitration of the compounds II is carried out by methods known per se.

The nitration can be performed, for example, with nitric acid. Hydrolysis (by the reaction water) and deamination (possibly by the presence of nitric acid) are conveniently prevented by the addition of a water-binding agent such as concentrated sulfuric acid, fuming sulfuric acid, acetic anhydride and / or a nitrite-binding agent such as urea.

The nitration is expediently carried out at low temperatures, preferably between -30 ° and 25 ° C, in particular between -10 ° C and -0 ° C.

In general, mixtures of 2'-O-nitro, 3'-O-nitro and 2'3'-di-O-nitro compounds are obtained, which can be separated and refined into pure compounds by generally known methods, e.g. using chromatography. However, it is also possible to control the synthesis so that the 2 ', 3'-di-O-nitro compounds are isolated as exclusive reaction products, as is particularly the case when using fuming sulfuric acid as a dehydrating agent.

The possible conversion of the compounds of the formula I into physiologically acceptable acid addition salts and also the formation of such salts from physiologically acceptable acid addition salts can be carried out in the customary manner.

The compounds of the formula I and their acid addition salts have valuable dynamic properties affecting the heart and the circulation, and can thus be used as medicaments, e.g. for the treatment of angina pectoris or hypertension. The dosage may be 0.010 to 30 mg / kg of body weight per day, which may be taken as a single dose, but preferably several times a day in divided doses.

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

Mixed breed dogs weighing between 20 and 38 kg are used in the studies. Experimental animals are anesthetized with about 30 mg / kg pentobarbital intravenously. Anesthesia is maintained with chlorose-urethane. The breathing of the animals is artificially maintained by room air. After opening the thorax, the heart 4 611 94 is excavated and a pre-calibrated electromagnetic flowmeter flow sensor is installed around the left coronary artery (Ramus circum-flexus) to measure the amount of blood flowing through. Arterial blood pressure is measured through a conduit in the femoral artery with a pressure transducer. In addition, a calibrated strain gauge tape is sewn onto the upper surface of the left ventricle to directly measure the contractile force of the myocardium. A blood pressure pulse wave knocks the tachometer to measure the heart rate. The compounds are dissolved in propylene glycol, administered intravenously or as a suspension in gum arabic pohjakaissuolen internally. The maximum effect of the substance is calculated as a percentage of the initial value after each dosing. When measuring the amount of blood flowing through the coronary artery, special attention is also paid to the duration of the effect.

The results obtained are summarized in the following table, where n is the number of animals used.

Pharmacological comparative experiments were performed with the compounds of the present invention and known chemically similar adenosine derivatives having a similar pharmacological effect. Adenosine 31,5'-dinitrate (known from U.S. Pat. No. 3,832,341), adenosine 21,3 ', 5'-trinitrate (known from DE Application No. 2,105,560), adenosine-5-ethyl were used as reference compounds. ester (known from FI patent application 2481/72) and adenosine 5-amide (known from FI patent publication 54 316) and nitroglycerin. The effect of the compounds on blood pressure, heart rate, coronary blood flow and coronary resistance was determined. Table II below shows the changes (in percent) (a%) caused by the test compounds for these four parameters compared to the corresponding values before compound administration and the time (min) it takes for complete recovery from the test compounds. The most significant of the parameters studied is "resistance in the coronary artery" (LCAR). It is therapeutically desirable to lower the LCAR because this will result in better distribution of coronary blood flow to the subendocardial layers of the heart muscle. It has been found that it is in these layers that the heart fraction easily develops.

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Nitroglycerin is a prototype of LACR-lowering drugs. However, it has the disadvantage that it simultaneously lowers coronary blood flow. Adenosine 5'-ethyl ester and adenosine-5'-amide increase coronary blood flow and pressure in the coronary artery. Adenosine 3 ', 5'-dinitrate has the disadvantage that it has a very short duration of action. The effect of adenosine 2 ', 3', 5'-trinitrate on LCAR is dose-dependent (at lower doses the LCAR increases, while at higher doses the effect is twofold). In contrast, the compounds of the present invention lower coronary artery pressure and surprisingly affect coronary blood flow in the desired direction or less unfavorably than nitroglycerin. The compounds known from U.S. Pat. No. 3,832,341 (adenosine 3 ', 5'-dinitrate) do not affect the coronary blood flow when administered intraduodenally, whereas the compounds of the present invention have such an effect. Comparison of Compound I of the present invention (2 ', 3'-di-O-nitroadenosine-5'-carboxylic acid ethyl ester) and adenosine 3', 5'-dinitrate gave the following results:

Compound Dose Blood pressure Heart rate Blood flow in the coronary artery

Ttg / kg Δ% min Δ% min Δ% min I 0.6 -10 120 0 120 +50 240 2.6 -18 120 +5 30 +60 30

Adenosine 3 ', 5'-dinitrate 10.0 -22 to 0-0 s 61194

The starting materials of the formula II are known, for example, from F1 patent publication 54,316 or can be prepared from known compounds in a manner known per se.

Example I

To 90 ml of fuming nitric acid (d = 1.5) was added 6.7 g of urea at -15 ° so slowly that the temperature did not exceed -10 °. To this solution was immediately added 10.8 g of adenosine-5'-carboxylic acid ethyl ester at -10 ° C. The reaction solution was stirred for 3 hours in an ice bath, poured into a mixture of 225 g of KHCO 3 and 1000 g of ice / water, and the precipitated crude product (4.4 g) was suction filtered. Extraction of the filtrate with chloroform / methanol (95: 5) gave an additional 4.4 g of crude reaction product in which the following nitroadenosines were detected by chromatography on silica gel with chloroform / ethyl acetate / methanol (45:45:10): 2.65 g of 2 ', 3'-di -O-nitroadenosine-5'-carboxylic acid ethyl ester, m.p. 135 ° (decomposes, ethyl acetate / chloroform); 0.41 g of 2'-nitroadenosine-5'-carboxylic acid ethyl ester, m.p. 170-171 ° (decomposes, from ethyl acetate / diethyl ether); 1.3 g of 3'-O-nitroadenosine-5'-carboxylic acid ethyl ester, m.p. 166.5-167 ° (decomposes, from ethanol).

Example 2 100 ml of fuming nitric acid (d = 1.50) was carefully mixed at -20 ° with 6.7 g of urea. To this solution was dissolved 10.8 g of adenosine-51-ethylamide, keeping the temperature at -20 °. The reaction mixture was then stirred at -20 °, then slowly warmed to -5 ° and after a total of 5 hours was added slowly to excess aqueous potassium carbonate solution (230 g KHCO 3 in 800 mL H 2 O) with stirring. After suction filtration of the precipitate and washing with water, the filtrate was extracted 5 more times with 400 ml of a mixture of ethyl acetate + 5% tetrahydrofuran. The organic phases were washed with brine, dried over MgSO 4 and evaporated under reduced pressure. Total yield: 11.5 g.

To separate the crude product into three nitrate esters, it was recrystallized several times from ethanol to give pure 31-O-nitroadenosine-5'-ethylamide. 2 ', 3'-Di-O-nitroadenosine-51-ethylamide was obtained from the mother liquors by crystallization from acetonitrile, while complete fractionation of the mother liquors by chromatography on silica gel with chloroform / methanol / 961194 glacial acetic acid (90: 10: 1, v / v) gave a further 2 '-O-nitroadeno-thyroxine-5'-karbonihappoetyyliamidin.

Total obtained: 3.0 g (24%) of 3'-O-nitroadenosine-51-carboxylic acid ethylamide, m.p. 210 ° (decomposes) from ethanol; 2.5 g (17.8%) of 2 ', 3'-di-O-nitroadenosine-5'-carboxylic acid ethyl ester, m.p. 164 ° (decomposes) from acetonitrile and 0.77 g (6.2%) of 21-O-nitroadenosine-51-carboxylic acid ethylamide, m.p. 208 ° (decomposes) from ethanol.

Example 3 72 ml of fuming nitric acid was carefully mixed at -20 ° with 4.9 g of urea. To this solution was slowly added 6.9 g of adenosine-5'-carboxylic acid amide, whereby the temperature of the reaction mixture was not allowed to rise above -15 °. After stirring for a further 5 hours under cooling at at least -5 °, the solution was slowly added dropwise to aqueous excess potassium carbonate solution (175 g KHCO 3 in 500 ml H 2 O), whereupon part of the reaction product precipitated. After suction filtration and washing with water, 2.9 g of a mixture of 2 ', 3'-di-O-nitroadenosine-5'-carboxylic acid amide and 3'-O-nitroadenosine-5'-carboxylic acid amide were obtained. The aqueous solution was extracted three times with 150 ml each of chloroform + 5% ethanol and then three times with 150 ml each of ethyl acetate + 5% tetrahydrofuran. The chloroform-ethanol extract was then washed with brine, dried over MgSO 4 and evaporated to give 2.0 g of almost pure 2 ', 3'-di-O-nitroadenosine-5'-carboxylic acid amide, and the ethyl acetate-tetrahydrofuran extract gave 5 g of .7 g of a mixture of 3'-O-nitroadenosine-5'-carboxylic acid amide and 21-O-Onitroadenosine-5'-carboxylic acid amide. Multiple recrystallization of the residue from the chloroform-ethanol extract from acetonitrile gave 1.17 g (12.8%) of pure 2 ', 3'-di-O-nitroadenosine-5'-carboxylic acid amide, mp 172.5 ° (dec). Repeated recrystallization of the residue from ethyl acetate-tetrahydrofuran extract from ethanol / isopropanol followed by methanol / water gave 2.25 g (28.1%) of 31-O-nitroadenosine-5'-carboxylic acid amide, m.p. 211 ° (decomp.).

Example 4 6.16 g of adenosine-5'-carboxylic acid dimethylamide were dissolved at -40 ° C in 60 ml of fuming nitric acid (d = 1.50).

A mixture of 30 ml of fuming sulfuric acid and 30 ml of nitromethane was added dropwise to this solution over 30 minutes so that the reaction temperature did not rise above -30 °. The reaction mixture was stirred for 45 minutes at -30 to 25 ° and then poured into a solution of 325 g of potassium carbonate in 1 L of water. Extraction with chloroform or addition of 5% n-propanol with chloroform gave virtually pure 2 ', 3'-di-O-nitroadenosine-5'-carboxylic acid dimethylamide, which, after recrystallization from ethyl alcohol, melted with decomposition at 156.5 ° (yield 5.78 g = 72.7% in theory).

In a similar manner the following 2 ', 3'-O-nitroadenosines were obtained: 21,3'-di-O-nitroadenosine-51-carboxylic acid isopropylamide, m.p. 183 ° (decomposes), yield 77.4%; 2 ', 31-di-O-nitroadenosine-51-carboxylic acid cyclohexylamide, m.p. 168 ° (decomposes), yield 69.5%; 2 ', 3'-di-O-nitroadenosine-51-carboxylic acid [2- (dimethylamino) ethyl] amide, m.p. 169 ° (decomposes), yield 63%; 21,31-di-O-nitroadenosine-5'-carboxylic acid Z2- (2,4-dinitro-phenyl) -ethyl] -amide, m.p. 134 ° (decomposes), yield 30.6%; 2 ', 3'-di-O-nitroadenosine-5'-carboxylic acid piperidide, m.p. 160 ° (decomposes), yield 76.2%; 21,3'-di-O-nitroadenosine-5'-carboxylic acid [2- (nitrooxy) ethyl] -7-amide, m.p. 164 ° (decomposes), yield 58.9%; 2 ', 3'-di-O-nitroadenosine-51-carboxylic acid isopropyl ester, m.p. 158 ° (decomposes), yield 71.6%.

Example 5

Reaction of 6.16 g of adenosine-5'-carboxylic acid dimethylamide with 60 ml of fuming nitric acid and further work-up as described in Example 4, but without the addition of fuming sulfuric acid / nitromethane, gave a mixture of 3'-O-nitroadenosine-5 '-carboxylic acid dimethylamide, m.p. 214 ° (decomposes), yield 21% of theory, and 2 ', 3'-di-O-nitroadenosine-5'-carboxylic acid dimethylamide, m.p. 156 ° (decomposes), yield 9.3% of theory.

Claims (2)

A process for the preparation of therapeutically useful adenosine nitrates of the formula I and their physiologically tolerable acid addition salts, in which R and R are hydrogen atoms or nitro groups, at least one of which is a nitro group; and is hydroxy, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, aryl-lower alkylamino, cycloalkylamino, piperidino, 1- (dimethylamino) ethylamino or [2- (nitrooxy) ethyl] amino, characterized in that that the compound of formula II & II S-4 HHOH OH 5 in which R is as defined above, the nitrate 3a is, if desired, converted into a physiologically acceptable acid addition salt. 12 „61194 For the manufacture of therapeutic adenosine adenosine with the formulation I as well as physiologically acceptable syrup supplementation, HV r5-co K — pt '1 2 OR OR 1 2 and a single formula R and R is a vateatomer or a nitro group; and R 5 is hydroxy, alkoxy, amino, alkylamino, di-alkylamino, aryl-alkylamino, cycloalkylamino, piperidino, [2- (dimethylamino) ethyl]> 7 amino or 2- (nitrooxy) ) ethylamine, whether or not obtained by the action of formula II nh2 CQ II r5T ^ ° · ^ <f V --— HH OH OH color R5 physiological godtagbart syraadditions-salt.