CH606084A5 - (Di) nitrates of adenosine -5'-carboxylic acid derivs - Google Patents

Abstract

(Di) nitrates of adenosine -5'-carboxylic acid derivs with cardiac and circulatory activity, e.g. for treating angina pectoris and hypertension(BE170876)

Description

  

  
 



   The present invention relates to a process for the preparation of new adenosine nitrates of the general formula
EMI1.1
 wherein R1 and R2 are hydrogen or nitro, but at least one of the two radicals is nitro, and R5 is hydroxyl, lower alkoxy, amino, lower alkylamino or di-lower alkylamino, and their physiologically tolerable acid addition salts and their preparation.



   The terms lower alkyl and lower alkoxy include straight or branched chain radicals 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



  The lower alkylamino groups are methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino and diisopropylamino.



   Physiologically compatible acid addition salts are taken to mean salts of compounds of the formula I with suitable organic or inorganic acids, such as hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, acetates, lactates, oleates, nitrates, mesylates, tosylates, citrates, maleates, succinates, tartrates, etc.



   The compounds of formula I and their physiologically tolerable acid addition salts can be prepared by using a compound of the general formula
EMI1.2
 wherein R5 has the meaning given above, nitrided and, if desired, converted into a physiologically acceptable acid addition salt.



   The compounds 11 can be nitrided by methods known per se.



   For example, nitration can be accomplished with nitric acid. Hydrolysis (by water formed during the reaction) or deamination (by any nitrous acid present) is expediently suppressed by adding a water-binding agent such as concentrated H2SO4, oleum, P2O5, acetic anhydride and / or a nitrite scavenger such as urea.



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



   As a rule, mixtures of the relevant 2'-O-nitro, 3'-O-nitro and 2'3'-di-O-nitro compounds are obtained, which are separated according to generally known methods, for example by chromatography, and added to the pure connections can be worked up. However, it is also possible to steer the synthesis in such a way that the 2 ', 3'-di-O-nitro compounds are isolated as the sole reaction products, which is predominantly the case when using the dehydrating agents mentioned.



   Any conversion of the compounds of the formula I into physiologically tolerable acid addition salts and the formation of such salts from physiologically incompatible addition salts can be carried out in the customary manner.



   The compounds of formula 1, as well as their acid addition salts, have valuable cardiac and circulatory dynamic properties and can therefore be used as remedies, inter alia for the treatment of angina pectoris or essential hypertension. An amount of 0.010 to 30 mg / kg body weight per day can be used as a dosage guideline, which can be administered both as a single dose, but preferably several times a day in partial doses.



   The coronary dilating effect can be measured using the following method:
Bastard dogs weighing between 20 and 38 kg are used for the tests. The test animals are administered at about 30 mg / kg i.v. Anesthetized pentobarbital.



  Anesthesia is maintained with chloralose urethane.



  The animals are artificially ventilated with indoor air. After opening the thorax, the heart is exposed and a previously calibrated flow probe of an electromagnetic flow meter is placed around the circumflex ramus of the left coronary artery to measure the amount of blood flowing through. Arterial blood pressure is measured via a catheter in the femoral artery with a pressure transducer. In addition, a calibrated strain gauge is sewn onto the surface of the left ventricle for direct measurement of the myocardial contraction force. The pulse wave of blood pressure triggers a tachograph to measure the heart rate.



  The compounds are dissolved in propylene glycol, administered intravenously or administered intraduodenally as a suspension in gum arabic. The maximum effect of a substance is calculated as a percentage of the initial value after each dose. When measuring the coronary blood flow, particular attention is paid to the duration of action.



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



  Table compound n dose BP HR CF CABF i.V.



     [mg / kg] A0 / 0 [min] A / o [min] A / 0 [min] A0 / o [min] 2 ', 3'-di-O-nitroadenosine +8.5> 2 -27> 27 +356 21 5'-carboxylic acid ethyl ester 2 3.0 -45 31 2'-O-nitroadenosine 2 1.0 -14 27 +2.5> 2 - +244 30 5 '<arbonic acid ethyl ester 3.0 -49 50 + 2.5> 2 - +412 67 2'-O-nitroadenosine 0 120 - +115 120 5'-carboxylic acid ethyl amide 3 0.01 -38 120
BP = arterial blood pressure CF = contractile force
HR = heart rate CABF = coronary flow
The compounds according to the invention can be used as pharmaceutical preparations with direct or delayed release of the active ingredient in a mixture with an organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as water, gelatin, gum arabic,

   Milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. can be used. The pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules; in semi-solid form, for example as ointments; or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain other auxiliary substances. such as preservatives, stabilizers, wetting agents or emulsifiers, agents for improving the taste, salts for changing the osmotic pressure or buffer substances. The pharmaceutical preparations can be produced in the manner familiar to any person skilled in the art.



   The starting compounds of formula 11 are known or can be prepared from known compounds in a manner known per se.



  example 1
To 90 ml of smoking nitric acid (d = 1.5), 6.7 g of urea were added so slowly at -15 "that the temperature did not exceed -10". To this solution were successively added at -10 "10.8 g of ethyl adenosine-5'-carboxylate. The reaction solution was stirred in an ice bath for 3 hours, introduced into a mixture of 225 g of KHCO3 and 1000 g of ice / water and the precipitated crude product (4th , 4 g) is suctioned off.

  Extraction of the filtrate with chloroform / methanol (95: 5) again gave 4.4 g of the crude reaction product which, by chromatography on silica gel with chloroform / ethyl acetate / methanol (45:45:10), gave the following nitroadenosines: 2.65 g 2 ', 3'-di-O-nitroadenosine-5'-carboxylic acid ethyl ester, melting point 135 (decomp., from ethyl acetate / chloroform); 0.41 g of 2'-nitroadenosine-5'-carboxylic acid ethyl ester, melting point 170 to 171 "(dec., From ethyl acetate / diethyl ether); 1.3 g of 3'-O-nitroadenosine-5'-carboxylic acid ethyl ester, melting point 166 , 5 to 167 (decomp., From ethanol).



  Example 2
100 ml of fuming nitric acid (d = 1.50) were carefully mixed with 6.7 g of urea at -20 ". 10.8 g of adenosine-5'-ethylamide were dissolved in this solution, the temperature being kept at -20" . The reaction mixture was then initially stirred further at -20 ", then slowly warmed to -5" and, after a total of 5 hours, slowly stirred into excess aqueous potassium bicarbonate solution (230 g KHCO3 in 800 ml H2O). After suctioning off and washing the precipitate with water, this became
Filtrate extracted 5 times with 400 ml of a mixture of ethyl acetate + 5/0 tetrahydrofuran.

  The organic phases were washed with saturated saline, over
MgSO4 dried and concentrated under reduced pressure. Total raw yield: 11.5 g.



   To separate the crude product into the 3 nitrate esters, the product was recrystallized several times from ethanol, giving pure 3'-O-nitroadenosine-5'-ethylamide. 2 ', 3'-Di-O-nitroadenosine-5'-ethylamide could be obtained from the mother liquors by crystallization from acetonitrile, while the complete separation of the mother liquors by chromatography on silica gel with chloroform / methanol / glacial acetic acid (90: 10: 1, v / v) also delivered the 2'-O-nitroadenosine-5'-carboxylic acid ethyl amide.



   A total of:
3.0 g (240 / o) 3'-O-nitroadenosine-5'-carboxylic acid ethylamide, mp 210 (dec.) From ethanol; 2.5 g (1 17.8%) 7.80 / o) 2 ', 3'-di-O-nitroadenosine. 5'-carboxylic acid ethyl amide, mp. 164 "(dec.) From acetonitrile and
0.77 g (6.2 / o) 2'-O-nitroadenosine-5'-carboxylic acid ethylamide, mp. 208 (dec.) From ethanol.



  Example 3
72 ml of fuming nitric acid were carefully mixed with 4.9 g of urea at -20 ". 6.9 g of adenosine-5'-carboxamide were slowly introduced into this solution, taking care that the temperature of the reaction mixture did not exceed -15" rose. The mixture was stirred for a further 5 hours with cooling to at least -5 "and then slowly dripped into excess aqueous potassium bicarbonate solution (175 g KHCO3 in 500 ml H2O), part of the
Reaction product failed. After suction extraction and washing with water, 2.9 g of a mixture of 2 ', 3'-di-O-nitroadenosine-5'-carboxamide and 3'-O-nitroadenosine-5'-carboxamide were obtained.

  The aqueous solution was extracted 3 times with 150 ml of chloroform + 50 / o ethanol and then 3 times with 150 ml of ethyl acetate +50/0 tetrahydrofuran. After washing with saturated sodium chloride solution and drying over MgSO4, 2.0 g of almost pure 2 ', 3'-di-O-nitroadenosine-5'-carboxamide and from the ethyl acetate-tetrahydrofuran were extracted from the chloroform-ethanol extract. Extract 5.7 g of a mixture of 3'-O-nitroadenosine-5'-carboxamide and 2'-O-nitroadenosine-5'-carboxamide obtained. Repeated recrystallization of that obtained from the chloroform-ethanol extract
Residue from acetonitrile gave 1.17 g (12.80 / o) of pure 2 ', 3'-di-O-nitroadenosine-5'-carboxamide, mp 172.5 (dec.).

 

   Repeated recrystallization of the residue obtained from the ethyl acetate tetra hydrofuran extract from ethanol-isopropanol and then from methanol-water gave 2.25 g (28.1%) of 3'-O-nitroadenosine-5'-carboxamide, mp.



     2110 (dec.).



  Example 4
6.16 g of adenosine-5'-carboxylic acid dimethylamide were dissolved at -40 "in 60 ml of fuming nitric acid (d = 1.50). A mixture of 30 ml of oleum and 30 ml of nitromethane was added dropwise so that the reaction temperature did not exceed -30 ". The reaction mixture was stirred for 45 minutes at a temperature between -30" C and -25 "C and then poured onto a solution of 325 g of potassium bicarbonate in 1 liter of water.

  By extraction with chloroform or with chloroform with the addition of 5010 n-propanol, practically pure 2 ', 3'-di-O-nitroadenosine-5-carboxylic acid dimethylamide was obtained, which after recrystallization from alcohol melted at 156.5 with decomposition (yield 5, 78 g = 72.7% of theory).



   The following 2 ', 3'-di-O-nitroadenosines were obtained in an analogous manner: 2', 3'-di-O-nitroadenosine-5'-carboxylic acid isopropylamide, mp. 183 (dec.), Yield 77.40 / 0; 2 ', 3'-Di-O-nitroadenosine-5'-carboxylic acid isopropyl ester, mp 158 (dec.), Yield 71.6%.

 

  Example 5
The reaction of 6.16 g of adenosine-5'-carboxylic acid dimethylamide with 60 ml of fuming nitric acid and working up as described in Example 4, but without the addition of oleum / nitromethane, gave a mixture of 3'-O-nitroadenosine-5'-carboxylic acid dimethylamide , Mp. 214 (dec.), Yield 21% of theory, with 2 ', 3'-di-O-nitrnadenosine-5'-carboxylic acid dimethylamide, mp. 156 (dec.), Yield 9.30 / 0 of Theory.

 

Claims (1)

PATENT CLAIM Process for the preparation of adenosine nitrates of the general formula EMI3.1 wherein R1 and R2 are hydrogen or nitro, at least one of the two radicals but nitro, and R5 are hydroxy, lower alkoxy, amino, lower alkylamino or di-lower alkylamino, and their physiologically compatible acid addition salts, characterized in that a compound of the general formula EMI3.2 wherein R5 has the meaning given above, nitrided and, if desired, converted into a physiologically acceptable acid addition salt.