JPH04261121A - Preventive or therapeutic agent for pulmonary hypertension - Google Patents

Abstract

PURPOSE:To provide the title agent having activity with little side effects, also sufficiently high in safety. CONSTITUTION:The objective agent containing, as active ingredient, 3-{2-[4-(4- fluorobenzoyl)piperidine-1-yl]ethyl}-6,7,8,9-tetrahydro-2H-pyrido[1,2- a]-1,3,5- triazine-2,4(3H)-dione (or its salt) of the formula. The present agent can be cylindrically, orally, subcutaneously, intramuscularly or intravenously administered; its dosage, in terms of said compound or its salt, being pref. 50-2000mg a day per adult, and 1-200mg a day per adult, for oral administration and intravenous administration, respectively. The compound or its salt gives inhibitory effects, in a pulmonary hypertension model, against rise in angiopneumonic resistance, right ventricular hypertrophy and muscle type pulmonary artery media hypertrophy.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to a preventive or therapeutic agent for pulmonary hypertension.

0002

BACKGROUND OF THE INVENTION Pulmonary hypertension includes diseases that primarily damage pulmonary blood vessels, such as primary pulmonary hypertension, and secondary pulmonary hypertension caused by various diseases such as respiratory diseases. Conventionally, the first treatment methods for pulmonary hypertension have been administration of bronchodilators and long-term oxygen therapy to improve hypoxic conditions. Other treatments include calcium channel blockers, direct vasodilators, prostaglandins, alpha
The symptoms have been alleviated as much as possible by administering drugs that have a vasodilatory effect, such as receptor blockers, nitrites, and angiotensin-converting enzyme inhibitors.

0003

[Problems to be Solved by the Invention] However, the effects of conventional treatment methods are not fully satisfactory, and there is a need for the development of new drugs that have fewer side effects and are more effective in preventing and treating pulmonary hypertension. It was getting worse.

0004

[Means for Solving the Problems] Under these circumstances, the present inventors have investigated the pharmacological effects of various compounds using pulmonary hypertension disease models, and found that the following formula (1
) 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,
9-tetrahydro-2H-pyrido[1,2-a]-1,
3,5-triazine-2,4(3H)-dione or a salt thereof has an excellent preventive or therapeutic effect on pulmonary hypertension,
They discovered that the invention was also sufficiently safe, and completed the present invention.

[0005] That is, the present invention is based on the following formula (1)

3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9 represented by
-tetrahydro-2H-pyrido[1,2-a]-1,3
, 5-triazine-2,4(3H)-dione or a salt thereof as an active ingredient.

Compound (1) and its salts, which are the active ingredients of the preventive or therapeutic agent for pulmonary hypertension of the present invention, can be produced, for example, according to the following reaction formula (A).

[0007]

[Chemical formula 3]

That is, a compound represented by formula (2) and a compound represented by formula (
The compound represented by 3) is heated from 0°C to the boiling point of the solvent in an organic solvent such as dimethylformamide, tetrahydrofuran, or dioxane in the presence of a mixture of various dehydrating reagents such as triphenylphosphine and azodicarboxylic acid dialkyl ester. By reacting at temperature, the compound (
1) can be manufactured.

Compound (2), which is the starting material here, can be obtained by a known method, for example, by reacting 2-amino-3,4,5,6-tetrahydropyridine with phenoxycarbonyl isocyanate by a conventional method. Manufactured by

Compound (1) can also be produced according to the following reaction formula (B).

[0011]

[C4]

[In the formula, X represents a halogen atom, a paratoluenesulfonyloxy group, or a methanesulfonyloxy group]

That is, the compound represented by formula (2) and the formula (
4) in an equimolar or more amount of an alkali carbonate, an alkali hydride such as sodium hydride, or an organic base such as triethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene. The compound of formula (1) can also be produced by reacting in an organic solvent such as ethanol, methanol, dimethylformamide, tetrahydrofuran, dioxane, benzene, etc. at a temperature from room temperature to the boiling point of the solvent in the presence of It is. It is also possible to add a catalytic amount of alkali iodide such as sodium iodide or potassium iodide during this reaction.

Furthermore, compound (1) has the following reaction formula (C
) can also be manufactured.

[0015]

[C5]

[In the formula, Y represents an arylsulfonyloxy group, an alkylsulfonyloxy group, or a halogen atom, and Ar represents an aryl group which may have one or more substituents.]

To obtain compound (1) according to the above reaction formula (C), first, the compound represented by formula (5) is dissolved in an organic solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, dioxane, dimethylformamide, etc. So, triethylamine, dimethylaniline, 1,8-diazabicyclo[5.4.0]
In the presence of a base such as -7-undecene, the aryloxycarbonyl chloride is reacted at a temperature from -30 degrees Celsius to the boiling point depending on the solvent used to obtain a compound represented by formula (6). Next, this compound (6) and 2-
By reacting iminopiperidine with an organic solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, dioxane, dimethylformamide, etc. at a temperature from room temperature to the boiling point of the solvent used, a compound represented by formula (7) can be obtained. Obtain the compound. The thus obtained compound (7) was mixed with pyridine, triethylamine, dimethylaniline, 1,8-diazabicyclo[5. 4
．． 0]-7-Undecene by sulfonylation with arylsulfonyl chloride or methanesulfonyl chloride at a temperature of -30 degrees Celsius to 50 degrees Celsius depending on the solvent used, formula (8)
A compound in which Y is an arylsulfonyloxy group or an alkylsulfonyloxy group can be obtained.

In addition, by reacting compound (7) with a halogenating reagent such as thionyl chloride, thionyl bromide, phosphorus oxychloride, or phosphorus tribromide in an organic solvent such as benzene, toluene, chloroform, or dichloromethane, the general formula (8
), a compound in which Y is a halogen atom can be obtained.

Furthermore, the general formula (8
) and 4-(4-fluorobenzoyl)piperidine in an organic solvent such as tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, chloroform, dichloromethane, dimethylformamide, etc., to triethylamine, dimethylamine, 1,8-diazabicyclo[
5.4.0] - Produce the target compound (1) by reacting in the presence of an organic base such as -7-undecene or an inorganic base such as anhydrous alkali carbonate at a temperature from room temperature to the boiling point of the solvent used. You can.

[0020] In addition, as the salt of the present compound (1), hydrochloric acid,
Acids with mineral acids such as sulfuric acid and nitric acid, or organic sulfonic acids such as methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid, or organic carboxylic acids such as oxalic acid, maleic acid, fumaric acid, succinic acid, malic acid, and tartaric acid. Examples include addition salts.

As shown in Example 1 below, the above compound (1) or a salt thereof has an excellent ability to significantly suppress the increase in pulmonary vascular resistance, right ventricular hypertrophy, and muscular pulmonary artery media hypertrophy in a pulmonary hypertension model. It is useful as a preventive or therapeutic agent for pulmonary hypertension. In addition, as shown in Examples 2 and 3 below, compound (1) or a salt thereof was administered to rats repeatedly once a day for 10 days to examine its toxicity. No deaths were observed during administration, and even after a single intravenous administration to rats, no deaths were observed after administration of 150 mg/kg, indicating that the drug is sufficiently safe.

The prophylactic or therapeutic agent for pulmonary hypertension of the present invention includes:
It is usually administered orally, subcutaneously, intramuscularly, or intravenously, and the dosage depends on the patient's weight, age, gender, administration method, etc.
Although it varies depending on the physical condition and symptoms, when administered orally, the dose of Compound (1) or its salt is usually 50 to 2,000 m/day.
g/adult, and when administered intravenously, usually 1 to 20 g/day
It may be 0 mg/adult.

[0023] The preventive or therapeutic agent for pulmonary hypertension of the present invention is
Compound (1) or a salt thereof can be blended and prepared into various dosage forms such as tablets, granules, capsules, powders, suspensions, and injections by conventional methods. To produce a preparation for oral administration, compound (1) or a salt thereof is added with an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent,
After adding fillers, coating agents, sugar coating agents, etc., tablets, granules, powders, capsules, etc. may be prepared by conventional methods. Also,
When preparing an injection, compound (1) or a salt thereof may be dissolved, dispersed, or emulsified in advance in an aqueous carrier such as distilled water for injection, or it may be made into a powder for injection and dissolved at the time of use. .

[0024]

Effects of the Invention Compound (1) or a salt thereof, which is an active ingredient of the preventive or therapeutic agent for pulmonary hypertension of the present invention, has been shown to improve pulmonary blood vessels in an experimental model of pulmonary hypertension, that is, in a monocrotaline-induced rat pulmonary hypertension model. It showed excellent effects in suppressing the increase in resistance, right ventricular hypertrophy, and muscular pulmonary artery medial hypertrophy. Therefore, compound (1) or a salt thereof is useful as a prophylactic or therapeutic agent for pulmonary hypertension.

[0025]

EXAMPLES The present invention will be explained below with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]- Synthesis of 1,3,5-triazine-2,4(3H)-dione (compound (1)) a) 0.83 g of sodium metal and 40 g of absolute ethanol
4.8 g of 2-amino-3,4,5,6-tetrahydropyridine hydrochloride was added to an ethanol solution of sodium ethoxide prepared from ml under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After removing insoluble materials by filtration, the filtrate was dried under reduced pressure. 30 ml of tetrahydrofuran was added to the residue to suspend it, and 5.9 g of phenoxycarbonyl isocyanate was added to 10
It was dripped in minutes. After leaving it at room temperature overnight, the precipitated crystals were collected by filtration, and 1.4 g was obtained. Furthermore, the filtrate was dried under reduced pressure, and the residue was applied to a silica gel column (100 g), and after elution with chloroform containing 5% methanol, 2.04 g of crystals were obtained. Combined with the previous crystal, 6,7,8,9-tetrahydro-
3.44 g (yield 57%) of colorless crystals of 2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione (compound (2)) were obtained. mp. 185-187°C 1H-NMR (DMSO-d6) δ: 1.6-1.
9 (4H, m), 2.65 (2H, t), 3.64
(2H, t), 11.39 (1H, b). IRν(KB
r) cm-1: 3450, 3200, 3070,1
700, 1590, 1490, 1440, 13
90. Calculated value (%) as elemental analysis value C7H9N3O2
:C, 50.30; H, 5.43; N, 25.14
．． Actual value (%): C, 50.37; H, 5.45;
N, 24.91.

b) 6 obtained in the above section a,
7,8,9-tetrahydro-2H-pyrido[1,2-a
]-1,3,5-triazine-2,4(3H)-dione 34.1 g, 4-(4-fluorobenzoyl)-1-(
51.2 g of 2-hydroxyethyl)piperidine and 56.1 g of triphenylphosphine were added to 9 g of tetrahydrofuran.
00 ml, and 38 g of azodicarboxylic acid diethyl ester was added dropwise over 15 minutes while cooling with ice. 20 at room temperature
After stirring for a minute, the solvent was distilled off under reduced pressure, 500 ml of ethyl acetate was added to the residue, and the mixture was extracted with 1N hydrochloric acid. This 1N-
Potassium carbonate was added to the hydrochloric acid extract to make it alkaline, and the mixture was extracted with chloroform. It was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethanol, and then recrystallized from a mixture of methanol and ethanol to obtain 33.7 g of colorless crystals of the title compound (yield: 41%).
I got it. mp. 170-172°C 1H-NMR (CDCl3) δ: 1.8-2.2(
10H, m), 2.26 (2H, t), 2.81 (
2H, t), 3.0-3.3 (3H, m), 3.8
4 (2H, t), 4.06 (2H, t), 7.13
(2H, t), 7.95 (2H, dd) IRν (KB
r) cm-1: 1730, 1670, 1600, 1
490, 1450, 1410. Elemental analysis value C2
Calculated value (%) as 1H25FN4O3: C, 62.
99; H, 6.29; N; 13.99. Actual value (%
): C, 62.68; H, 6.28; N; 13.8
3.

Reference Example 2 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]- Synthesis of 1,3,5-triazine-2,4(3H)-dione (compound (1)) hydrochloride 3-[2-[4-(4-fluorobenzoyl)piperidine-1 obtained in Reference Example 1 above] -yl]ethyl]-6,7,
8,9-tetrahydro-2H-pyrido[1,2-a]-
1,3,5-triazine-2,4(3H)-dione 33
．． Dissolve 0g in 150ml of hot ethanol and add 15ml of concentrated hydrochloric acid.
ml was added. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 27.4 g (yield: 76%) of the title compound as colorless crystals. mp. 256-259 °C (decomposition) 1H-NMR (D2O) δ: 1.4-2.4 (8H, m
), 2.86 (2H, t), 3.1-4.0 (9H
, m), 4.37 (2H, t), 7.30 (2H, t
), 8.07 (2H, dd). IRν (KBr) cm
-1:3450, 2940, 2510, 1730,
1670, 1600, 1480, 1420. Elemental analysis value Calculated value (%) as C21H25FN4O3・HCl: C, 57.73; H, 6.00;
N, 12.82. Actual value (%): C, 57.50; H
, 5.82; N, 12.59.

Reference Example 3 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]- Synthesis of 1,3,5-triazine-2,4(3H)-dione (compound (1)) maleate salt 3-[2-[4-(4-fluorobenzoyl)piperidine- obtained in Reference Example 1 above] 1-yl]ethyl]-6,7,
8,9-tetrahydro-2H-pyrido[1,2-a]-
1,3,5-triazine-2,4(3H)-dione2.
0 g of maleic acid was dissolved in 50 ml of methanol.
Added 58g. After the solution was concentrated under reduced pressure, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 1.27 g (yield: 49%) of the title compound as colorless crystals. mp. 150-152°C (decomposition) 1H-NMR (DMSO-d6) δ: 1.6-2.
1 (8H, m), 2.71 (2H, t), 2.9-
3.4 (4H, m), 3.5-3.8 (5H, m),
4.12 (2H, m), 6.06 (2H, s), 7.
39 (2H, t), 8.10 (2H, dd). IRν
(KBr)cm-1:3650-3300, 2950
, 1730, 1680, 1600, 1485. Elemental analysis value C21H25FN4O3・C4H4O4
Calculated value (%): C, 58.13; H, 5.6
6; N, 10.85. Actual value (%): C, 58.28
; H, 5.64; N, 10.87.

Reference Example 4 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]- Synthesis of 1,3,5-triazine-2,4(3H)-dione (compound (1)) a) Add 5.0 g of 2-oxazolidone (compound (5)) and 9.08 g of phenylchloroformate to 50 ml of dichloromethane. 6. Dissolve triethylamine under ice-cooling and stirring.
07g was added dropwise. After stirring for 20 minutes, add 50ml of water to the reaction solution.
1 was added and the organic layer was separated. The solvent was distilled off under reduced pressure, and hexane was added to the residue to crystallize it, which was then collected by filtration to give 3-phenoxycarbonyl-2-oxazolidone (compound (6-a)
9.89 g (yield: 83%) of colorless crystals of ) were obtained. mp. 157-160°C 1H-NMR (DMSO-d6) δ: 4.0-4.
2 (2H, m), 4.3-4.5 (2H, m), 7
．． 2-7.6 (5H, m). IRν (KBr) cm-1: 3520, 3200-2
800, 1730, 1670, 1600, 14
80, 1420. Calculated value (%) as elemental analysis value C10H9NO4
:C, 57.97; H, 4.38; N, 6.76.
Actual value (%): C, 57.78; H, 4.36; N
, 6.78.

b) Metallic sodium 0.46
2-amino-3 under ice-cooling to an ethanol solution of sodium ethoxide prepared from
, 2.69 g of 4,5,6-tetrahydropyridine hydrochloride
was added and stirred at room temperature for 40 minutes. After removing insoluble materials by filtration, the filtrate was dried under reduced pressure. The residue was dissolved in 30 ml of acetonitrile, 4.14 g of 3-phenoxycarbonyl-2-oxazolidone (compound (6-a)) obtained in section a above was added, and the mixture was stirred at 60°C for 1.5 hours. The reaction solution was dried under reduced pressure,
The residue was applied to a column of silica gel (120 g) and eluted with a mixture of methanol and chloroform to give 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-2H-
pyrido[1,2-a]-1,3,5-triazine-2,
Colorless crystals of 4(3H)-dione (compound (7)) 3.4
5 g (yield 82%) was obtained. mp. 125-128°C 1H-NMR (DMSO-d6) δ: 1.8-2.
1 (4H, m), 2.69 (1H, s), 2.82
(2H, t), 3.86 (4H, t-like), 4
．． 14 (2H, t). IRν(KBr)cm-1:32
82, 2960, 1730, 1684, 1602
, 1504, 1452, 1416. Calculated value as elemental analysis value C9H13N3O3 (%
): C, 51.18; H, 6.20; N, 19.8
9. Actual value (%): C, 50.83; H, 6.43;
N, 19.64.

c) 3 obtained in section b above
-(2-hydroxyethyl)-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione (compound (7) )1
．． 80 g of triethylamine and 1.20 g of triethylamine were dissolved in 25 ml of acetonitrile, and 1.17 g of methanesulfonyl chloride was added dropwise while stirring under ice cooling. After stirring for 30 minutes, the reaction solution was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 3-(2-methanesulfonyloxyethyl)-6,
7,8,9-tetrahydro-2H-pyrido[1,2-a
2.34 g of yellow caramel-like substance of -1,3,5-triazine-2,4(3H)-dione (compound (8-a))
(yield 95%). 1H-NMR (CDCl3) δ: 1.8-2.1(
4H, m), 2.8 (2H, t), 3.1 (3H,
s), 3.9 (2H, t), 4.3 (2H, t),
4.5 (2H, t).

d) 3-(2-methanesulfonyloxyethyl)-6,7, obtained in the above section c.
8,9-tetrahydro-2H-pyrido[1,2-a]-
3.3 g of 1,3,5-triazine-2,4(3H)-dione (compound (8-a)) was dissolved in 25 ml of acetonitrile, and 1.01 g of triethylamine and 2.0 g of 4-(4-fluorobenzoyl)piperidine were added. 27 g was added and heated under reflux for 4 hours. The reaction solution was dried under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue was purified with silica gel (80 g).
column and eluted with a mixture of methanol and chloroform to obtain 2.17 g of yellow crystals of the title compound (yield 64%).
I got it. mp. 170-172°C 1H-NMR (CDCl3) δ: 1.8-2.2(
10H, m), 2.26 (2H, t), 2.81 (
2H, t), 3.0-3.3 (3H, m), 3.8
4 (2H, t), 4.06 (2H, t), 7.13
(2H, t), 7.95 (2H, dd). IRν(K
Br) cm-1: 1730, 1670, 1600,
1490, 1450, 1410. Elemental analysis value C
Calculated value (%) as 21H25FN4O3: C, 62.
99; H, 6.29; N, 13.99. Actual value (%
): C, 62.76; H, 6.32; N, 14.0
5.

Reference Example 5 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]- Synthesis of 1,3,5-toaridine-2,4(3H)-dione (compound (1)) maleate salt 3-[2-[4-(4-fluorobenzoyl)piperidine- obtained in Reference Example 4 above] 1-yl]ethyl]-6,7,
8,9-tetrahydro-2H-pyrido[1,2-a]-
Dissolve 1.0 g of 1,3,5-triazine-2,4(3H)-dione (compound (1)) in 30 ml of methanol,
0.29 g of maleic acid was added. The solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 0.64 g (yield: 49%) of the title compound as colorless crystals. mp. 150-152°C (decomposition) 1H-NMR (DMSO-d6) δ: 1.6-2.
1 (8H, m), 2.71 (2H, t), 2.9-
3.4 (4H, m), 3.5-3.8 (5H, m),
4.12 (2H, m), 6.06 (2H, s), 7.
39 (2H, t), 8.10 (2H, dd). IRν
(KBr)cm-1:3650-3300, 2950
, 1730, 1680, 1600, 1485.

Example 1 Effect in monocrotaline-induced rat pulmonary hypertension model: Experimental method: 60 mg/kg of monocrotaline was subcutaneously administered to 5-week-old SD male rats, and 3 weeks later, hemodynamic measurements (aortic pressure, pulmonary artery pressure) were performed. ), cardiac separation weighing (right ventricle/left ventricle +
septum/weight ratio) and pathomorphological examination. Thirty rats were divided into the following three groups, and the test drug; the compound obtained in Reference Example 3 (10 mg/kg) or physiological saline was orally administered at 12-hour intervals every day starting 3 days before the start of monocrotaline administration. 1. Control group (physiological saline administration; 10 cases)2. Test drug administration group (monocrotaline + test drug administration; 10 cases) 3. Monocrotaline administration group (monocrotaline + physiological saline administration; 10 cases)

[0036] Experimental results;

[Table 1]

As is clear from Table 1, administration of the compound of formula (1) significantly suppressed the increase in pulmonary vascular resistance and right ventricular hypertrophy in the monocrotaline-induced rat pulmonary hypertension model. In addition, pathomorphological studies showed that the degree of hypertrophy of the muscular pulmonary artery media was significantly suppressed. Therefore, the compound of formula (1) was shown to be a useful drug for the prevention or treatment of pulmonary hypertension.

Example 2 Toxicity value after repeated oral administration for 10 days in rats: As shown in Table 2 below, the compound of formula (1) obtained in Reference Example 3 was administered once a day to 5-week-old Slc-SD male rats. As a result of repeated oral administration for 10 days and examining its toxicity, 800mg/
No deaths were observed after oral administration.

[0039]

[Table 2]

Example 3 Toxicity value by single intravenous administration to rats: As shown in Table 3 below, the compound of formula (1) obtained in Reference Example 3 was administered to 5-week-old Sl.
After a single intravenous administration to c-SD male rats, the toxicity was examined and the LD50 value was 150-200 mg/kg.
It was estimated that

[0041]

[Table 3]

Claims (1)

[Claims] Claim 1: 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9 represented by the following formula (1):
-tetrahydro-2H-pyrido[1,2-a]-1,3
, 5-triazine-2,4(3H)-dione or a salt thereof as an active ingredient.