JPH0383983A - Nitrate derivative and vasodilator containing the same - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I or salt thereof. USE:Vasodilator useful as treating agent of ischemic cardiac disease or cerebral blood flow improver. Has a low toxicity with a low side-effect. PREPARATION:At first, 2,3-pyridine dicarboxylic anhydride expressed by formula II is reacted with monoethanolamine in heating, preferably at 150-200 deg.C to obtain quinolinimide modification expressed by formula III (R is protecting group of H or OH). Next, 1-10 equiv. reducing agent (e.g. sodium boron hydride) is reacted with said compound in a solvent such as THF preferably at a temperature from -20 deg.C to 120 deg.C to obtain pyrrolopyridinone derivative expressed by formula IV. Furthermore, said derivative is reacted with nitrating agent (e.g. fuming nitric acid) at a temperature from -40 deg.C to 100 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel nitrate ester derivative having an effect of improving coronary circulation and cerebral circulation, and its uses. The compounds of the present invention have coronary blood vessel and cerebral vasodilatory effects, and are useful as therapeutic agents for ischemic heart diseases such as angina pectoris, and cerebral circulation improving agents.

(Prior art and problems to be solved by the present invention) As a therapeutic agent for angina pectoris caused by myocardial ischemia.

Conventionally, nitrites, β-blockers, calcium antagonists, etc. have been used, but β-blockers and calcium antagonists can have side effects such as suppression of cardiac function and impaired conduction. Drug resistance is a problem with nitrate ester agents such as glycerin and isosorbitol nitrate. On the other hand, calcium channel blockers, which are frequently used as cerebral circulation improving agents, generally have a strong antihypertensive effect, and should be used with particular caution in the elderly.

(Means for Solving the Problems) In view of the above circumstances, the present invention has been made as a result of intensive research to develop a stable and effective vasodilator with few side effects. The inventors discovered that the nitrite compound of the invention has the desired effect and completed the present invention.

The present invention relates to a novel nitrate derivative useful as a therapeutic agent for ischemic heart diseases such as angina pectoris and a cerebral circulation improving agent. It is an ester derivative or its addition salt with a pharmacologically acceptable acid.

The present invention also relates to the use of this novel nitrate ester derivative and its addition salt with a pharmacologically acceptable acid as a vasodilator as an active ingredient.

The compound of formula [1] according to the present invention exhibited a relaxing effect superior to that of the control nicorandil [N-(2-hydroxyethyl) nicotinic acid amide nitrate 1] in an in vitro test using isolated guinea pig aorta, and also showed a relaxing effect superior to that of the control nicorandil [N-(2-hydroxyethyl) nicotinic acid amide nitrate 1]. In an in vivo test, it showed an effect of increasing coronary blood flow and vertebral artery blood flow under administration with almost no effect on heart rate or blood pressure.

Details of the pharmacological activity of the compounds according to the present invention are shown in the test examples described later.

Clinical indications for the compounds of the present invention include ischemic heart diseases such as angina pectoris and myocardial infarction, and sequelae of cerebral infarction.

The compound according to the present invention is a nitrate ester derivative represented by the above formula [I] or an addition salt thereof with a pharmacologically acceptable acid.

Acid addition salts of the compounds of the present invention with appropriate pharmacologically acceptable acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and formic acid, acetic acid, propionic acid,
Organic acids such as succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, phenylacetic acid, benzoic acid, salicylic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, and amino acids such as aspartic acid and glutamic acid. Salt is an example.

The novel compound according to the present invention [N is the main feature that N has a nitrate ester at the 6-position of the pyrroloviridinone ring. Compound [I] of the present invention can be synthesized by any method suitable for introducing the skeleton 1t8 of the pyrrolobilidinone ring structure and substituents.

Suitable synthetic methods include the following production examples. The compound represented by formula [I] of the present invention or its acid addition salt can be produced by various methods, but can be produced mainly according to the synthetic route shown below. That is, [I] The idization reaction in the first step is carried out in a conventional manner by reacting the I-NO-M body with f,-quinoethanolamine under heating, and the quinoline imide (2XR is (representing a hydrogen or hydroxyl protecting group) can be obtained. The reaction is usually carried out in the presence or absence of a solvent, such as methanol, ethanol, acetonitrile, tetrahydrofuran, ethyl acetate,
in an organic solvent such as N,N-dimethylformamide, chloroform, methylene chloride, benzene, hexane, toluene, or a mixed solvent thereof, optionally in the presence of a base, preferably in a temperature range from room temperature to 250°C. Preferably, the temperature range is 150 to 200°C. The reaction is completed in 30 minutes to several hours. Examples of the base used if necessary include alkali metal carbonates such as potassium carbonate and sodium carbonate, and organic amines such as triethylamine and pyridine.

The reduction reaction in the second step was performed by H. von Dobeneck
(Chem, Ber, 105.3611-36
21.1972) and T.

Goto et al. (Bull, Chem, Soc, J.
pn,, 60.4178-4180゜11'107"
1If1-ni&I-mtl”pu4JII-/IS!I-
k(su)a)-with the monoacid group protected or unprotected,
This is achieved by reaction using a reducing agent. Examples of the protecting group for the hydroxyl group represented by R in compound 2 include acetyl, benzyl, benzyloxymethyl, p-methoxybenzyl, and t-butyldimethylsilyl groups.

After completion of the reduction reaction, if necessary, the protecting group is removed according to a conventional method to obtain a pyrrolobilidinone derivative in which the 7-position is selectively reduced (the definition of 3XH is as shown above). I can do it. Examples of the reducing agent used in this case include metals such as tin and zinc, and alkali metal hydrides such as sodium borohydride and lithium aluminum hydride. Usually, 1 to 10 equivalents of the reducing agent are used in the reaction. . As the reaction solvent, for example, acetic acid, hydrochloric acid, formic acid, water, methanol, ethanol, acetonitrile, tetrahydrofuran, chloroform, or a mixed solvent thereof is used. The reaction is carried out at a temperature ranging from -20 to 200'O, preferably from -20 to 1
It is carried out at a temperature range of 20'O and completed in 109 to 20 hours.

The nitrate esterification reaction in the third step is achieved by converting compound 3 into a reactive derivative as necessary and reacting it with a nitrate esterification agent. The nitric acid esterification agent used in this reaction includes fuming nitric acid, acetic anhydride-fuming nitric acid mixture, fuming nitric acid-concentrated sulfuric acid mixture, or tetra-n-
Examples include butylammonium nitrate (see JP-A-61-15847). Conversion of compound 3 into reactive derivatives, such as methanesulfonic acid chloride, p-
This is carried out by using toluenesulfonic acid chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, or the like. The reaction is usually carried out in the presence or absence of a solvent in the temperature range of -40 to 100°C, and suitable solvents include, for example, methanol, ethanol, acetonitrile, dioxane, chloroform, dichloromethane, acetic acid, etc. be. The reaction is 10
It can be completed in minutes to 6 hours.

The obtained nitrate ester derivative is converted into an acid addition salt with a pharmacologically acceptable acid such as hydrochloric acid, nitric acid, or citric acid in the presence of a solvent such as water, methanol, ethanol, acetone, or nityl, if necessary. It can be prepared.

After the completion of each reaction, the reaction products obtained in each step are purified by known separation means such as solvent extraction, recrystallization, and chromatography, and finally the compound [I] included in the present invention is purified.
can be collected.

- A vasodilator containing as a main component the compound represented by format [1] and its acid addition salt with a pharmacologically acceptable acid is mainly administered orally or parenterally (e.g., intramuscularly, intravenously, It can be administered (subcutaneously, rectally, transdermally, etc.), preferably orally, and is used as a drug in various dosage forms suitable for oral or parenteral administration. for example,
Tablets, capsules, granules, powders,
It can be prepared in any of the following formulations: oral preparations such as pills, fine granules, and troche tablets, injections, rectal preparations, oil-based suppositories, and water-soluble suppositories. These various formulations contain commonly used excipients, fillers, binders, wetting agents,
It can be produced by a conventional method using a disintegrant, a surfactant, a lubricant, a dispersant, a buffer, a preservative, a solubilizing agent, a preservative, a flavoring agent, a soothing agent, a stabilizer, and the like. In the case of intravenous infusion, the injection solution is prepared as is or by diluting it with physiological saline or glucose solution. Examples of the above-mentioned non-toxic additives that can be used include lactose,
Fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or its salts, gum arabic, polyethylene glycol, syrup, vaseline, glycerin, ethanol,
Examples include propylene glycol, citric acid, sodium chloride, sodium sulfite, and sodium phosphate.

The content of the compound of the present invention in a drug varies depending on its dosage form, but is usually 1 to 70% by weight, preferably 5 to 50% by weight of the total composition. A specific example of the formulation method is as shown in the experimental example below.

The dosage of vasodilators using the compounds of this invention is:

The dosage is determined as appropriate, taking into consideration the usage, patient's age, gender, severity of symptoms, etc., but it is usually about 0.1 to 100 m per day for adults.
g, preferably about 0.5 to 50 mg,
This can be administered once a day or in several divided doses.

Regarding the toxicity of the compound of the present invention, for example, even when the compound of Example 2 was orally administered to mice at 1000 mg/kg, no deaths were observed and the toxicity was low.

Below, the compound of the present invention will be explained in detail by giving test examples, formulation examples, and examples. These examples are merely illustrative and do not limit the present invention, and it goes without saying that various changes and modifications can be made without departing from the scope of the present invention. In addition, N in the following experimental example
MR data.

Using measurement data from 400MHz NMH,
The δ value (ppm) based on TMS is shown.

(Effects of the Invention) According to the present invention, an excellent vasodilator can be provided.

The effects of the present invention will be demonstrated in detail in the following pharmacological experimental examples.

Test Example 1 Guinea Pig Extracted Aorta Relaxation Effect (1) Experimental Method A guinea pig was exsanguinated to death, and a glass rod was inserted into the aorta from which the thoracic aorta had been removed to prepare a spiral strip. The spiral strip was suspended in an aerated Magnus tube filled with Krebs-Henseleit solution. Tension was recorded on a minipolygraph (Nihon Kohden RM6100) via an FD pickup.

The experiment consisted of pre-contraction with 6 x 10-'M norepinephrine, followed by cumulative administration of test compounds from low doses. The experimental results were obtained by calculating the 50% relaxation concentration from the dose-response curve and taking its logarithm to give pIC. Shown as a value.

(2) Results The results are shown in Table 1.

First effect (1) Experimental method Pegle dogs were treated with pendoparbital Na (35mg/k).
After anesthesia in step g), the heart was exposed under open thoracotomy, and an electromagnetic blood flow meter probe was attached to the descending coronary artery to measure blood flow. Furthermore, blood pressure was measured from the femoral artery, and heart rate was measured via a tachometer (Nihon Kohden RT-5).

Each cardiovascular parameter was measured using a polygraph (Nihon Kohden RM80).
0) recorded above. The data was set as 100 before administration of the test compound (compound of Example 2), and the change value was expressed in %.

(2) Results The results are shown in Table 2.

Formulation Example 1 Tablet Compound of Example 1 2.5g Lactose 12g 6% RPC lactose 8g Potato starch 2g Magnesium stearate 0.5g Total 25g The above amounts are thoroughly mixed and tableted to produce 1000 tablets.

Formulation Example 2 Capsule Compound of Example 1 2.5g Lactose 18g Potato starch 4g Magnesium stearate 0.5g Total 25g The above amounts are thoroughly mixed and filled into hard capsules to produce 1000 capsules.

Formulation example 3. Injection Compound of Example 2 0.5g Glucose 7g Distilled water for injection Appropriate total amount 1000 + n12 The compound of Example 2 and glucose were dissolved in distilled water for injection, and the total amount was 100
After filtering it with a glass filter, it is dispensed into ampoules of 1 rnQ to make 100 ampoule preparations.

Reference example 1 7-hydro-6-(2 hydroxyethyl 2.3-pyridinedicarboxylic anhydride log was suspended in 300 mff of toluene, and 2-amino-l-ethanol 4
．． Drop 1 g of triethylamine and 0-94 m of triethylamine (D
Heat under reflux for 3 hours with an Ean-Stark tube attached. After the reaction is completed, the solvent is distilled off under reduced pressure, ethyl ether 300IIIQ is added to the residue, and the precipitate is filtered and dried to obtain 8.2 g (64%) of the title compound.

NMR(DMSO-ds)δ:3.60(
2H, m), 3.69 (2H, t), 4.84 (L
H,t).

7.79 (IH, dd), 8.30 (IH, d),
8.97 (IH, d).

E I M S: m/z 192 (M”).

Reference example 26,7-cyhydro6-(2-hydroxyethyl)-5H-pyrrolo[3,4-b]pyridine-5-onerolo[3,4-b]pyridine-5,7-cyoneReference example 1
1.92 g of the compound is dissolved in 4 mQ of pyridine, 1.9 ml of acetic anhydride is added dropwise under water cooling, and the mixture is allowed to react at room temperature for 10 minutes. After the reaction is complete, ice water and ethyl acetate are added, extracted with ethyl acetate, the extracted layer is washed with water and saturated brine, and dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent under reduced pressure was washed with ethyl ether to obtain 1.86 g (72%) of the title compound.
).

NMR (DMSO-dI) δ: 1.94 (3H, s), 3.88 (2H, t), 4
．． 24 (2H, t).

7.80 (LH.

dd), 8.32 (IH.

d).

8.99 (IH.

d).

IMS: m/z 235(M+1)"-(
1.17 g of the compound obtained in a) is dissolved in 20 m4 of acetic acid, 1.64 g of zinc dust is added little by little, and the mixture is reacted at 120'O for 11 hours. After the reaction is completed, the zinc dust is filtered off and washed with a small amount of acetic acid, and then a saturated aqueous solution of hydrogen carbonate and chloroform are added to the reaction solution for extraction. The chloroform extract layer was washed with a mixture of saturated aqueous sodium bicarbonate solution and brine, dried over potassium chloride, and concentrated to dryness under reduced pressure to yield 1.07 g (97%) of the title compound.
get.

NMR (CD CI 3) δ: 2.08 (3H, s), 3.93 (2H, t), 4
．． 36 (2H, t).

4.57 (2H, s), 7.42 (IH, dd),
8.13 (LH, dd).

8.75 (IH, dd).

EIMS: 1.05 g of the compound obtained in (b) was dissolved in methanol lom
After dissolving in Q, IN Na OH5-25- was added dropwise under ice cooling, and the mixture was reacted at 10 to 15°C for 30 minutes. After the reaction is completed, the reaction solution is adjusted to pH 7.4 with INHcI, the solvent is distilled off under reduced pressure, and methylene chloride and ice are added to the residue for extraction.

The methylene chloride extract layer was washed with brine, dried over magnesium chloride anhydride, and concentrated to dryness to obtain 0.69 g (81%) of the title compound.

NMR(CDCl3)δ: 3.82(2H,t), 3.95(2H,t), 4
．． 60 (2H, s).

7.39 (LH, dd), 8.09 (IH, dd),
8.72 (IH, dd).

E I M S: m/z 178 (M”).

-on 3 g of the compound obtained in Reference Example 1 was dissolved in 100 mQ of acetic acid, log of zinc dust was added little by little, and after reacting at 100°C for 8 hours, the zinc dust was removed by filtration, and the reaction solution was concentrated to dryness under reduced pressure. do. 30 mff of pyridine and 1 ml of acetic anhydride were added to the resulting residue.
Add 5 m4 under water cooling and react overnight at room temperature. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residue is extracted with water and ethyl acetate. The ethyl acetate extract layer is washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The obtained residue was subjected to silica gel column chromatography (chloroform:methanol=50:1 to 20:1
) to give 500 mg of the title compound (1
2%) and Reference Example 2. 770 mg of compound (b) (2
2%).

NMR (CD CI 3) δ: 2.06 (3H, s), 2.22 (3H, s), 3
．． 53 (IH, m).

4-10 (IH, m), 4.22 (IH, m), 4
．． 46 (LH, m).

7.17 (IH.

s).

7.48 (IH.

dd).

8.12 (IH.

d).

8.80 (LH.

d).

DMS :　m/z 278 (M+).

180 mg of rate 6.7-sihydro6-(2-hydroxyethyl)-5H-pyrrolo[3,4-bl pyridin-5-one was dissolved in 0.4 raQ of pyridine, and 85 μα of methanesulfonic acid chloride was added dropwise under water cooling. The mixture was stirred for 1 hour under water cooling and further stirred for 30 minutes at room temperature to react. After the reaction is complete, add ice water.

Extract with chloroform. The extracted layer is washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure. The resulting residue was washed with ethyl ether and then crystallized from ethyl acetate-ethyl ether to obtain 150 mg (59%) of the title compound.

NMR (CD CI 3) δ: 3.04 (3H, s), 4.02 (2H, t), 4
．． 52 (2H, t).

4.62 (2H, s), 7.43 (IH, dd),
8-14 (IH, d).

8.77 (IH, dd).

EDMS: m/z 256(tJ”)-(a
) and 304 mg of tetra-n-butylammonium nitrate were mixed with 0.25 mg of dioxane.
Suspend in mQ and react at 90°C for 1 hour. After the reaction is complete, a dilute aqueous sodium bicarbonate solution is added to the reaction solution, extracted with ethyl acetate, and the extracted layer is washed with water and brine, and then dried over anhydrous magnesium sulfate. The residue obtained by concentration to dryness under reduced pressure is purified by silica gel column chromatography (chloroform:methanol-50:l) to obtain 35 mg (31%) of the title compound.

NMR(CDCls)δ: 4.02(2H,t), 4.59(2H,s), 4
-75 (2H, t).

7.43 (IH, dd), 8.14 (18, d),
8.80 (IH, da).

F　D　M　S　:　m/z　222(M”-1).

I R (K B r) cm-' (C□0) 1680
．． (ONOz) 1620.1270° Melting point: 82.
5-83°C rate hydrochloride 6.7-sihydro6-(2-hydroxyethyl)-5
H-pyrrolo[3,4-b]pyridin-5-one 356
mg was suspended in 3 ml of acenitrile, and under water cooling,
Methanesulfonic anhydride 418 mg and pyridine 26
Add 0 μa and stir for 1 hour. Then, 1.307 g of tetra-n-butyl ammonium nitrate (melting point: 113.5-116°C) was added at room temperature, and the
Allow time to react.

After the reaction is completed, ethyl acetate and water are added to the reaction solution, the pH is adjusted to about 6.0 with an aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate. The extracted layer is washed with brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The resulting residue is purified by silica gel chromatography (chloroform:methanol-100:l) to obtain 110 mg (25%) of the same compound as in Example 1. 87 mg of this was dissolved in a mixed solution of 1 mQ of ethyl ether and 2 mQ of acetone, and while cooling with water, 0.5 ml of a hydrochloric acid gas-saturated ethyl ether solution was added dropwise, followed by stirring for about 10 minutes. The precipitated white crystals were collected and mixed with ethyl ether-acetone (1:
70 mg (69%) of the title compound are obtained by washing with l) and ethyl ether and drying.

NMR (CDCl2) δ: 4.01 (2H, t), 4.58 (2H, s), 4
．． 75 (2H, t).

7.43 (IH, dd), 8.13 (II (, d),
8.76 (IH, dd).

Claims (2)

[Claims] (1) A nitrate ester derivative represented by the following formula or an addition salt thereof with a pharmacologically acceptable acid. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (2) A vasodilator containing the nitrate ester derivative according to claim 1 or its addition salt with a pharmacologically acceptable acid as an active ingredient.