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United States Patent ()??ce 3,692,634 Patented June 4, 1963 l 2 on the skin alone, serious side reactions, such as profound 3,l}92,634 NOVEL [NITRIC ACID ESTER] DERHVATWEg lowering of the flood pressure, as well as direct action on the heart muscle, require that these drugs be used very cautiously. Severe headache is also common for the patient who takes nitrates in larger dosages, and this limits 0F NHCUTINIC ACID Alfred Halpern, Great Neck, N.Y., assignor to Synergis tics, Inc, New York, N.Y., a corporation of New York No Drawing. Filed Aug. 24, E59, Ser. No. 335,406 the amount of the drug which may be administered, con ' sequently may prevent a patient from receiving the opti 5 Claims. (Ql. zen-295.5) mal therapeutic dosage. Furthermore, the duration of The present invention relates to novel nitric acid ester derivatives of nicotinic acid and their method of prepara 10 the pharmaocologic effects of a nitrate compound is run predictable, with certain nitrates causing a short and fleet tion. In particular, it describes the bis-nitric acid ester ing e?ect (as for example, nitroglycerin), while others, of nicotinic acid-‘bis—i(beta -hydroxyethyl) - amide, which derived from closely relating materials, cause a rather may also be referred to as nicotinic acid-bis-(beta-nitro prolonged effect (such as erythritol tetran-itrate). A ethyl)~amide; its acid addition salts as well as the salt, the tolerance to nitrate drugs is known to develop and this nitric acid ester of bis-(beta-hydroxyethyl)amine nicotin 15 requires increasing dosage to sustain its effect. ate, which may also be referred to as, bis-(beta-nitro ethyl)amine nicotinate and the chemical processes for In contrast to these problems associated with the use of the older vasodilating drugs, the products or“ the present their synthesis. invention exert a uniform vasodilating effect on the blood An object of this invention is the provision of new and vessels situated both in [the skin and in the deep muscles. improved therapeutic agents which may be used to relax 20 The compounds are non-toxic and highly effective as blood vessels, thereby causing a vasodilatation, with con vasodilati-ng drugs capable of causing a rapid onset of sequent lowering of the systemic blood pressure as well action, which extends over a su?-lcient period of time to as improving the circulation of blood through the tissues. permit a continuous therapeutic action by proper spacing The role of vIasodi'la-tation in modern medical practice is of dosage administration. These agents may be com becoming increasingly more important since it has been determined that many serious diseases are caused by cir culatory de?ciencies. These de?ciencies may arise from a spasm (or a blockade) of conducting blood vessels, which 25 pounded into tablets or liquid preparations suitable for use reduces the volume of blood coursing through the tissues which these vessels supply. While the immediate e?ect of a reduction of the blood supply to an area may be evi denced through pain and cyanosis, this state, if allowed to persist, will result in gangrene and loss of a limb. Should this reduced blood supply occur in a vital area, such as the blood supply of the heart muscle ‘or ‘the blood supply of the brain, 'the immediate elfects may be total incapacitation and very often death. The method of treatment of such circulatory disturb ances involves the institution of appropriate vasodil-ating measures, either by pharmacologic means or through sur 40 gery. Because of the ‘general widespread nature of oc clusive artertial disease, the surgical approach is of limited value and has been found useful in relatively ‘few types of these pathologic entities. In addition, the inherent risks of surgery to a patient with an already deteriorating vas in both veterinary and human medicine. The bis-nitric acid ester of nicotinic acid-‘bis-(beta-hy droxyethyl)amide is obtained as a result of the inter reaction between nicotinyl acid chloride and the bis-nitric acid ester of diethanolamine, carried out under anhydrous conditions in the presence of a hydrogen chloride acceptor, for example, triethyl amine. The reaction may be pos tulated to proceed as fol-lows: CHI-CH —-ONO2 HN \ z CHz-CHz-ONOa + I 0001 onou -__-_> (UHa)aN N/ OHPOHZONOI CON I CH2_CH2ONO | Bis-nitric acid ester of nicotinic acid-b-is-(beta-hydroxy ethyl)amide is a crystalline compound, melting at 147° cular system further detracts trom this manner of therapy. to 149 ° C., which is di?icultly soluble in isoprop'anol, but Conservative medical management remains the method of is soluble in methanol. This compound, obtained in choice for approaching problems of diminished blood the monohydrate form, has an empirical ‘formula of circulation resulting :trom occlusive vascular disease. C1OH12O7N4l-I2O and the molecular weight of 318.2. It 50 Vasodilating drugs have been widely employed for this analyzes for carbon, hydrogen, and nitrogen in good purpose although with varying success. agreement with the theoretical values which are calculated Among the ‘drugs utilized for vasodilatation are included as 37.74 percent carbon, 4.43 percent hydrogen, and 17.61 nicotinic acid; its derivatives, and the inorganic and or percent nitrogen. The analysis of the product obtained ganic nitrates. Both of these classes of compounds have by the method described shows that it contains carbon, 55 many speci?c advantages, as well as limitations (in the 38.37%; hydrogen, 4.43%; and nitrogen, 17.94%. The scope of their application to vascular medicine). Thus, structural formula of the base may be postulated as: it is found that the action of nicotinic acid is ?eeting and, CHz—CH20NO5 since short transient vasodilatation is of little value in CON the over-all management of these disease entities, con tinued administration of nicotinic acid therapy becomes a CHr-CHzONOa necessity. This is both impractical and uneconomic for \N the patient. Another limitation of the use of nicotinic The nicotinic acid salt ‘of the bis-nitric acid ester of di acid is its predominant action on the vessels of the skin, ethanolamine although having the same empiric formula resulting in both a ‘feeling of discomfort and an onset Of a disturbing reddening of the skin which has been noted as a 65 (C10H14O3N4) as the “amide” monohydr-ate exhibits dif ‘ “blush.” Furthermore, uasodilatation of the surface ves sels is only of ancillary importance to the over-all thera peutic program. The nitrates exert a direct vasodilating action on the muscle of the arteries. While the action of the nitrates is exerted on the deeper vessels of the muscles rather than ferent chemical and pharmacologic properties. The major and signi?cant ‘difference between the two resides in the manner and site of action of these drugs. The salt, which is a polar compound, is dissociated at the pH of physiologic ?uid so that rapid tissue availabil ity of the nicotinic acid moiety results, when the com pound reaches the physiologic pH range of the blood 3,092,634 3 4 ice water, and the solvent evaporated under diminished stream. This earlier availability of nicotinic acid permits pressure. The residue is dried in vacuo over phosphorus pentoxide and consists of a dark-red oil which readily the vasodilatation of the vessels of the skin to precede that of the deeper vessels which results from the nitric acid ester of diethanolamine portion of the molecule. Thus, the more ?eeting vasodilatation of the nicotinic acid is dissolves in methanol and ethanol although after standing (for approximately 12 hours) the ethanol solubility is greatly diminished. The “oil” is boiled with isopropanol and a large insoluble fraction remains which is slightly soluble in methanol. The isopropanol extract is ?ltered supported and sustained by the onset of secondary action of the nitrates. This synergism of physiologic etfects is extremely important since it permits a more etfective dual and the ?ltrate set aside to crystallize. approach to the problem of obtaining an increased blood The crystalline precipitate which develops in the iso supply to surface areas and consequently is important to 10 propanol extract melts between 135° and 139° C. This the treatment of cold induced vaso-constrictive disorders crystalline material is only slightly soluble in boiling iso of the skin, such as Raynaud’s disease, acrocyanosis, propanol but can be readily recrystallized from methanol, chilbains and the like. Since the nicotinic amide is much more resistant to cleavage than is the polar bond of the after which, it melts at 147° to 149° C. The pure, crystal line material is the bis-nitric acid ester of nicotinic acid salt, the “amide" compound begins its principal actions bis-(beta-hydroxyethyl)-arnide (monohydrate) with an through the nitrate moiety on the deeper vessels. In the course of its metabolic degradation, however, the empirical formula of C101'I140g1‘14 and a molecular weight of 318.2. It analyzes for carbon, hydrogen and nitrogen as 38.3% carbon; 4.43% hydrogen; and 17.94% nitrogen. pharmacologic activity is transferred to the nicotinic acid portion and the vessels of the skin. Thus, virtually op The theoretical content of these atoms are carbon, posite pathways of pharmacologic activity are obtained through the administration of these separate compounds, 37.74%; hydrogen, 4.43%; and nitrogen, 17.61%. This compound is the monohydrate corresponding to the fol lowing structural formula: although a similar end-result of an increased blood supply to the tissues is obtained. It is just these differences in the mechanism of therapeutic action that bestow special signi?cance to each of these compounds in therapy. Each 25 compound has an important and valuable place in supply ing a special pharmacologic effect ‘for a particular patient requirement. CHz—CH2ON0l CON \N The nicotinic acid salt of the bis-nitric acid ester of Example 2 diethanolamine is obtained by reacting stoichiometric 30 To 3.5 grams ‘of the bis-nitric acid ester of diethanol equivalents ‘of nicotinic acid and bis-nitroethanolamine amine dissolved in 75 cc. of absolute ether and contained in an alcoholic solvent. The desired compound, obtained in a glass vessel ?tted with a delivery funnel, a moisture by precipitation with ether, is a crystalline, yellow colored trap, and a stirring device, and cooled to a temperature solid melting at 130° to 131° C. The compound is ob tained as a monohydrate corresponding to the formula C10H14O8N4-I-12O, with a molecular weight of 336.26 and has a theoretical nitrogen content of 16.66% (Found per of less than 5° C., is added 2.5 grams of nicotinyl chloride dissolved in 25 cc. of absolute ether. A light yellow precipitate forms immediately which after 15 minutes of stirring is vacuum ?ltered at room temperature and cent nitrogen, 16.50%). The following structure may be washed with dry ether. The dried precipitate is ground postulated for the salt: 40 with 30 cc. of methanol and the mixture heated to boil 0 II CHz-CHz-ONO: ing and allowed to crystallize by cooling. The crystal line material obtained in this manner melts at 153°-155° CHz-CH2—ONO2 C. and is the hydrochloride of the bis-nitric acid ester of nicotinic acid-bis- (beta-hydroxyethyl ) -amide. The base material may be obtained by neutralization When it is desired to utlize these novel nitric acid alkyl 45 with sodium carbonate solution, although this is not neces ester derivatives of nicotinic acid in clinical practice, they may be compounded into tablets, capsules and solutions both for oral and parenteral administration. These pharmaceutical preparations are prepared so that each sary since the hydrochloride salt of the amide may be utilized in therapy. Should it be desired to utilize other pharmacologieally acceptable acid addition salts than the hydrochloride salt unit will supply a dose of from 25 to 50 mg. of the active 50 of the “base,” then these may be formed from the base compound and may be administered several times daily in accordance with the individual patient’s needs. The following examples describe the products of my in vention and the processes for obtaining them: Example 1 To 3.5 grams of nicotinyl chloride hydrochloride dis solved in 25 cc. of dry chloroform, is added 2.0 grams compound by treatment with the appropriate acid in either aqueous or alcoholic media. Thus, through the utilization of either hydrogen bromide, sulfuric acid or dilute nitric acid, the respective acid salts of the base would be ob 55 tained. Other pharmacologically ‘acceptable acid addition salts may be similarly formed. Such salts may also be obtained by metathesis between the hydrochloride and a salt of the desired acid. However, other than from of triethylamine in the cold. This mixture is slowly added, the viewpoint of different solubility characteristics and 35:117 (1935)) and 4.0 grams of triethylarnine in 50 cc. of dry chloroform, contained in a ?ask ?tted with a mois Example 3 with constant stirring, to a mixture of 5.0 grams of nitric 60 physical properties, these acid salts impart no new thera acid ester of diethanolamine nitrate (Mem. Poudres. peutic properties. ‘ ture trap, a delivery tube and a stirring device. The tem A mixture of 1.5 grams of the bis-nitric acid ester of perature of the reacting mixture is maintained below 65 diethanolamine and 0.95 gram of nicotinic acid in 10 cc. 0° C., and the reaction allowed to proceed until no further of methanol are heated for 15 to 30 minutes to dissolve evolution of hydrogen chloride occurs. The stirring is the components. The solution is allowed to cool slowly continued while the reaction mixture is allowed to warm to room temperature and set aside to stand overnight. to room temperature and then maintained ‘at room tem The dark-red solution is then mixed with su?icient ether perature for an additional two hours. The ‘resultant pre 70 to just initiate precipitation and the mixture cooled. The cipitate is ?ltered and consists of the hydrochloride acid precipitate is ?ltered; dried and is found to melt (with salt of the bis~nitric acid ester of diethanolamine (melt decomposition) ‘over a range of from 110° to 160° C. ing point 145° C. and may be identi?ed by mixed melt This dried impure salt is recrystallized several times from ing point techniques as well as chloride analysis). a mixture of ethanol and ether until a light-yellow, crys The chloroform solution is extracted several times with 3,092,634 talline ?ake is obtained which melts sharply at 130° to 131° C. This compound is the m‘onohydrate of nicotinic acid salt of the bis-nitric acid ester of diethanolamine simple solution of the active material in the desired ve hicle which may consist of from 10 to 30 percent of alco i101 and water. It is desirable to maintain the concen tration of active material per unit dose (teaspoonful) of drum 25 to 50 mg. of active material whether the aqueous syrup solutions are used or the hydroalcoholic vehicles are and has a molecular weight of C10H16O9N4 corresponding to the ‘following structural formula: utilized. Example 7 |\ H OHPCHsONOz Solutions for injection may also be prepared by dissolv N/ 10 ing the appropriate quantity of the active material in The compound analyzes for nitrogen, as follows: Calcu sterile water for injection, maintaining an aseptic tech lated percent nitrogen, 16.66%; found percent nitrogen, nique throughout. The solution may be sterilized through the process of bacteriol-ogic ?ltration and ?lled 16.50%. Example 4 ‘In place of the nicotinyl chloride, described in Example 2, may be substituted nicotinyl bromide, in stoichiometri 15 into sterile glass ampules so that each cc. contains from 25 to 50 mg. of active material. The solution may be administered by either intravenous ‘or intramuscular injec c-ally equivalent amounts and the remainder of the process carried out as described in Example 2. The resultant tion, in accordance with the patient’s needs, utilizing the able cations may be substituted for the chlorine atom When it is desired to take advantage of the different well-known precautions common to this method of admin product is the hydrobromide salt, in place of the hydrogen 20 istration. chloride salt. Similarly, other pharmacologically accept and other pharmacologically acceptable acid salts secured Example 8 times of action of the “amide” base and/ or its acid addi directly as the reaction product. ‘In each case the base tion salts, on the one hand and the “salt” on the other, may be obtained by neutralization of the salt. 25 the two may be combined in a tablet or any of the other dosage forms mentioned above in unit dosages so that the Example 5 combined active material equals 25 to 50 mg. Ordinarily When it is desired to utilize ‘for therapy the bis-nitric 50 percent of each group is preferred, but if the action acid ester of nicotinic acid-lbis-(beta-hydroxyethyl) amide, desired calls for more emphasis on the quicker action of or its acid salts, or the salt, bis~(beta-nitroethyl)amine 30 one or the other the percentage mixture may be varied. nicotinate, as a tablet or a capsule, the ‘concentration of What is claimed is: active material per unit dose is adjusted so that it con tains from 25 to 50 mg. of active material and is admin 1. A compound selected from the group consisting of the nitric acid ester of bis-(beta-hydroxyethyl)-amine nieotinate, bis-nitric acid ester of nicotinic acid-bis~(beta— istered according to the patient’s needs. Tablets may be prepared by granulating the active ma terials with a diluent, as for example, milk sugar, in ratio hydroXyethyD-amide and the pharmacologically accept able acid addition salts of the last mentioned compound. of at least one part active material to 9 parts of diluent. 2. The nitric acid ester of ibis-(beta~hydroxyethyl) The use of the well-known binders or lubricants which amine nicotinate. are essential to good tablet manufacture also may be 3. Bis-nitric acid ester of nicotinic acid~bis~(beta-hy added in appropriate concentrations as is well known to 40 droxyethyl) amide. the art, in accordance with the particular tablet require 4. Bis-nitric acid ester of nicotinic acid-bis-(betaby ments. After the granulation step, in the preparation of droxyethyD-amide hydrogen chloride. tablets, the mixture is compressed into tablets each con 5. The bis-nitric acid ester of nicotinic acid-bis-(beta taining from 25 to 50 mg. of active material. These tab hydroxyethyl) -amide hydrogen bromide. lets are then administered to the patient in accordance 45 with his own needs dependent upon the age of the patient References Cited in the ?le of this patent and the severity of the disease. UNITED STATES PATENTS The granulating mixture which is obtained prior to 2,688,617 Hein et al. ____________ __ Sept. 7, 1954 compressing of tablets may be ?lled into gelatin capsules, 2,767,192 O?e et al. ____________ __ Oct. 16, 1956 utilizing the same unit range of dosage (viz. 25 to 50 mg. 2,776,923 N-ishizawa _____________ __ Jan. 8, 1957 of active material per capsule). These capsules are ad 2,834,786 Mueller ______________ __ May 13, 1958 ministered to the patient in the same order of frequency as would be the tablets. Example 6 55 2,890,984 2,900,388 2,947,741 Should a solution be preferred as a dosage form for FOREIGN PATENTS therapeutic administration then both aqueous and hydro alcohol-ic solutions may be prepared. The preparation of an aqueous solution is accomplished by dissolving the appropriate amount of the active material in simple syrup 60 and adding ?avoring and coloring agents, if desired. The preparation of hydroalcoholic solutions is achieved by Sahyun ______________ __ June 16, 1959 Tien ________________ __ Aug. 18, 1959 Ferguson _____________ __ Aug. 2, 1960 904,534 Germany ____________ __ Feb. 18, 1954 OTHER REFERENCES Karrer: “Org. Chemistry,” page 131 (1950). Drefahl et al.: Chem. Ber, volume 87, pages 1628-31 (1954).