GB1562962A

GB1562962A - Nicotinamide derivatives processes for producting the same and pharmaceutical compositions containing the same

Info

Publication number: GB1562962A
Application number: GB1254177A
Authority: GB
Original assignee: Chugai Pharmaceutical Co Ltd
Current assignee: Chugai Pharmaceutical Co Ltd
Priority date: 1976-04-02
Filing date: 1977-03-24
Publication date: 1980-03-19
Also published as: HU174118B

Description

(54) NICOTINAMIDE DERIVATIVES, PROCESSES FOR PRODUCING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME (71) We, CHUGAI SEIYAKU KABUSHIKI KAISHA, a Japanese body corporate, of No. 5-1, 5-chome, Ukima, Kita-ku, Tokyo, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to nicotinamide derivatives, processes for producing the same, and pharmaceutical compositions containing the same.

Some nicotinic acid derivatives or nicotinamide derivatives have been reported in some references, for example Japanese Patent Dis- closure No. 1624/1976, United States Patent No. 3,092,634, United States Patent No.

3,168,438 and "Mie Medical Journal", Vol.

16(3), pp. 207-211, (1967).

The aforementioned Japanese Patent Disclosure discloses that nicotinic ester derivatives are prepared by reacting 1-nicotinylglycerine or 1 - nicotinyl -2,3 - isopropylidene glycerine with fuming nitric acid, to obtain 1 - nicotinyl glycerine - 2,3 - dinitrate and then converting the compound to its dioxane addition compound which has a coronary vasodilating action.

United States Patents Nos. 3,092,634 and 3,168,438 disclose that bis-nitric acid of N,Nbis - ( - hydroxyethyl)nicotinamide which has coronary vasodilating action is prepared by reacting nitric ester of diethanolamine with nicotinic acid chloride.

However, the aforementioned compounds which have been reported have short term action or adverse action against blood pressure or function of heart and, thus, do not suffice as a drug to stimulate the circulatory system, for example, in the case of ischemic heart disease. Under the circumstances, the development of an ideal drug has been desired.

In "Mie Medical Journal", Vol. 16(3), pp.

207-211 (1967), 2-nicotinamido ethanol is mentioned. However, the compound is merely shown as a test compound for anti-tumor action and the Journal reported no remarkable pharmacological action.

Also, United States Patent No. 3,036,074 discloses esters of nitric acid of hydroxyalkylamines, which have low toxicity and cause an increased coronary flow; and the production of such esters. That Patent relates to nitroxyalkyl - carboxyy - amides having the general formula

where n is the figure 0 or 1, A is a lower alkyl residue, R is alkyl, aryl, aralkyl, cycloalkyl or a heterocyclic residue, and R1 is hydrogen, alkyl or nitroxy alkyl, and more than one correspondingly substi tuted group of carboxylic acid can k contained in the molecule.

One compound particularly referred to in that U.S. Patent, in fact in Example 8 thereof, has the formula

According to one aspect of the present invention there is provided nitric ester of N (2 - hydroxyethyl) - nicotinamide having the following formula:

or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are novel and have, compared with known compounds, improved actions for treating various circulatory diseases, such as coronary vasodilating action, antihypertensive action, antiarrhythmic action, anticoagulative action and peripheral vasodilating action, and thus they are useful for treating ischemic heart disease, as an antihypertensive drug, anticoagulative drug, antiarrhythmic drug, and as peripheral vasodilator including cerebral vasodilator and renal vasodilator. The diseases ta be treated include hyperpiesia and thrombosis.

According to another aspect of the present invention, there is provided a process for producing a compound having the formula:

or a pharmaceutically acceptable salt thereof, which comprises: (1) reacting a compound having the formula

or a reactive derivative thereof at the carboxyl group, with a compound having the formula NH2-CH2--C;H2-ONO2 (III) or a reactive derivative thereof at the amino group; or (2) reacting a compound represented by the formula

with a nitrating agent; and, if necessary, converting the compound of formula I to a pharmaceutically acceptable salt thereof, or vice versa.

The reactive derivative of the compound (II) at carboxyl group may be, for example1 an acid halide, acid anhydride, active amide or active ester. The derivatives which may be commonly used are acid chlorides; acid azides: acid anhydrides such as anhydrides derived from two moles of the compound (II) and anhydrides of the compound (II) with another acid, for example a dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, benzylphosphoric acid, a halogenated phosphoric acid, a dialkylphosphorous acid, sulphurous acid, thiosulphuric acid, sulphuric acid, an alkylcarbonic acid, a fatty acid such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid or trichloroacetic acid, or an aromatic carboxylic acid such as benzoic acid; amides, for example amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; arid esters, for example cyanomethyl ester, 4nitrophenyl ester, 2,4 - dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, ntetnanesulphonylphenyl ester, phenylazophenyl ester, phenyltulo ester, 4-nitrophenylthio ester, p-cresylthio ester, carboxymethylthio ester, pyranyl ester, pyridyl ester, Squinolylthio ester or an ester with N,N dimethylhydroxylamine, l - hydroxy - 2- (1H) - pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide.

The starting compound (III) may be used in the form of a derivative activated at the amino group, which can be activated by the reaction with phospohorus trichloride, ethyl chlorophosphite or methyl chlorophosphite.

The process as defined in reaction (1) above may be carried out by reacting, for example, a reactive derivative of the compound (II) at the carboxyl group with the compound (III) to effect condensation at a temperature of from -10 to 50 C, preferably 0-100C, for from 0.5-4 hours. The solvents which may be used for this reaction include water, benzene, toluene, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, chloroform, methylene chloride, acetonitrile, acetone, carbon tetrachioride and ethyl acetate. An accelerator for the condensation reaction may be used, which includes inorganic basic substances, for example, the hydroxide, carbonate or acetate of an alkali metal or alkaline earth metal, such as sodium acetate, sodium carbonate, potassium acetate, potassium carbonate, sod~m hydroxideL calcium acetate or calcium carbonate; and amine compounds such as pyridine, triethylamine, dimethylaniline and picoline.

The condensation reaction of the compound (II) with the compound (III) the amino group of which has been activated with phosphorus trichloride, ethyl chlorophosphite or methyl chlorophosphite may be conveniently carried out at from room temperature to the reflux temperature of a solvent used, for from 0.5-3 hours. The solvent usually used for this reaction includes a neutral solvent, such as benzene, toluene, xylene, dioxane or tetrahydrofuran; or an organic basic solvent such as pyridine, triethylamine, dimethylamine, dimethylaniline or picoline. When the neutral solvent is used, it is preferable to add an amine compound such as pyridine, triethylamine, dimethylaniline or picoline.

In another embodiment of the process of the present invention, the compound (II) may be reacted with the compound (III) is an inert solvent in the presence of an amideformation accelerator, for example, an imide compound such as N,N'-dicydohexylcarbodi- imide, N-cyclohexyl - N' - morpholinoethyl carbodiimide or N,N'-diethylcarbodiimide; an imine compound such as diphenylketene-N cyclohexylimine or pentamethyleneketene-N N-cyclohexylimine; or a phosphate or phosphite such as triethyl phosphite, ethyl polyphosphate or isopropyl polyphosphate, at from room temperature to the reflux temperature of the solvent used, for 1-5 hours. The inert solvent which may be used in this reaction includes, for example, benzene, toluene, tetrahydrofuran, chloroform, dioxane, acetonitrile, methylene chloride, and dimethylformamide.

The aforementioned reaction (2) may be carried out by reacting the compound (IV) with a nitrating agent in an inert solvent such as chloroform or dichloromethane at a temperature of from - 50C to room temperature for 1-3 hours. The nitrating agent which may be generally used in this reaction is fuming nitric acid or nitryl chloride.

The compound of formula (I), when produced by reaction (1) or reaction (2), may be converted to its organic or inorganic acid addition salt such as the hydrochloride, nitrate, oxalate, p-toluenesulfonate or maleate.

The compounds of the present invention may be formulated by a conventional way into a pharmaceutical composition in the form of a tablet, granule, powder, capsule, suspension, parenteral injection or suppository. For the preparation of a tablet, powder, granule or capsule filled with powder or granule, the compound of the present invention may be mixed with one or more pharmaceutical carriers such as lactose, starch, mannitol, kaolin, crystalline cellulose, talc, calcium carbonate or magnesium stearate. For the preparation of a soft capsule filled with liquid preparation, the compound of the present invention may be dissolved in an oil. The compound of the present invention may also be suspended in an arabic gum or sucrose aqueous solution and the pH adjusted. On the other hand the compound of the present invention may be blended with mannitol to make it suitable for parenteral injection.

The nicotinamide derivatives according to the present invention may be present in any form of the pharmaceutical composition in an amount sufficient to cause the actions for treating or preventing circulatory disease but not to exhibit any advert action by the administration of the composition. A unit dosage form such as a tablet or capsule may contain usually 5-20 mg of the active compound when the composition s orally administered. In the event that the composition is given parenterally, a unlit dosage such as a vial may usually contain about 1-10 mg of the compound.

It will be understood that the actual dosage changes, as a matter of course, depend upon the conditions of individual patient and, therefore, it should be specifically determined when used. However, it will be safe and convenient if the dosage in terms of the active compound is usually 10-100 m, preferably 10-60 mg, per day for an adult when administered orally, and usually 1 100 mg, preferably 150 mg, per day for an adult in the case of the parenteral injection.

Fig. 1 is a graph showing percent increase in coronary blood flow when the compound of the present invention prepared according to Example 1, or nitroglycerin (as a control), was intravenously administered in accordance with Experiment 1.

Fig. 2 is a graph showing the duration of increase in coronary blood flow when the compound of Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.

Fig. 3 is a graph showing the change in the left ventricular tension when the compound of Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.

Fig. 4 is a graph showing the change in heart rate when the compound of Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.

Figs. 5, 6 and 7 are graphs showing the change in electrocardiograms when the compound of Example 1 was intravenously administered.

Fig. 8 is a graph showing the change in systemic blood pressure when the compound of Example 1 or nitroglycerin was intravenously administered in accordance with Experiment 1.

Figs. 9 and 10 are graphs showing the change in systemic blood pressure when the compound of Example 1 was intravenousty administered according to Experiment 1.

Figs. 11 and 12 are graphs showing the change in aortic blood flow when the compound of Example 1 was intravenously administered.

Fig. 13 is a test chart showing the effect of the compound of Example 1 to the platelet coagulation caused by adenosine diphosphate in accordance with Experiment 7.

Fig. 14 is a test chart showing the effect of the compound to the platelet coagulation caused by collagen in accordance with Experiment 7.

Experiment 1.

The acute tonicity (LDSo) of the compound of Example 1 was determined by the use of SD strain male and female rats (4 weeks old) which were orally and intravenously administered the compound. LD,,, against both male and female rats ranged from 1,200 to 1,300 mg/kg for oral administration and from 800 to 1,000 mg/kg for intravenous administration.

Experiment 2.

Adult mongrel dogs which had been anesthetized by the intravenous administration of 30--40 mg/kg of pentobarbital sodium were subjected to thoracotomy under oxygenic ventilation by use of Bird's respirator and thereafter various physical phenomena were measured in the following manner.

1) Coronary blood flow (CBF).

An electromagnetic flowmeter probe was attached to a circumflex branch of an origin of an anterior descending branch of the left coronary artery.

2) Coronary perfusion pressure (CBP).

The fine catheter connected to a pressure transducer was inserted into the distal side of the probe in the circumflex branch of the left coronary artery.

3) Aortic blood flow (AoBF).

An electromagnetic flowmeter probe was attched to the origin of aorta.

4) Left ventricular tension (LVT).

A strain gauge was sewn on the anterior wall of the left ventricle.

5) Systemic blood pressure (SBP).

A catheter connected to a pressure transducer was inserted into the right femoral artery 6) Heart rate (HR).

Heart rate was measured by a cardiotachometer using pulse pressure as trigger pulse.

7) Electrocardiogram (ECG).

An electrocardiogram was recorded according to an unipolar lead in the cardiac surface using different electrode set on a portion of anterior wall of left ventricle.

In addition to the test Items 1-7 above, some of the test animals were subjected to the measurements of renal blood flow (RBF) and femoral blood flow (FBF) by attaching an electromagnetic flowmeter probe to the left renal artery and the left femoral artery.

The test compound of Example 1 was dissolved in the physiological saline solution or in the distilled water and administered intravenously, orally or sublingually; nitroglycerin was administered in the same manner as an active control drug to compare with the test compound.

Results.

(I) Intravenous Administration.

a) Change in coronary blood flow.

Diastolic coronary flow began to increase 10-20 seconds after the intravenous administration of the test compound with a dose of 10 ag/kg or more. Systolic coronary flow was increased with a dose of 250 ag/kg or more, accompanied by transient decrease just after the administration. Mean coronary flow showed a persistent increase after the administration of the test compound.

The increasing degree of coronary flow is shown in Figs. 1 and 2 in terms of maximum percent change and duration against the values before administration.

The administration of the compound of this invention even in a dose level of 10 lKg/kg i.v. produced a significant increase in coronary flow and in a dose level of 500 pg/kg i.v.

caused a increase so remarkable as to appear to be reactive hyperemia. In the latter case, the duration of increase in coronary flow became to near 3 hours. The effect of the compound of this invention was superior to that of nitroglycerin, particularly in the duration of action.

b) Change in left ventricular tension.

As shown in Fig. 3, the left ventricular tension caused a slight decrease after the intravenous administration of the compound of Example 1 in a dose level of 50 ,ug/kg or more. The decrease was almost equivalent to that of nitroglycerin in the tested dose range.

However, the maximum percent decrease was 33% or less even in a dose level of 500 kg i.v.

c) Change in heart rate.

As shown in Fig. 4, the heart rate showed almost no change by the administration of the compound of this invention in a dose level up to 20,pg/kg i.v., while, in a dose level of 50 ag/kg i.v. or more, presented a silght dosedependent decrease to reach 17% in a dose level of 500 Fg/kg i.v. In contrast, the administration of nitroglycerin in a dose level of more than 10 pg/kg i.v. increased the heart rate.

d) Change in electrocardiogram.

As shown in Figs. 5 and 7, PP and QTc intervals were prolonged dose-dependently by the intravenous administration of the compound of Example 1 with a dose more than 5G ,ag/kg, while the PQ interval had almost no change by the administration of dose up to 1,000 ,ag/kg i.v.

e) Change in systemic blood pressure.

As shown in Figs. 8, 9 and 10, the systemic blood pressure presented a significant, dosedependent fall by the intravenous administration of the test compound in a dose level of more than 50 ,ag/kg. The effect of the compound on blood pressure was not stronger than that of nitroglycerin, but the duration was longer than that produced with nitroglycerin.

f) Change in aortic blood flow.

As shown in Figs. 11 and 12, the aortic blood flow presented a slight, dose-dependent increase by the intravenous administration of the compound of Example 1 in a dose level of 10 ,ug/kg or more. The percent increase in a dose level of 500 ,ag/kg i.v. reached maximum 40%, but the duration was not so long in comparison with the degree of increase in coronary flow.

g) Change in renal or femoral flow.

The renal and femoral flows were increased in spite of a fall in systemic blood pressure by the intravenous administration of the compound of Example 1 in a dose level of 100 to 250 ag/kg. However, the increase in the renal and femoral flows were less than that in coronary flow concerning the degree and the duration.

From the test results stated above, it was confirmed that the compound of this invention had an increasing effect on coronary flow far superior to that of nitroglycerin and, in addition, it produced a fall in blood pressure, a decrease in heart rate and a reduction in cardiac tension, which were not excessive even in a high dose level.

Moreover, the fact that the compound of this invention did not disturb the conduction of excitation in the heart as shown in no prolonged PQ interval of electrocardiogram, indicates that it may be very useful as a drug for ischemic heart disease.

The compound could be used as an antihypertensive drug or a peripheral vasodilator because it has a long lasting and mild antihypertensive action and a dilating action for femoral and renal vessels, as well as a desirable effect on ischemic heart.

(II) Oral and Sublingual Administration.

The compound prepared according lo Example 2 was sublingually administered to dogs as a tablet containing 1-10 mg of the compound. About 2 minutes after the administration, coronary flow was apparently increased. The compound in a dose level of 10 mg showed almost no change in systemic blood pressure, cardiac tension and aortic flow.

In contrast, the sublingual administration of a tablet containing the hydrochloride of the active compound did not show any substantial increase in coronary flow. When the compound prepared according to Example 1 or 2 in either its free form or hydrochloride was intraduodenallv administered in a dose level of 50 kag/kg or more, an apparent, long lasting increase in coronary flow was observed.

From the test results, the compound of this invention may be used as various preparations, such as for parenteral injection; or in the form of capsule, tablet, granule or powder for oral administration or in sublingually adminisuative form. In contrast, nitroglycerin is not absorbed through the intestinal wall and, therefore, only sublingual administration is available.

Experiment 3.

Adult mongrel dogs which had been anesthetized by the intravenous administration of 3040 mg/kg of pentobarbital sodium were subjected to thoracotomy under oxygenic ventilation by the use of Bird's respitator. A catheter was inserted towards a proximal direction into a branch of an origin of the left coronary artery and a contrast media such as "Conlaxin" H (registered Trade Mark) or "Angio-Conray" (registered Trade Mark) was injected through the catheter. The morphological change in the left coronary artery was filmed using a 35 mm cinefilm before and after the injection of the compound. From the analysis, it was found that the coronary artery was remarkably dilated by the intravenous administration of the compound of this invention in a dose level of 100 Uag/kg or more.

Experiment 4.

The same preparation as in Experiment 2 was set up using adult mongrel dogs anesthetized by the intravenous administration of pentobarbital sodium. The left anterior descending branch or circumflex branch of rhe coronary artery was mechanically strictured or occluded in the distal side of the portion attaching the electromagnetic flowmeter probe to experimentally induce cardiac ischemic phenomenon, and then the effect of the compound of Example 1 on the phenomenon was observed.

Under incomplete stricture, the coronary flow was slightly increased when the compound of Example 1 was intravenously administered in a dose level of 100 4ag/kg or less, while slightly decreased when administered in a dose level of more than 250 Fg/ kg. After the administration of the compound of this invention, ST elevation of the electrocardiogram in the cardiac ischemic portion was apparently improved and, at the same time, the recovery of ventricular tension in an ischemic part was also observed. Under complete occlusion, the compound did not improve ST elevation or ventricular tension in the midpoint of the ischemic portion, but the improvement in the surrounding point of the ischemic portion was recognized.

Similarly, when a tablet containing 10 mg of the free form of the compound prepared in Example 2 was sublingually administered, the coronary flow was increased and ST elevation in the electrocardiogram and a reduction in ventricular tension were improved.

Experiment 5.

(I) A papillary muscle isolated from a guinea pig was set in the organ bath filled with the oxygenized Tyrode's solution (Ca: 1.8 mM, K: 2.7 mM) at 30"C. One end of the muscle was fixed to the organ bath and the other end was connected to a tension meter by a thread. The effect of the compound of Example 1 on the muscle contraction force was observed by giving electric stimulation (20V, 5 msec, 1Hz) to the muscle with an Ag-AgCl electrode. The antagonistic action of the compound against calcium ion or isoproterenol was also investigated.

From the test results, it was found that the contraction of the papillary muscle induced by the electric stimulation was inhibited with application of the compound of this invention in a concentration level of more than 1 ag/ml and that calcium ion had antagonistic effect against such inhibitory action. On the other hand, when isoproterenol was applied in a concentration level of 0.08 Qag/ml, the papillary- muscle exhibited excessive excitement to produce two or more irregular contractions per single electric stimulation. Under this state, the addition of the compound of this invention to the solution in a concentration level of more than 2 g/ml inhibited the excessive excitement.

(II) A spiral strip isolated from the dog coronary artery was set in the organ bath filled with a Ca+±free Lock's solution. One end of the strip was fixed to the organ bath and the other end was connected to a tension meter. The effect of the compound of Example 1 on the contraction of the strip induced by the polarization of the solution with the addition of 43 mM of K+ and 1 mM of Ca++ was investigated.

The test results shoyed that the contraction induced by K+ depolarization was inhibited by the compound of this invention and such inhibitory action was diminished by the addio tion of Ca++.

(III) The effect of Ca++ on the increase in coronary flow was investigated using the dog anesthetized with pentobarbital sodium according to the same procedure as in Experiment 2-(I). The increase in coronary flow induced by the administration of the compound of this invention was inhibited by a larger dose of Ca++.

(IV) Taenia coli of a guinea pig was suspended in the organ bath filled with Tyrode's solution and the effect of the compound of Example 1 on the spontaneous contraction and the contraction induced by K+ depolarization was investigated.

The test results showed that the spontaneous contraction and the K+ depolarization induced contraction were inhibited by application of the compound in a concentration level of 2 Sag/ml and such inhibitory action was diminished by the addition of Ca++.

Analysis of the test results indicates that the compound of the present invention has an antagonistic action to Ca++, so that the inhibitory action to cardiac contraction, the dilating action to smooth muscle of dog coronary artery and the inhibitory action to contraction of taenia coli of guinea pig induced by the application of the compound were antagonized by the addition of Ca++.

Further, it was also found that the compound of this invention has an antiarrhythmic action because the compound inhibited the excessive excitement of papillary muscle induced by the administration of isoproterenol.

Experiment 6.

The blood flow was made insufficient by loading experimentally the coronary artery of a dog, for example, by stricturing the coronary artery for a certain period of time, and the artery was allowed to sustain in this condition.

According to this treatment, its peripheral blood pressure and peripheral blood flow repeated periodical and spontaneous fluctuations within minutes order period accompanied with ST elevation in electrocardiogram.

This phenomenon was closely similar to the fit of variant angina pectoris in a clinical case.

The periodical fluctuation has been proved to be caused by the periodical spasms in the strictured coronary artery. The effect of the compound on such a variant angina pectoris model was investigated.

The test results show that the periodical fluctuations in the coronary blood pressure and coronary flow was inhibited by the intravenous administration of the compound of Example 1 in a dose level of 250 Isag/kg or more. That is, the periodical fluctuation in blood flow apparently reduced, and only fine fluctuations remained. The effective duration of the inhibitory action ranged from 25 to 40 minutes.

As stated above, the compound of this invention is believed to be effective on the treatment of variant angina pectoris.

Experiment 7.

According to the procedure explained below, the compound of Example 1 was subjected to investigate as to whether or not it has an anticoagulative action to platelets, namely antiembolic action.

1. Preparation of the test solution.

1-1 Adjustment of platelet-rich plasma (PRP solution). dissolved in the physiological saline solution to obtain the test solution.

2. Method of measurement.

The measurement was performed by the use of a meter identified by the registered Trade Mark "Aggregometer" (Evans Electroselenium Ltd., Model 169).

PRP solution (0.5 ml) and the test solution (0.025 ml) or a physiological saline solution as the control (0.025 ml) were charged into two cuvettes, respectively, and then subjected to incubation at 37"C for 2 minutes. Further, after 0.025 ml of ADP solution or 0.025 ms of the collagen suspension was added to each cuvette, the effect of the compound on platelet aggregation induced by ADP or collagen was measured.

As shown in Figs. 13 and 14, the initial rate of ADP-induced aggregation in the test compound was the same as that in the control, but the test compound accelerated the dissociation of the aggregated platelets. On the other hand, the test compound delayed the onset of the collagen-induced aggregation and made a maximum extent of the aggregation lower than the control. From these results, the inhibitory effect of the compound on the platelet aggregation was confirmed, so that the compound of this invention was also found to be useful as an anticoagulant.

Experiment 8.

By the same method as disclosed in Experiment 2, item 5, change in systemic blood pressure when test compounds were intravenously administered was measured. The results obtained are shown in the following Table.

TABLE

Dose Percent Charge Duration Test Compound (llg/kg) of S.B.P. (s) (min.) Compound of Example 1 50 16 22 Nitroglycerin 50 45 8 Example 1.

To a mixture of 5 g of sodium hydrogen carbonate, 15 ml of water, 1.69 g of the nitric ester of monoethanolamine nitrate and 20 ml of chloroform was added slowly 2.5 g of nicotinyl chloride hydrochloride over 10 to 30 minutes under stirring at 0 to 5"C. The stirring was continued for an additional 30 minutes and then the chloroform layer was separated. The remained aqueous layer was extracted with chloroform and the extract was combined with the separated chloroform layer.

The organic layer was washed with a potassium carbonate aqueous solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. The residue was dissolved in ether-isopropanol '(1:1) and then hydrogen chloride was bubbled into the solution under cooling to give 2.35 g of the nitric ester of N - (2 - hydroxyethyl) nicotinamide hydrochloride. Recrystallization from ethanol afforded colorless needle crystals having a melting point of 1320C.

Analysis: Calcd. for CSHloNsO4CI: C, 38.80; H, 4.07; N, 16.96 (%) Found: C, 38.89; H, 4.02; N, 16.72 (%) IR(cm-1): NH, 3255; C=O, 1669; ONO2, 1640.

Example 2.

To a solution of 1.69 g of the nitric ester of monoethanolamine in 20 ml of pyridine was added slowly 2.5 g of nicotinyl chloride hylrochloride over 10 to 30 minutes under stirring at 5"C. After stirring for an additional 30 minutes, the reaction mixture was evapor ated to dryness. The residue was dissolved in chloroform and the solution was washed with a sodium hydrogen carbonate aqueous solution. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. The residue was chromatographed on silica gel (Wakogel C 200; Wako Pure Chemical Industries, Ltd., Japan) and eluted with benzene-ethanol (5:1). The eluent was evaporated to a semi-solid mass which was crystallized from diethyl ether to give 1.97 g of the nitric ester of N - (2 - hydroxyethyl) nicotinamide.

Recrystallization of the crystals from diethyl ether-ethanol afforded colorless needles having a melting point of 92 to 93"C.

Example 3.

A solution of 10 g of the nitric ester of N - (2 - hydroxyethyl) nicotinamide hydrochloride in water was neutralized with a sodium hydrogen carbonate aqueous solution.

The solution was extracted with chloroform and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to dryness. The residue was crystallized from diethyl ether to give 7 g of the nitric ester of N - (2 - hydroxyethyl) nicotinamide. Recrystallization from isopropanoldiethyl ether gave colorless needles having a melting point of 930C.

IR (cml): NH, 3250; ONO2, 1630 Example 4.

N - (2 - hydroxyethyl) nicotinamide nitrate (1.145 g) was gradually added to 3 ml of fuming nitric acid which had been cooled to a temperature of from - 10 to -50C while stirring. After stirring for additional one hour at 0--5"C, diethyl ether was added to the solution to precipitate 1.15 g of nitric ester of N - (2 - hydroxyethyl) nicotinamide nitrate as colorless crystals. The crystals were dissolved in a sodium carbonate aqueous solution and ethyl acetate was added to the solution.

The ethyl acetate layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from diethyl ether to give nitric ester of N (2 - hydroxyethyl) nicotiamide. Recrystallization from diethyl ether afforded colorless crystals having a melting point of 90--92"C.

Analysis: Calcd. for CSH9N304: C, 45.50; H, 4.29; N, 19.89 (%) Found: C, 45.37; H, 4.09; H, 19.71 (%) Example 5 (Pharmaceutical Preparation).

a) Sublingual Tablet Compound prepared according 5 mg to Example 2 Lactose 19.7 mg Mannitol 25 mg Magnesium Stearate 0.3 mg Total 50 mg/tablet The ingredients were uniformly blended in the proportions described above and the mix5 mm in diameter and 50 mg in weight ture was formed into tablets, each tablet being b) Tablet for Internal Use Compound prepared according 10 mg to Example 1 Lactose 44.5 mg Corn Starch 20 mg Crystalline Cellulose 25 mg Magnesium Stearate 0.5 mg Total 100 mgZtablet The ingredients were uniformly blended in the proportions described above and the mixture was formed into tablets, each tablet being 7 mm in diameter and 100 mg in weight c) Hard Capsules Compound prepared according 20 mg to Example 2 Lactose 176 mg Magnesium Stearate 4 mg Total 200 mg/capsule The ingredients were uniformly blended in the proportions described above and hard capsules each being identified as No. 3 were filled with 200 mg each of the mixture by a packing machine to form capsules each weighing 250 mg.

d) Granules Compound prepared occording 10 mg to Example 2 Lactose 710 mg Paste of Cornstarch 280 mg Total 1,000 mg/wrapper The ingredients were uniformly kneaded and then granulated to form granules, each granule having a diameter of about 1 mm.

e) Parenteral Injection Compound prepared according 5 mg to Example 2 Mannitol 50 mg Total 55 mg/vial The ingredients were dissolved in 1 ml of distilled water and the solution was sterilized and filtered. The solution was filled in a vial and freeze-dried and the vial was sealed to form a parenteral injection. The freeze-dried mixture was dissolved in 1 ml of distilled water when it is used as parenteral injection.

WHAT WE CLAIM IS: 1. Nitric ester of N - (2 - hydroxyethyl)nicotinamide having the following formula:

or a pharmaceutically acceptable salt thereof.

2. Nitric ester of N - (2 - hydroxyethyl) nicotinamide.

3. A process for producing a compound having the formula:

or a reactive derivative thereof at the carboxyl group, with a compound having the formula NH2---CHH2-ONO2 (III) or a reactive derivative thereof at the amino group; or (2) reacting a compound represented by the formula

with a nitrating agent: and, if necessary, converting the compound of formula I to a pharmaceutlcally acceptable salt thereof, or vice versa.

4. A process according to claim 3, wherein, in the reaction (1), the reactive derivative of the compound (II) is an acid halide, active amide or active ester.

5. A process according to claim 4, wherein the reaction (1) is carried out at a temperature in the range from - 10 to 500C for from 0.5 to 4 hours.

6. A process according to claim 5, wherein the temperature is in the range from 0 to 10 C.

7. A process according to claim 4, 5 or 6, wherein the reaction is carried out in water or in an organic solvent selected from benzene, toluene, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, chloroform, methylene chloride, acetonitrile, acetone, carbon tetra chloride and ethyl acetate.

8. A process according to any one of claims 4 to 7, wherein the reaction is carried out in the presence of an inorganic basic substance selected from potassium acetate, sodium acetate, potassium carbonate, sodium car bonate, sodium hydroxide, calcium acetate, and calcium carbonate; or an amine compound selected from pyridine, triethylamine, dimethylaniline and picoline.

9. A process according to claim 3, wherein, in the reaction (1), which is effected in the presence of a solvent, the reactive derivative of the compound (III) is compound (III) activated by reaction with phosphorus tri chloride, methyl chlorophosphite or ethyl chlorophosphite.

10. A process according to claim 9, wherein the reaction (1) is carried out at a temperature in the range from room temperature to the reflux temperature of the solvent used, for from 0.5 to 3 hours.

11. A process according to claim 9 or 10, wherein the solvent used in reaction (1) is a neutral solvent selected from benzene, toluene, xylene, dioxane and tetrahydrofuran.

12. A process according to claim 11, wherein the reaction (1) is carried out in the presence of an amine compound selected from pyridine, triethylamine, dimethylaniline or picoline.

13. A process according to claim 9 or 10, wherein the reaction (1) is carried out in an organic basic solvent selected from pyridine, triethvlamine, dimethylaniline and picoline.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. The ingredients were uniformly kneaded and then granulated to form granules, each granule having a diameter of about 1 mm. e) Parenteral Injection Compound prepared according 5 mg to Example 2 Mannitol 50 mg Total 55 mg/vial The ingredients were dissolved in 1 ml of distilled water and the solution was sterilized and filtered. The solution was filled in a vial and freeze-dried and the vial was sealed to form a parenteral injection. The freeze-dried mixture was dissolved in 1 ml of distilled water when it is used as parenteral injection. WHAT WE CLAIM IS:

1. Nitric ester of N - (2 - hydroxyethyl)nicotinamide having the following formula:

or a pharmaceutically acceptable salt thereof.

2. Nitric ester of N - (2 - hydroxyethyl) nicotinamide.

3. A process for producing a compound having the formula:

14. A process according to claim 3, wherein

the reaction (1) is carried out in the presence of a solvent and of an amide-formation accelerator selected from N,N' - dicyclohexylcarbodiimide, N - cyclohexyl - N' - mor pholinoethylcarbodiimide, N,N' - diethylcarbodiimide, diphenylketene - N - cyclohexyl- imine pentamethyleneketene - N - cyclohexylimine, triethyl phosphite, ethyl polyphosphite and isopropyl polyphosphate.

15. A process according to claim 14, wherein the reaction is carried out at a temperature of from room temperature to the reflux temperature of the solvent used.

16. A process according to claim 14 or 15, wherein the reaction is carried out in an inert solvent selected from benzene, toluene, tetrahydrofuran, chloroform, dioxane, methylene chloride, dimethylformamide and acetonitrile.

17. A process according to claim 3, wherein the reaction (2) is carried out using fuming nitric acid or nitryl chloride as nitrating agent.

18. A process according to claim 3 or 17, wherein the reaction (2) is carried out in an inert solvent selected from chloroform and dichioromethane.

19. A process according to claim 3, 17 or 18, wherein the reaction (2) is carried out at a temperature in the range from - S C to room temperature for from 1 to 3 hours.

20. A process for producing a compound according to claim 1, substantially as hereinbefore described.

21. A compound according to claim 1, whenever produced by a process according to any one of claims 3 to 20.

22. A pharmaceutical composition for treating a circulatory disease, which comprises a compound according to claim 1, 2 or 21, and a pharmaceutically acceptable carrier therefor.

23. A pharmaceutical composition according to claim 22, which composition is in an orally administrative form selected from tablet, granule, powder, capsule or suspension.

24. A pharmaceutical composition according to claim 22 or 23, wherein the carrier is selected from lactose, starch, kaolin, crystalline cellulose, talc, calcium carbonate and magnesium stearate.

25. A pharmaceutical composition according to claim 22, which composition is in a form suitable for parenteral injection.

26. A pharmaceutical composition according to claim 20, substantially as hereinbefore described.