WO2003033471A1

WO2003033471A1 - Novel pyridone derivative and remedial agent for circulatory disease containing the same

Info

Publication number: WO2003033471A1
Application number: PCT/JP2001/009121
Authority: WO
Inventors: Yasumi Uchida; Masashi Ogawa; Norihiro Iibuchi; Tadashi Morita
Original assignee: Tobishi Pharmaceutical Co.,Ltd; Cardiovascular Institute,Ltd
Priority date: 2001-10-17
Filing date: 2001-10-17
Publication date: 2003-04-24

Abstract

A compound represented by the following general formula (I) or a salt thereof. It functions to open calcium-sensitive potassium channels and is useful in the treatment of ischemic heart diseases, hypertension, etc. (I) (In the formula, R1 is hydrogen, lower alkyl, lower aminoalkyl substituted by one or two lower alkyls, or benzyl which has not been substituted or has been substituted by any one to three substituents selected among lower alkoxys, halogenos, cyano, trifluoromethyl, methylenedioxy, and cyclopropylmethyloxy; R2 is hydrogen or a lower nitrooxyalkyl group; and R3 is hydrogen or a lower nitrooxyalkyl group.)

Description

Description New pyridone derivatives and therapeutic agents for cardiovascular diseases Field of the invention

The present invention relates to a novel pyridone derivative having a selective calcium-sensitizing lithium channel opening action. Background art

Vasodilators are mainly used as drug treatments for ischemic heart disease such as hypertension, angina pectoris, myocardial infarction, cerebrovascular disease, and obstructive peripheral arteriosclerosis. Many of them exert their effects by acting on receptors and channels in the cell membrane of vascular smooth muscle to relax vascular smooth muscle. Typical clinically used ones are those that block calcium channel nernole, those that block the nervous system, those that block the sympathetic alpha receptor, those that block the sympathetic beta receptor, and those that block the angiotensin receptor. And blockers of its converting enzymes, nitrates that act on cyclic GMP, and ATP-sensitive rhodium channel openers. Calcium-sensitive calcium channels are also present in vascular smooth muscle cell membranes and play an important role in the relaxation of blood vessels. However, there is no known compound that selectively opens this channel. Disclosure of the invention

The present invention relaxes the blood vessels by selectively opening the calcium-sensitive realm channel, and prevents vasospasm associated with a part of angina pectoris and cerebral ischemia. New pyridone derivative It is intended to provide.

The present inventors have made various studies to solve the above-mentioned problems, and as a result, the novel pyridone derivative having a nitrate group selectively opens the calcium-sensitive rheumatic channel, thereby improving the blood vessel. The present inventors have found that they exhibit a diastolic effect, a hypotensive effect, an effect of increasing coronary blood flow, and an effect of preventing vasospasm arrest, and thus completed the present invention.

Accordingly, the present invention provides the following general formula (I):

R 1

(I)

(1 ^ is a hydrogen atom, a lower alkyl group, an amino lower alkyl group substituted by one or two lower alkyl groups, or a benzyl group, and the benzyl group is unsubstituted or optionally substituted. Substituted by one to three selected lower alkoxy, halogen, cyano, trifluoromethyl, methylenedioxy or cyclopropylmethyloxy;

R ₂ is a hydrogen atom or a diethoxy lower alkyl group; and

R ₃ is a hydrogen atom or a ditoxoxy lower alkyl group) or a salt thereof.

The present invention also provides a pharmaceutical composition comprising a compound as described above. This pharmaceutical composition is useful as a therapeutic agent for cardiovascular disease, and examples of the cardiovascular disease include ischemic heart disease, hypertension, peripheral circulatory insufficiency, vasospasm, and ischemic brain disease. . The pharmaceutical composition is also useful as a potassium-sensitive potassium channel opener. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the effect of Compound 1 on blood pressure and coronary blood flow in anesthetized beagle dogs. In the figure, ECG indicates electrocardiogram, HR indicates heart rate, SBP indicates body pressure, and CBF indicates coronary artery blood flow.

FIG. 2 shows the effect of Compound 1 (1) on the model of coronary spasm. In the figure, the upper part indicates the periodicity spasm suppression in the case of 10- ⁵ M administering the compound 1, and the lower, pro spasm suppression when Compound 1 was administered 10- ⁵ M is at I Berio toxin (IBTX) Indicates that it is locked.

FIG. 3 shows the effect (2) of compound 1 on the model of coronary spasm. In the figure, the upper row shows that Compound 1's anti-convulsant activity is not affected by dalipene clamide (GC), and the lower row shows that Compound 1's anti-convulsive action is not blocked by methylene blue (MB) . Embodiment of the Invention

In the present invention, the lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as a methyl group, an ethyl group, and a -Propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, linear or branched heptyl group, linear or branched hexyl group, and the like.

In the present invention, the halogen is fluorine, chlorine, bromine, or the like, and is preferably chlorine.

"Nitorookishi lower alkyl group in the definition of substituents R ₂ and R ₃ - (CH ₂₎ represented Ri by the n-0n0 _2, n is 1-4, preferably a 2, - (CH ₂ ) represented Ri by the _₂ -0N0 _2. one substituent R ₂ and R ₃ least for the even is a representative compound that is preferred. the present invention is a two-preparative Rookishi lower alkyl group, for example, the following Compounds. 1- (3,4-Dimethoxybenzyl) -3- {2- (nitroxoxy) ethylcarpamoinole] -5-nitro-2-pyridone;

1- (3,4-Dimethoxybenzyl) -3- [bis (2- (nitrooxy) ethyl) carbamoyl] -5-nitro-2-pyridone;

2-Hydroxy— 3 -— [2- (Nitrooxy) ethylcarbamoyl] -5-2-Tropyridine;

1- (2-Methoxybenzyl) -3-[2- (Nitrooxy) ethylcarbamoyl]-5-Nitro-2-Pyridone

1- (3,4,5-Trimethoxybenzyl) -3- [2- (Nitrooxy) ethyl-norecanoleno-moinole] -1-5-2-toro-2-pyridone

1- (3-Trifluoromethylbenzyl) -3- [2- (nitrooxy) ethynolecarno moinole] -5-Nitro-2-pyridone

1- (3-cyanobenzyl) -3- [2- (nitroxy) ethylcarpamoinole] -5-2-to-2 mouth 2-pyridone

1- (3,4-methylenedioxybenzyl) -3--[2- (nitroxy) ethylcarbamoinole]-5--2-toguchi-2-pyridone

1- (3-Methoxy-4-cyclopropylmethoxybenzyl) -3- [2- (2-ethoxy) ethylcarbamoyl] -5-nitro-2-pyridone

1_benzinole-3- [2- (Nitrooxy) ethylcarbamoyl]-5-2to mouth-2-pyridone

1_ (3,4-Dimethoxybenzyl) -3--[3- (Nitrooxy) propyl Cananoleno Moinole] — 5-Nitro-2-pyridone

1_ (2-Methoxybenzyl) -3- [bis (2- (nitroxy) ethyl) canoleno moinole] — 5_nitro—2-pyridone

1- (3-Black mouth-4-methoxybenzyl) -3--[2- (Nitrooxy) ethyl-lupamoinole] -5-Nitoopen-2-pyridone

1-Methinole-3- [2- (Nitrooxy) ethylcarbamoyl] -5-Nito Mouth-2-pyridone

1- (2-Dimethylaminoethyl) -3- [2- (nitroxy) ethylca noreno moi] —5-Nitro—2-pyridone

The compounds of the present invention further include salts of the above compounds, especially pharmaceutically acceptable salts. Examples of the salt include acid addition salts, for example, acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as acetic acid.

The compound represented by the general formula (I) of the present invention can be produced by utilizing any known reaction. For example, the compound represented by the general formula (II) as a starting material may be used. It is manufactured from the roucotic acid derivative through the following three steps.

1st step

(Π) (IV)

(IV) (I) In the above formula, the definitions of 1 ^, R ₂ and R ₃ are defined in the above formula (I). It is justified.

1st step

A nicotinic acid derivative (II), an alcohol represented by the general formula RiOH, and triphenylphosphine (Ph ₃ P) are dissolved in a solvent such as dimethylformamide, tetrahydrofuran, and dioxane. A solution of diisopropylpropylazocarboxylate (DIAD) is added dropwise to this solution over about 5 minutes to 1 hour under ice-cooling stirring, and the mixture is further stirred at about 5 to 50 ° C for about 0.5 to 36 hours. The reaction product is extracted and purified by silica gel chromatography or the like to obtain an N-substituted pyridone derivative (III).

Second step

Dissolve the N-substituted pyridone derivative (III) in a solvent such as tetrahydrofuran, methanol, ethanol, etc., add an aqueous solution of alkali metal hydroxide such as LiOH, NaOH, K0H, etc. at about 5 to 50 ° C. Hydrolysis for 0.5 to 24 hours gives the corresponding carboxypyridone derivative (IV).

3rd step

Carboxypyridone derivative (IV), 1-hydroxybenzotriazole (H0BT), and triethylamine in dichloromethane, chlorophonolem, ethylethyl acetate, tetrahydrofuran, and dimethinolehonolem was dissolved in a solvent such as Ami de, mono- or di-substitution Arukanoruami down nitrate ester nitrate and 3- (3-Jimechirua Mi Nopuro pill) represented by the general formula _{_{_{R 2 R 3 NH · HN0 3}}} - Bok Echirukarupojii Mi To the mouth of the hydrochloride or disc, add xylcarposimide and stir at about 5-50 ° C for about 0.5-36 hours. The reaction product is extracted and purified by silica gel chromatography to obtain the pyridone derivative (I).

The present invention also provides a pharmaceutical composition comprising the above-mentioned compound of the present invention or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. The compounds of the present invention are shown in the experimental examples described below. As described above, it selectively opens the calcium-sensitive potassium channel, so that it can be generally used as a calcium-sensitive potassium channel opener, specifically, vasodilatory, hypotensive, coronary blood flow It exerts an increasing action, a vasospasm stopping action, etc., and is therefore an active ingredient of a preventive or therapeutic agent for cardiovascular diseases, for example, ischemic heart disease, hypertension, peripheral circulatory failure, vasospasm, ischemic brain disease It can be used as

The pharmaceutical composition of the present invention is administered orally or parenterally. Examples of parenteral administration include intravenous administration, intramuscular administration, subcutaneous administration, and intraperitoneal administration. The dosage varies depending on the condition of the patient, the type of disease to be treated or prevented, the mode of administration, and the like, but it should be 0.01 mg to 100 mg / kg.

In the pharmaceutical composition of the present invention, carriers used together with the active ingredient include generally known extenders, excipients, stabilizers, and the like, and extenders. Physiological saline, sucrose, buffer, lactose, crystalline cellulose, corn starch, etc. are used, and as stabilizers, for example, sodium bisulfite, para-hydroxybenzoic acid ethyl ester / tocopherol, etc. Is mentioned. Example

Next, the present invention will be described more specifically with reference to examples and experimental examples. Next, examples of the compound of the present invention will be shown, but the present invention is not limited thereto.

Example 1. 1- (3,4-Dimethoxybenzyl) -3-[2- (dimethoxy) ethylcarbamoyl 1-5-nitro-2-pyridone (Compound 1)

(1) 1- (3,4-Dimethoxybenzyl) -3-ethoxycarbonyl-5-dito-2-pyridone

1.00 g of 3-ethoxycarbonyl-2-hydroxy-5-nitropyridine, 1.19 g of 3,4-dimethybenzylbenzyl alcohol, 1.19 g of triphenylinolephosphine, 1.85 g of N, N -Dissolve in 16 mL of dimethylformamide, and dissolve 1.43 g of diisopropylpropylazodicarboxylate in 4 mL of N, N-dimethylformamide under ice-cooling for 15 minutes. And the mixture was stirred at room temperature for 20 hours. Water and ethyl acetate were added, and the mixture was extracted with ethyl acetate (50 mL × 3). The extract was washed with water (50 mL × 5), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 15 mL of ethyl acetate was added to the concentrate, and the insolubles were filtered off.The filtrate was concentrated and applied to silica gel chromatography to obtain 1.089 g of the desired product as a yellow powder (yield 64%). Obtained.

(2) 1- (3,4-Dimethoxybenzyl) -3-carboxy-5-dito-2-pyridone

1.089 g of 1- (3,4-dimethoxybenzyl) -3-ethoxycarbonyl-5-nitro-2-pyridone obtained in (1) above was dissolved in 10 mL of tetrahydrofuran and 5 mU of methanol. A solution of 632 mg of lithium hydroxide monohydrate in 5 mL of water was added to this solution at once, and the mixture was stirred at room temperature for 5 hours. After evaporating the organic solvent, water and dichloromethane were added to carry out liquid separation. The aqueous layer was lightly concentrated, the remaining dichloromethane was distilled off, and lmol / L hydrochloric acid aqueous solution was added to the residue to precipitate crystals. The crystals were collected by filtration, washed with water, and dried at 60 ° C for 2.5 hours.The target compound was obtained as pale yellow powdery crystals (801 mg, yield Rate 79%).

(3) l- (3,4-Dimethoxybenzyl) -3- [2- (2-ethoxy) ethylcarbamoyl] -5-nitro-2_pyridone

200 mg of 1- (3,4-dimethoxybenzyl) -3-carboxy-5-nitro-2-pyridone obtained in (2) above, 137 mg of 1-hydroxybenzotriazole-hydrate and 151 mg of triethylamine Was dissolved in 4 mL of dichloromethane, and 152 mg of monoethanolamine nitrate nitrate and 172 mg of 3- (3-dimethylaminopropyl) -1-ethylcarposimide hydrochloride were sequentially added thereto, followed by stirring at room temperature for 20 hours. To this mixture was added a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate, and the mixture was extracted with ethyl acetate (20 mL × 3). The extract was then washed with a saturated aqueous solution of sodium hydrogen carbonate, a 10% aqueous solution of citric acid, and a saturated aqueous solution of sodium chloride. The organic layer was washed sequentially with an aqueous solution of lime, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography to obtain the desired product as pale yellow amorphous. Hexane was added to this to form a powder, and 201 mg (80% yield) was obtained as a pale yellow powder.

mp 117-120 ° C (decomposition)

_{NMR (DMS0 - d 6) δ} ppm:

3.6 to 3.8 (2H, m), 3.73 (3H, s), 3.74 (3H, s), 4.65 (2H, brt), 5.27 (2H, s), 6.94 (2H, s), 7.10 (lH , s), 8.85 (lH, d, J = 3.3 Hz), 9.0 (1H, brt), 9.57 (lH, d, J = 3.3 Hz).

Example 2. l- (3,4-Dimethoxybenzyl) -3- [bis (2- (2-hydroxyl) ethyl) carpamoyl] -5-nitro-2-pyridone (Compound 2)

150 mg of 1- (3,4-dimethoxybenzyl) -3-carboxy-5-nitro-2-pyridone obtained in Example 1 (2), 103 mg of 1-hydroxybenzotriazole-hydrate, and 113 mg of triethylamine are dissolved in 3 mL of dichloromethane, and 174 mg of N, N-bisethanolamine nitrate nitrate and 129 m of 3- (3-dimethylaminopropyl)-1-ethylcarposimid hydrochloride are added. _g were sequentially added, and the mixture was stirred at room temperature for 18 hours. To this is added a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the mixture is extracted with ethyl acetate (20 mL × 3) .The extract is then washed with a saturated aqueous solution of sodium hydrogencarbonate, a 10% aqueous solution of citric acid, and a saturated aqueous solution of chloride. It was sequentially washed with an aqueous sodium solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography to obtain 160 mg (yield: 70%) of the desired product as a pale yellow amorphous.

Awakening: (CDC1 ₃₎ δ ppm:

3.62 (2H, brt), 3.7 to 4.0 (2H, m), 3.89 (3H, s), 3.90 (3H, s), 4.61 (2H, brt), 4.78 (2H, brt), 5.13 (2H, s ), 6.8 to 7.0 (3H, m), 8.29 (lH, d, J = 3.0 Hz), 8.61 (lH, d, J = 3.0 Hz).

Example 3. 2-Hydroxy-3- [2- (2-nitroxy) ethylcarbamoyl] -5-nitropyridine (Compound 3)

3-hydroxy-2-hydroxy-2-pentapyridine 200 mg, 1-hydroxy 200 mg of xybenzotriazole monohydrate, 220 mg of monoethanolamine nitrate nitrate, and 250 mg of 3- (3-dimethylaminopropyl) -11-ethylcarposimid hydrochloride were suspended in 2 mL of dichloromethane. A solution obtained by adding 2 mL of dichloromethane to 220 mg of lyethylamine was added, and the mixture was stirred at room temperature for 5 hours. Water and ethyl acetate were added to this mixture, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography. The product was obtained as pale yellow powder (72 _mg, yield 24%).

_{NMR (DMS0 - d 6) δ} ppm:

3.71 (2H, brq), 4.66 (2H, brt), 8.83 (lH, d, J = 3.3Hz), 8.91 (lH, d, J = 3.3Hz), 9.44 (lH, brt) ₀

Examples 4-1 to 5 (Compounds 4 to 15)

In the same manner as in Examples 1 and 2, compounds 4 to 15 shown in the following Tables 1 to 3 were obtained.

table 1

Table 2

Experimental Example 1. Effects on circulatory dynamics of anesthetized beagle dogs Male and female beagle dogs weighing 8 to 15 kg were used. After tracheal intubation under anesthesia by intravenous administration (35 mg / _kg ) of bentanorebital sodium (pent obarbital sodium), artificial ventilation by air (20 / min, 20-25 ml) / kg). Systemic blood pressure was measured using a pressure transducer by inserting a polyethylene tube through the left femoral artery. The heart rate was measured with an instantaneous heart rate monitor, using the blood pressure pulse wave as trigger. The coronary artery blood flow was measured at the 4th intercostal space, the left circumflex coronary artery was detached from the surrounding tissue, a non-invasive electromagnetic blood flow meter probe was attached to the origin, and measured with an electromagnetic blood flow meter. The aortic blood flow meter was fitted with a non-invasive electromagnetic blood flow meter probe at the start of the aortic arch, and measured with an electromagnetic blood flow meter, which was defined as the cardiac output. The left ventricular pressure was measured by a retrograde catheter inserted from the left carotid artery and a pressure-inhibited amplifier. Furthermore, the left ventricular pressure was differentiated, and the rise rate (max dP / dt) of the left ventricular systolic pressure was obtained. The electrocardiogram recorded the standard limb lead III. Each parameter was recorded simultaneously on a recorder. The test drug was rapidly intravenously administered from a polyethylene tube inserted into the left femoral vein. The dose of the drug was 100 ii g / kg. The solvent used was 100% dimethyl sulfoxide (DMS0) as a rule, and the water-soluble compounds were dissolved in physiological saline by reducing the amount of DMS0 appropriately if it was soluble in water. The maximum dose volume was 0.1 ml / _kg . % Was calculated by subtracting the effect of DMS0. The results were as shown in Table 4 below. Table 4

Mean blood pressure Heart rate Coronary artery blood flow (mmHg%) (beats / min i%)) Compound 4 11 +26 Compound 5 -11 — +16 Compound 6 -15 1 +13 Compound 7 -7 +6 +27 Compound 11 1 One +52 Compound 12--+20 Compound 14-One +72

(No change)

Experimental example 2.

The experiment was performed in the same manner as in Experimental Example 1 except that the dose of Compound 1 was changed, and the results are as shown in Table 5 below. The results are also shown in Fig. 1.

Dose (g Zkg) 10 30 100 300 Mean blood pressure (mm¾l%)-5.2 ± 1.0-13.3 ± 4.1-33.8 ± 9.6-52.0 ± 17.5 Coronary artery blood flow (l%) + 10.2 ± 2.1 + 52.4 ± 11.4 + 120.5 ± 31.4 171.5 ± 36.1 Experimental example 3. Selective calcium sensitivity using vasospasm model Lithium channel opening action

Coronary from anesthesia beagle dogs hearts were excised, create an annular piece of 3mm width, allowed Kakashita Krebs over Heng Ze Lai preparative liquid 37 ° C, 3, 4-diamine Roh pyridinium Jin 10- ² M The addition induced periodic spasm. This in vitro cyclic spasm closely resembles the pathology of coronary vasospastic angina in the clinic and has been used as a model for spasm in drug screening (UCHIDA Y: Japanese Circulation). J 49 128 (1984)). Then a solution of compound 1 was added.

As shown in FIG. 2, the periodicity spasm administration 10_ above ⁶ M of Compound 1 was completely inhibited.

This inhibitory effect was blocked by the calcium-sensitive potato lithium channel inhibitors ibeliotoxin and sialidodotoxin, and periodic spasm reappeared. As shown in FIG. 3, the inhibitory action of compound 1 was not affected by methylene blue, which has a cyclic GMP inhibitory effect, and dalibenclamide, which is an ATP-sensitive potassium channel inhibitor. It was not affected by beta blockers. The inhibitory effects of nitroglycerin and nicorandil having a nitrate group on the twitch model were not affected by iberiotoxin or sialybdotoxin.

The above results indicate that Compound 1, unlike nitric acid-containing drugs such as nitroglycerin / nicorandil, suppresses spasm by opening calcium-sensitive potassium channels. Industrial applicability

The compounds of the present invention can selectively open calcium-sensitive potassium channels to provide therapeutic agents for cardiovascular diseases, especially ischemic heart disease such as angina, ischemic brain disease, hypertension, peripheral circulatory insufficiency, and vascular disease. It is useful for treatment of spasm and the like.

Claims

5 ^ an range of request

1. The following general formula (I)

(: Is a hydrogen atom, a lower alkyl group, an amino lower alkyl group substituted by one or two lower alkyl groups, or a benzyl group, and the benzyl group is unsubstituted or optional. 1 to 3 lower alkoxy, halogen, cyano, trifluoromethyl, methylenedioxy or cyclopropylmethyloxy selected from:

R ₂ is a hydrogen atom or a diethoxy lower alkylene group; and

R ₃ is a hydrogen atom or a nitroxy lower alkylene group) or a salt thereof.

2.1- (3,4-Dimethoxybenzyl) -3- {2- (nitroxoxy) ethylcanolepamoiole ”—5-Nitro-2-pyridone;

1- (3,4-Dimethoxybenzyl) -3- [bis (2- (nitroxy) ethyl) canolebamoinole] -5- -Toro-2-pyridone;

2-Hydroxy-3- [2-(-Trooxy) ethylcarbamoyl] -5-2-Tropyridine;

1- (2-Methoxybenzyl) -3- [2- (2-ethoxy) ethylcarbamoyl] -5-nitro-2-pyridone

1- (3,4,5-trimethoxybenzyl) _3-[2- (Nitrooxy) ethinolecanoreno moinole] — 5 Nitro—2-pyridone 1- (3-Trifluoromethylmethylbenzyl) -3- [2- (Nitrooxy) ethylcarbamoyl] -5-Nitro-2-pyridone

1- (3-cyanobenzyl) -3- [2- (nitroxy) ethylcarbamoyl] — 5-2 toto-2-pyridone

1- (3,4-methylenedioxybenzyl) -3_ [2_ (nitroxy) ethylcarbamoyl] -5-nitro-2-pyridone

1_ (3-Methoxy-4 -cyclopropyl methoxybenzyl) -3--[2- (Nitrooxy) ethylcarbamoyl] -5-Nitro-2-pyridone

1_Benzyl-3- [2- (nitroxy) ethylcarbamoyl] -5-nitole-2-pyridone

1- (3,4-Dimethoxybenzyl) -3- [3- (Nitrooxy) propyl Canolepamoinole] — 5-Nitro-2-Pyridone

1- (2-Methoxybenzyl) -3- [bis (2- (nitroxy) ethyl) carpamoinole] —5-nitro-2-pyridone

1- (3- ク口口 -4-methoxybenzyl) -3- [2- (Nitrooxy) ethyl phenol

1-methyl-3- [2- (nitrooxy) ethylcarbamoyl] -5-nitole-2-pyridone

1- (2-dimethylaminoethyl) -3- [2- (nitrooxy) ethylca noreno moinole] — 5-nitro-2-pyridone

Or pharmaceutically acceptable salts of these compounds.

3. A pharmaceutical composition comprising the compound according to claim 1 or 2.

4. The compound according to claim 3, wherein the compound is 1- (3 ', 4-dimethoxybenzyl) -3- "2- (nitrooxy) ethylcarbamoyl" -5-nitro-2-pyridone. A pharmaceutical composition according to claim 1.

5. The pharmaceutical composition according to claim 3, which is a therapeutic agent for a cardiovascular disease.

6. The pharmaceutical composition according to claim 5, wherein the circulatory disease is an ischemic heart disease.

7. The pharmaceutical composition according to claim 5, wherein the circulatory disease is hypertension.

8. The pharmaceutical composition according to claim 5, wherein the circulatory disease is peripheral circulatory failure.

9. The pharmaceutical composition according to claim 5, wherein the circulatory disease is vasospasm.

10. The pharmaceutical composition according to claim 5, wherein the circulatory disease is an ischemic brain disease.

11. The pharmaceutical composition according to claim 3 or 4, which is a calcium sensitizing agent for opening a lithium channel.