JP3058955B2 - Hexitol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a nitrate of deoxy-1,4; 3,6-dianhydrohexitol having a vasodilating action.

[0002]

BACKGROUND ART As hexitol derivatives having pharmacological activity, isosorbide (The Merck Index, 11th edition, 5113 (1989)) as a diuretic, and isosorbide dinitrate (The Merck Index, 11th edition) as a coronary vasodilator. 5114 (1989)].

Further, 5- (4-methylpiperazin-1-yl) -5-deoxy-1,4; 3,6-dianhydro-L-iditol 2 which has a vasodilatory effect in connection with the present invention.
-Nitrites are disclosed in JP-A-57-58686.

[0004]

As a nitrate ester drug, nitroglycerin has been widely used during the attacks of angina for a long time. However, nitroglycerin cannot be used as a preventive drug for seizures in angina due to poor oral absorbability, and is always used by sublingual administration as an emergency treatment for seizures. Isosorbide dinitrate has also been used in the treatment of angina and heart failure, but is not always satisfactory in terms of potency and side effects (headache, vomiting, etc.). Since these nitrate drugs are explosive, care must be taken when handling them.

According to the present invention, substituted piperazino-1,4; 3,6 having excellent oral absorption and exhibiting potent anticoronary vasospasm activity.
A nitrate of dianhydrohexitol is provided.

[0006]

The present invention relates to a compound of the formula (I)

[0007]

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Wherein R is hydrogen, unsubstituted or lower alkyl-substituted cycloalkyl, lower alkenyl, lower alkoxy, lower alkanoyl, piperidyl or

[0009]

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Wherein m and n are the same or different and represent an integer of 0 to 3, and X, Y and Z are the same or different and are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, lower alkanoyloxy, hydroxyl, A hexitol derivative represented by｝ or a pharmaceutically acceptable salt thereof.

Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to compounds of other formula numbers. The cycloalkyl portion of the cycloalkyl and the lower alkyl-substituted cycloalkyl in the definition of R in the formula (I) includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like having 3 to 6 carbon atoms. Lower alkenyl is straight or branched having 2 to 2 carbon atoms.
6, for example, vinyl, allyl, methacryl, crotyl and the like. The alkyl portion of lower alkyl and lower alkyloxy has 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl. And the like. Lower alkanoyl, the alkanoyl moiety in lower alkanoyloxy is a straight-chain or branched C1-6, for example,
Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like. Halogen includes fluorine, chlorine, bromine and iodine.

The pharmacologically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate, phosphate and the like, acetate, maleate, fumarate, tartrate, citric acid Organic acid salts such as salts are mentioned. Next, a method for producing the compound of the present invention will be described. Production Method 1 Compound (I) can be obtained by reacting compound (II) with compound (III), preferably in the presence of a base.

[0013]

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(Wherein, R is as defined above and L is a leaving group) The leaving group represented by L is
For example, halogen atoms such as chlorine, bromine and iodine, alkylsulfonyloxy groups such as methanesulfonyloxy, arylsulfonyloxy groups such as phenylsulfonyloxy and p-toluenesulfonyloxy, tert-butoxycarbonyloxy, ethoxycarbonyloxy, isobutyloxycarbonyl And an alkoxycarbonyloxy group such as oxy.

Examples of the reaction solvent include solvents that do not participate in the reaction, for example, ethers such as tetrahydrofuran and dioxane, fatty acid dimethylamides such as dimethylformamide and dimethylacetamide, ketones such as acetone and methyl ethyl ketone, and methanol. , Alcohols such as ethanol and isopropyl alcohol, halogenated hydrocarbons such as methylene chloride, chloroform and ethane dichloride, esters such as ethyl acetate, and dimethyl sulfoxide are used alone or in combination.

As the base, for example, sodium bicarbonate,
Alkali metal bicarbonates such as potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate,
Alkali metal hydrides such as sodium hydride; alkali metal alkoxides such as sodium methoxide and sodium ethoxide; ammonium salts such as trimethylbenzylammonium hydroxide (Triton B); organic bases such as triethylamine and pyridine; Is raised.

The reaction is carried out at -30 to 150 ° C, preferably at -10 to 10 ° C.
Perform at 0 ° C. and finish in 5 minutes to 20 hours. Starting compound (II
I) was prepared according to the method described in Reference Example, and the starting compound (I
I) can be obtained from the corresponding carboxylic acid by a method usually used in organic synthetic chemistry.

Production Method 2 Compound (I) can be obtained by reacting compound (IV) with compound (III), preferably in the presence of a base.

[0019]

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(Wherein R is as defined above) The reaction solvent, base and reaction conditions are the same as in Production Method 1.

Production Method 3 Compound (I) can be obtained by reacting compound (V) with a nitrating agent in the presence or absence of a solvent.

[0022]

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(Wherein R is as defined above) Examples of the nitrating agent include acetic anhydride-fuming nitric acid, fuming nitric acid, fuming nitric acid-concentrated sulfuric acid, and the like, and examples of the solvent include acetonitrile, chloroform, methylene chloride, and the like. Acetic acid or the like is used. The reaction is carried out at −40 to 20 ° C. and is completed in 30 seconds to 5 hours, depending on the reaction temperature.

Compound (V) can be synthesized according to Production Method 1 or Production Method 2 using the compounds obtained by the methods described in Reference Examples. Intermediates and target compounds in the above-mentioned production methods can be isolated and purified by applying purification means commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography to the reaction mixture. . In addition, the intermediate can be subjected to the next reaction without purification.

When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it may be purified as it is. If compound (I) is obtained in a free form, an appropriate organic solvent may be used. May be dissolved or suspended, and an acid may be added to form a salt. The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. Further, the compounds of the present invention include all possible stereoisomers including optically active isomers and mixtures thereof.

Specific examples of the compound (I) obtained by each production method are shown in Tables 1-1, 1-2, 1-3 and 1
-4 is shown in Table.

[0027]

[Table 1]

[0028]

[Table 2]

[0029]

[Table 3]

[0030]

[Table 4]

Next, the pharmacological effects of the representative compound (I) are shown in Test Examples. Test Example 1 (a) Effect on coronary vasoconstriction model (lysine-vasopressin test) Wistar rat males weighing 200 to 250 g were used in the experiments. The electrocardiogram (ECG) in this test was measured with an electrocardiograph (RB-5; Nihon Kohden) and recorded with a polygraph (RPM-6200; Nihon Kohden).

The test compound was administered to rats 30 minutes before anesthesia when administered orally and 20 minutes before anesthesia when administered intraperitoneally. After the rats were anesthetized with urethane, they were given 0.3 IU / kg of lysine-vasopressin (V-2875; Sigma) intravenously to induce coronary vasoconstriction. After administration of lysine-vasopressin, an increase in ST-segment was observed in the ECG [Arzneim. Forsh. 36, 1454
P. 1986].

In this test, the effect of attenuating ST-segment elevation after lysine-vasopressin administration was regarded as antianginal activity.
neim. Forsh.) 36, 1454, 1986], in the test compound-administered and non-administered groups, the ST-segment elevation was measured in rats for 20 to 30 seconds after lysine-vasopressin administration.
The decay rate due to the test compound was calculated by the following equation.

[0034]

(Equation 1)

In this test, a compound which significantly attenuated the increase of ST-segment by 20% or more was defined as effective for a coronary vasoconstriction model, and the compound was defined as a compound having anti-vasoconstriction activity. The minimum dose showing the anti-vasoconstrictor activity was defined as the minimum effective dose (MED). The results are shown in Table 2.

Test Example 2 (b) Effect on Propranolol-Induced Heart Failure Model Adult mongrel dogs (male and female 8 to 20 kg) were used. The animals were anesthetized by intravenous administration of 35 mg / kg of sodium salt of pentobarbital, and artificial respiration (for Takashima Shoten University animals) was started immediately after the tracheal cannula was inserted. A left ventricular pressure catheter (mirror chip 5F) is inserted into the left ventricle via the common carotid artery of the dog, and the left ventricular pressure (LVP), the maximum rate of change of the left ventricular pressure (Max dp / dt), the left ventricular diastolic end pressure (LVED
P) was measured with a mirror chip. For blood pressure (BP), a catheter is inserted into the femoral artery and a pressure transducer (MP
U-0.5; Nihon Kohden) and heart rate (HR) was measured from a femoral artery pressure with a heart rate monitor (AT610-G; Nihon Kohden). Records were recorded on a polygraph device (RPM-6200;
(Nihon Kohden) or a recorder (RAT-1200; Nihon Kohden).

After all parameters had stabilized, the dogs were dosed intravenously with 2 mg / kg of propranolol. Thereafter, propranolol (0.05 mg / kg / min) was continuously intravenously administered to prepare a heart failure state [Journal of Cardiovascular Pharmacology (J. Cardiovasc. Ph.
armacol.) 6, 35, 1984]. With continuous administration of propranolol, LVEDP is 10 to 10 as a sign of heart failure
Increased to 15mmHg. After the appearance of heart failure, test compounds were administered intravenously or intraduodenally. After administration of test compound, 1
Every 5 minutes, LVEDP, LVP, Max dp / dt, BP and HR were measured and recorded.

In this test, LVED was used as an indicator of heart failure.
P was used, but L increased by propranolol treatment
Drugs that reduced VEDP (10-15 mmHg) by more than 20%
It was defined as effective for heart failure and its effective dose was determined. The results are shown in Table 2.

[0039]

[Table 5]

Test Example 3 (c) Acute Toxicity The test compound was intraperitoneally and orally administered to dd-type male mice weighing 20 to 25 g. The MLD (minimum lethal dose) was determined by measuring the mortality 7 days after administration. The results are shown in Table 3.

[0041]

[Table 6]

Compound (I) or a pharmaceutically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier as an active ingredient. These pharmaceutical compositions are desirably in a unit dosage form suitable for oral or injection administration.

In preparing the compositions in oral dosage form, any useful pharmaceutically acceptable carrier can be used. Oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil,
It can be produced using oils such as soybean oil, preservatives such as alkyl parahydroxybenzoate, and flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets contain excipients such as lactose, glucose, sucrose, mannitol,
Using starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate, talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin Can be manufactured. Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration. When manufacturing tablets and capsules, a solid pharmaceutical carrier is used. The solution for injection is
It can be prepared using a carrier consisting of distilled water, salt solution, glucose solution or a mixture of saline and glucose solution. The effective dose and the number of administrations of the compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, the age, weight, and symptoms of the patient, but are usually 0.1 per day.
It is preferable to administer 5050 mg / kg in 3 to 4 divided doses.

Hereinafter, embodiments of the present invention will be described with reference to Examples, Reference Examples and Preparation Examples.

[0045]

【Example】

Example 1 5- (4-acetylpiperazin-1-yl) -5-deoxy-1,4; 3,6-dianhydro-L-iditol 2
-Nitrate (compound 1) 2.00 g (7.71 mmol) of compound b obtained in Reference Example 2
And 30 ml of methylene chloride were stirred at 0 ° C., and 0.73 ml (7.74 mmol) of acetic anhydride and 0.62
ml (7.67 mmol) were sequentially added dropwise. The mixed solution was further stirred at 0 ° C. for 30 minutes. After the reaction was completed, an aqueous solution of sodium hydrogen carbonate was added to the solution, and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 30/1) to obtain Compound 1. Chloroform was added thereto to dissolve, and a saturated ethyl acetate solution of hydrochloric acid was further added. This was poured into cold diethyl ether, and the precipitated crystals were collected by filtration and dried to obtain 2.57 g (yield 99%) of Compound 1 hydrochloride. Melting point: 137.0-140.0 ° C MS (EI) m / e: 301 (M ⁺ ) IR (KBr) cm ^-1 : 1658, 1640, 1434, 1279, 1083, 856 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.27 (1H, m), 4.
84 (1H, m), 2.70〜4.65 (13H, m), 2.04 (3H, s)

Example 2 5-deoxy-5- (4-propionylpiperazine-1
-Yl) -1,4; 3,6-dianhydro-L-iditol 2-nitrate (compound 2) Except for using propionic anhydride instead of acetic anhydride and changing the stirring time from 30 minutes to 1 hour and 30 minutes Was carried out in the same manner as in Example 1 to obtain Compound 2 as a hydrochloride (80% yield). MS (EI) m / e: 315 (M ⁺ ) IR (KBr) cm ^-1 : 1660, 1644, 1435, 1278, 1083, 857 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m) , 5.31 (1H, m),
4.83 (1H, m), 2.75〜4.75 (13H, m), 2.36 (2H, q, J = 7.5Hz),
0.99 (3H, t, J = 7.5Hz)

Example 3 5- (4-butyrylpiperazin-1-yl) -5-deoxy-1,4; 3,6-dianhydro-L-iditol 2
-Nitrate (Compound 3) Compound 3 was obtained as a hydrochloride by performing the same operation as in Example 1 except that butyric anhydride was used instead of acetic anhydride and that the stirring time was changed from 30 minutes to 1 hour and 30 minutes. Yield 79
%). Melting point: 113.5-114.0 ° C MS (EI) m / e: 329 (M ⁺ ) IR (KBr) cm ^-1 : 1657, 1641, 1431, 1277, 1082, 853 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.29 (1H, m), 4.
84 (1H, m), 2.80 ~ 4.70 (13H, m), 2.33 (2H, t, J = 7.4Hz),
1.52 (2H, m), 0.90 (3H, t, J = 7.3Hz)

Example 4 5-Deoxy-5- (4-isobutyrylpiperazine-1
-Yl) -1,4; 3,6-dianhydro-L-iditol 2-nitrate (compound 4) Except for using isobutyric anhydride instead of acetic anhydride and changing the stirring time from 30 minutes to 1 hour and 30 minutes Is Example 1
Compound 4 was obtained as a hydrochloride by performing the same operation as described above.
87%). Melting point: 140.5-141.0 ° C Elemental analysis: as C ₁₄ H ₂₃ N ₃ O ₆ .HCl Theoretical value (%): C, 45.97 H, 6.61 N, 11.49 Observed value (%): C, 45.84 H, 6.77 N, 11.52 IR (KBr) cm ^-1 : 1659, 1644, 1436, 1276, 1089, 996,
854 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.27 (1H, m), 4.
84 (1H, m), 2.70〜4.70 (13H, m), 2.89 (1H, m), 1.01 (6H,
d, J = 6.6Hz)

Example 5 5-Deoxy-5- (4-valerylpiperazin-1-yl) -1,4; 3,6-dianhydro-L-iditol 2
-Nitrate (compound 5) valeric acid 2.50 g (24.48 mmol) and methylene chloride 60 ml
Was stirred at 0 ° C., and 4.40 ml of pyridine (54.40 ml) was added thereto.
Mmol) and 1.78 ml of thionyl chloride (24.51 mmol)
Were sequentially added dropwise. The mixed solution was further stirred at 0 ° C. for 1 hour (hereinafter, referred to as solution A).

2.80 g of the compound b obtained in Reference Example 2 (10.
80 mmol) and 30 ml of acetonitrile at 0 ° C
And the solution A was added dropwise thereto. The mixed solution was further stirred at 0 ° C. for 3 hours, concentrated under reduced pressure, added with a saturated sodium hydrogen carbonate aqueous solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: chloroform / methanol = 50/1)
Then, Compound 5 was obtained.

Chloroform was added thereto to dissolve, and a saturated ethyl acetate solution of hydrochloric acid was further added. This was poured into cold diethyl ether, and the precipitated crystals were collected by filtration and dried to obtain 2.04 g (yield: 50%) of Compound 5 hydrochloride. Melting point: 61.0-61.5 ° C MS (EI) m / e: 343 (M ⁺ ) IR (KBr) cm ^-1 : 1642, 1432, 1276, 1086, 852 NMR (DMSO-d ₆ ) δ (ppm): 5.44 ( 1H, m), 5.26 (1H, m), 4.
83 (1H, m), 2.8 ~ 4.6 (13H, m), 2.34 (2H, t, J = 7.3Hz), 1.4
8 (2H, m), 1.30 (2H, m), 0.88 (3H, t, J = 7.2Hz)

Example 6 5-deoxy-5- (4-isovalerylpiperazine-1
-Yl) -1,4; 3,6-dianhydro-L-iditol 2-nitrate (compound 6) Compound 6 was converted to hydrochloric acid by the same operation as in Example 5 except that isovaleric acid was used instead of valeric acid. Obtained as salt (yield 58
%). Melting point: 181.5-183.0 ° C MS (EI) m / e: 343 (M ⁺ ) IR (KBr) cm ^-1 : 1658, 1641, 1432, 1279, 1087, 851 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.26 (1H, m), 4.
83 (1H, m), 2.8 ~ 4.3 (13H, m), 2.23 (2H, d, J = 7.0Hz), 1.9
8 (1H, m), 0.91 (6H, d, J = 6.6Hz)

Example 7 5-deoxy-5- (4-heptanoylpiperazine-1
-Yl) -1,4; 3,6-dianhydro-L-iditol 2-nitrate (compound 7) Using heptanoic anhydride instead of acetic anhydride and a reaction time of 30 minutes at 0 ° C. for 4 hours at room temperature Compound 7 was obtained as a hydrochloride by performing the same operation as in Example 1 except for changing to (yield 66%). Mp: 178.0 to 178.5 ° C. Elemental _{analysis: C 17 H 29 N 8 O} 6 · HCl as a theory (%): C, 50.06 H , 7.41 N, 10.30 Found (%): C, 49.87 H , 7.49 N, 10.28 IR (KBr) cm ^-1 : 1658, 1644, 1433, 1282, 1087, 855 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.26 (1H, m), 4.
83 (1H, m), 2.75〜4.30 (13H, m), 2.33 (2H, t, J = 7.4Hz),
1.49 (2H, m), 1.10-1.45 (6H, m), 0.87 (3H, t, J = 6.8Hz)

Example 8 5- (4-Cyclohexylcarbonylpiperazine-1-
Yl) -5-deoxy-1,4; 3,6-dianhydro-L
-Iditol 2-nitrate (compound 8) Compound 8 was obtained as a hydrochloride by performing the same operation as in Example 5 except that cyclohexanecarboxylic acid was used instead of valeric acid (yield 34%). Melting point: 141.0-141.5 ° C Elemental analysis: As C ₁₇ H ₂₇ N ₃ O ₆ .HCl Theoretical value (%): C, 50.31 H, 6.95 N, 10.35 Actual value (%): C, 50.10 H, 7.15 N, 10.32 IR (KBr) cm ^-1 : 1651, 1645, 1435, 1283, 1083, 858 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.26 (1H, m), 4.
83 (1H, m), 2.70-4.70 (13H, m), 2.59 (1H, m), 1.46-1.
82 (4H, m), 0.96-1.46 (6H, m)

Example 9 5-deoxy-5- (4-nipecotylpiperazine-1-
Yl) -1,4; 3,6-dianhydro-L-iditol
2-Nitrate (Compound 9) The same operation as in Example 5 was carried out except that the compound c obtained in Reference Example 3 was used instead of valeric acid, to obtain 5- [4- (1-t
-Butoxycarbonylpiperidin-3-ylcarbonyl) piperazin-1-yl] -5-deoxy-1,4; 3,
6-Dianhydro-L-iditol 2-natrate was obtained (yield 37%).

A mixture of 1.80 g (3.83 mmol) of the above compound, 20 ml of ethanol and 20 ml of 1N aqueous hydrochloric acid was stirred at room temperature for 6 days. After concentration under reduced pressure, the residue was triturated with ethyl acetate, and the crystals were collected by filtration and dried to give 1.33 g (yield 78%) of compound 9 hydrochloride. MS (FAB) m / e: 371 (M + +1) IR (KBr) cm -1: 1642, 1441, 1278, 1088, 857 NMR (DMSO-d 6) δ (ppm): 5.45 (1H, m) , 5.31 (1H, m), 4.
85 (1H, m), 2.7 ~ 4.6 (18H, m), 1.45 ~ 1.95 (4H, m)

Example 10 5-Deoxy-5- [4- (2-methylbutyryl) piperazin-1-yl] -1,4; 3,6-dianhydro-L-
Iditol 2-nitrate (Compound 10) Compound 10 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 2-methylbutyric acid was used instead of valeric acid (yield 69).
%). Melting point: 234.0-234.5 ° C MS (EI) m / e: 343 (M ⁺ ) IR (KBr) cm ^-1 : 1651, 1634, 1462, 1434, 1278, 1088,
857 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.28 (1H, m), 4.
84 (1H, m), 2.8-4.7 (13H, m), 2.72 (1H, m), 1.54 (1H, m
m), 1.32 (1H, m), 0.99 (3H, d, J = 6.8Hz), 0.85 (3H, t, J = 7.
6Hz)

Example 11 5-Deoxy-5- [4- (2-ethylbutyryl) piperazin-1-yl] -1,4; 3,6-dianhydro-L-
Iditol 2-nitrate (Compound 11) Compound 11 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 2-ethylbutyric acid was used instead of valeric acid (yield: 75).
%). Melting point: 197.3-197.5 ° C MS (EI) m / e: 357 (M ⁺ ) IR (KBr) cm ^-1 : 1650, 1641, 1461, 1436, 1278, 1229,
1085, 998, 955,851 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.30 (1H, m), 4.
83 (1H, m), 2.8 to 4.4 (13H, m), 2.63 (1H, m), 1.25 to 1.65
(4H, m), 0.81 (6H, t, J = 7.3Hz)

Example 12 5-Deoxy-5- [4- (methoxyacetyl) piperazin-1-yl] -1,4; 3,6-dianhydro-L-iditol 2-nitrate (compound 12) Example 5 except that methoxyacetic acid was used instead
Compound 12 was obtained as a hydrochloride (yield 89%). Melting point: 126.4-127.5 ° C MS (EI) m / e: 331 (M ⁺ ) IR (KBr) cm ^-1 : 1657, 1643, 1439, 1280, 1114, 958,
857 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.25 (1H, m), 4.
83 (1H, m), 4.13 (2H, s), 3.30 (3H, s), 2.75-4.40 (13H, m)

Example 13 5- [4- (2-acetoxybutyryl) piperazine-1
-Yl] -5-deoxy-1,4; 3,6-dianhydro-
L-iditol 2-nitrate (compound 13) 2-hydroxybutyric acid 5.00 g (48.0 mmol), acetic anhydride 4.98 ml (52.8 mmol) and pyridine 60 ml
Was stirred at 0 ° C. for 10 minutes. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform) to obtain 7.01 g (100% yield) of 2-acetoxybutyric acid.

Thereafter, the same operation as in Example 5 was carried out except that the above-mentioned 2-acetoxybutyric acid was used instead of valeric acid, to obtain Compound 13 as a hydrochloride (yield: 45%). Melting point: 125.2-125.7 ° C MS (EI) m / e: 387 (M ⁺ ) IR (KBr) cm ^-1 : 1735, 1660, 1645, 1441, 1376, 1279,
1243, 959, 856 NMR (DMSO -d 6) δ (ppm): 5.44 (1H, m), 5.15~5.35 (2H,
m), 4.83 (1H, m), 2.80-4.35 (13H, m), 2.05 (3H, s), 1.70
(2H, m), 0.92 (3H, t, J = 7.3Hz)

Example 14 5-deoxy-5- [4- (2-hydroxybutyryl)
Piperazin-1-yl] -1,4; 3,6-dianhydro-
L-Iditol 2-nitrate (compound 14) A mixture of 0.65 g (1.68 mmol) of compound 13 obtained in Example 13, 67 mg (1.68 mmol) of sodium hydroxide, 10 ml of water and 10 ml of tetrahydrofuran was added at room temperature. For 1 hour. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 20/1) to obtain Compound 14.

Ethanol was added to this to dissolve it, and a saturated ethyl acetate solution of hydrochloric acid was further added. This was poured into cold diethyl ether, and the precipitated crystals were collected by filtration and dried to give Compound 14
0.55 g (86% yield) of Melting point: 60.7-72.7 ° C MS (EI) m / e: 345 (M ⁺ ) IR (KBr) cm ^-1 : 3415 (br), 1641, 1636, 1439, 1278, 1
059, 988, 959, 858 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.27 (1H, m), 4.
84 (1H, m), 2.7 to 4.7 (15H, m), 1.35 to 1.80 (2H, m), 0.88
(3H, t, J = 7.5Hz)

Example 15 5- [4- (2-chlorobutyryl) piperazin-1-yl] -5-deoxy-1,4; 3,6-dianhydro-L-
Iditol 2-nitrate (compound 15) Compound 15 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 2-chlorobutyric acid was used instead of valeric acid (yield 79).
%). Melting point: 179.7-179.8 ° C MS (EI) m / e: 363 (M ⁺ ) IR (KBr) cm ^-1 : 1651, 1646, 1441, 1279, 1086, 957,
857 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.28 (1H, m), 4.
90 (1H, m), 4.84 (1H, m), 2.6 to 4.3 (13H, m), 1.65 to 2.10
(2H, m), 0.96 (3H, t, J = 7.3Hz)

Example 16 5- [4- (4-chlorobutyryl) piperazin-1-yl] -5-deoxy-1,4; 3,6-dianhydro-L-
Iditol 2-nitrate (Compound 16) Compound 16 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 4-chlorobutyric acid was used instead of valeric acid.
%). Melting point: 159.3-163.9 ° C MS (EI) m / e: 363 (M ⁺ ) IR (KBr) cm ^-1 : 1766, 1643, 1438, 1278, 1086, 998,
959, 858 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.30 (1H, m), 4.
84 (1H, m), 1.8-4.8 (19H, m)

Example 17 5- [4- (2-bromobutyryl) piperazin-1-yl] -5-deoxy-1,4; 3,6-dianhydro-L-
Iditol 2-nitrate (compound 17) Compound 17 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 2-bromobutyric acid was used instead of valeric acid.
%). Melting point: 180.9-181.2 ° C MS (EI) m / e: 407 (M ⁺ ) IR (KBr) cm ^-1 : 1650, 1642, 1440, 1278, 1086, 1000,
958, 857 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.26 (1H, m), 4.
90 (1H, m), 4.83 (1H, m), 2.7 to 4.3 (13H, m), 1.70 to 2.10
(2H, m), 0.96 (3H, t, J = 7.3Hz)

Example 18 5-Deoxy-5- (4-pivaloylpiperazine-1-
Yl) -1,4; 3,6-dianhydro-L-iditol
2-Nitrate (compound 18) Compound 18 was obtained as a hydrochloride by performing the same operation as in Example 5 except that pivalic acid chloride was used instead of solution A (yield: 100%). Melting point: 204.5-204.7 ° C MS (EI) m / e: 343 (M ⁺ ) IR (KBr) cm ^-1 : 1641, 1631, 1479, 1421, 1366, 1276,
1191, 1087, 995, 955,855 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.30 (1H, m), 4.
83 (1H, m), 2.8 to 4.5 (13H, m), 1.20 (9H, s)

Example 19 5- [4- (4-bromobutyryl) piperazin-1-yl] -5-deoxy-1,4; 3,6-dianhydro-L-
Iditol 2-nitrate (compound 19) Compound 19 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 4-bromobutyric acid was used instead of valeric acid (yield 53).
%). MS (EI) m / e: 407 (M ⁺ ) IR (KBr) cm ^-1 : 1658, 1650, 1629, 1576, 1447, 1370,
1322, 1166, 1001, 878, 830, 754 NMR (DMSO-d ₆ ) δ (ppm): 5.42 (1H, m), 5.11 (1H, m), 4.
82 (1H, m), 2.0-4.7 (19H, m)

Example 20 5- (4-crotonylpiperazin-1-yl) -5-deoxy-1,4; 3,6-dianhydro-L-iditol
2-Nitrate (Compound 20) Compound 20 was obtained as a hydrochloride by performing the same operation as in Example 5 except that crotonic acid chloride was used instead of solution A (yield: 91%). Melting point: 175.8-175.9 ° C MS (EI) m / e: 327 (M ⁺ ) IR (KBr) cm ^-1 : 1655, 1642, 1432, 1278, 1232, 1082,
961, 858 NMR (DMSO-d ₆ ) δ (ppm): 6.74 (1H, m), 6.51 (1H, dd, J = 1
4.9Hz, 1.2Hz), 5.44 (1H, m), 5.28 (1H, m), 4.83 (1H, m),
2.6 to 4.6 (13H, m), 1.85 (2H, dd, J = 6.6,1.2Hz)

Example 21 5-deoxy-5- [4- (3-nitropropionyl)
Piperazin-1-yl] -1,4; 3,6-dianhydro-
L-Iditol 2-nitrate (Compound 21) Compound 21 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 3-nitropropionic acid was used instead of valeric acid (yield: 75%). Melting point: 209.8-210.8 ° C MS (EI) m / e: 360 (M ⁺ ) IR (KBr) cm ^-1 : 2916, 1660, 1647, 1560, 1471, 1440,
1417, 1379, 1279, 1234, 1213, 1145, 1086, 1035, 9
99, 974, 858 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.27 (1H, m), 4.
84 (1H, m), 4.71 (2H, t, J = 5.7Hz), 3.08 (2H, t, J = 5.7Hz),
2.7 to 4.4 (13H, m)

Example 22 5-deoxy-5- [4- (3,3-dimethylbutyryl)
Piperazin-1-yl] -1,4; 3,6-dianhydro-
L-Iditol 2-nitrate (Compound 22) Compound 22 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 3,3-dimethylbutyric acid was used instead of valeric acid (yield 81%). Melting point: 272.0-278.0 ° C MS (EI) m / e: 357 (M ⁺ ) IR (KBr) cm ^-1 : 1651, 1633, 1427, 1374, 1285, 1241,
1090, 1033, 965, 848 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.31 (1H, m), 4.
84 (1H, m), 2.9 to 4.4 (13H, m), 2.27 (2H, s), 1.28 (9H, s)

Example 23 5-deoxy-5- [4- (2,2-dimethylbutyryl)
Piperazin-1-yl] -1,4; 3,6-dianhydro-
L-Iditol 2-nitrate (Compound 23) Compound 23 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 2,2-dimethylbutyric acid was used instead of valeric acid. Melting point: 197.2-198.0 ° C MS (EI) m / e: 357 (M ⁺ ) IR (KBr) cm ^-1 : 1641, 1636, 1417, 1276, 1089, 994,
954, 854 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.29 (1H, m), 4.
83 (1H, m), 2.8 to 4.4 (13H, m), 1.58 (2H, q, J = 7.4Hz), 1.
16 (6H, s), 0.80 (3H, t, J = 7.4Hz)

Example 24 5- [4- (2-chloropropionyl) piperazine-1
-Yl] -5-deoxy-1,4; 3,6-dianhydro-
L-Iditol 2-nitrate (Compound 24) Compound 24 was obtained as a hydrochloride by performing the same operation as in Example 5 except that 2-chloropropionic acid was used instead of valeric acid (yield 93%). Melting point: 165.7-167.4 ° C MS (EI) m / e: 349 (M ⁺ ) IR (KBr) cm ^-1 : 1658, 1640, 1466, 1437, 1375, 1277,
1199, 1067, 992, 956,852 NMR (DMSO-d ₆ ) δ (ppm): 5.43 (1H, m), 5.26 (1H, m), 5.
10 (1H, q, J = 6.4Hz), 4.84 (1H, m), 2.7 to 4.6 (13H, m), 1.
52 (3H, d, J = 6.4Hz)

Example 25 5-Deoxy-5- [4- (2-methylcyclopropylcarbonyl) piperazin-1-yl] -1,4; 3,6-dianhydro-L-iditol 2-nitrate (compound 25 ) Compound 25 was prepared in the same manner as in Example 5 except that 2-methylcyclopropanecarboxylic acid was used instead of valeric acid.
Was obtained as the hydrochloride salt (81% yield). Melting point: 172.7-177.1 ° C MS (EI) m / e: 341 (M ⁺ ) IR (KBr) cm ^-1 : 1641, 1637, 1466, 1433, 1277, 1234,
1081, 988, 958,853 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.29 (1H, m), 4.
84 (1H, m), 2.7 to 4.6 (13H, m), 1.76 (1H, m), 1.15 (1H, m
m), 1.07 (3H, d, J = 5.6Hz), 0.95 (1H, m), 0.58 (1H, m)

Example 26 5- (4-cyclopropylcarbonylpiperazine-1-
Yl) -5-deoxy-1,4; 3,6-dianhydro-L
-Iditol 2-nitrate (compound 26) Compound 26 was obtained as a hydrochloride by performing the same operation as in Example 5 except that cyclopropanecarboxylic acid was used instead of valeric acid (yield: 85%). Melting point: 139.5-142.0 ° C MS (EI) m / e: 327 (M ⁺ ) IR (KBr) cm ^-1 : 1642, 1636, 1462, 1436, 1381, 1280,
1235, 1086, 957, 855 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.29 (1H, m), 4.
85 (1H, m), 2.8 to 4.6 (13H, m), 2.01 (1H, m), 0.55 to 0.95
(4H, m)

Example 27 5-deoxy-5- [4- (2-oxopropionyl)
Piperazin-1-yl] -1,4; 3,6-dianhydro-
L-Iditol 2-nitrate (compound 27) Compound 27 was obtained as a hydrochloride by performing the same operation as in Example 5 except that pyruvic acid was used instead of valeric acid (yield: 27%).
42%). Melting point: 106.0-106.5 ° C MS (EI) m / e: 329 (M ⁺ ) IR (KBr) cm ^-1 : 1792, 1651, 1642, 1439, 1280, 1243,
1103, 957, 854 NMR (DMSO-d ₆ ) δ (ppm): 5.43 (1H, m), 5.24 (1H, m), 4.
83 (1H, m), 2.8-4.3 (13H, m), 2.39 (3H, s)

Example 28 5-Deoxy-5- (4-vinylacetylpiperazine-
1-yl) -1,4; 3,6-dianhydro-L-iditol 2-nitrate (compound 28) Compound 28 was converted to hydrochloric acid by performing the same operation as in Example 5 except that vinyl acetic acid was used instead of valeric acid. Obtained as salt (yield
42%). Melting point: 93.0-93.5 ° C MS (EI) m / e: 327 (M ⁺ ) IR (KBr) cm ^-1 : 1640, 1634, 1440, 1278, 1087, 1002,
961, 854 NMR (DMSO-d ₆ ) δ (ppm): 5.89 (1H, m), 5.44 (1H, m), 5.
27 (1H, m), 5.14 (1H, m), 5.08 (1H, m), 4.84 (1H, m), 3.21
(2H, d, J = 6.6Hz), 2.6 to 4.7 (13H, m)

Example 29 5-Deoxy-5- (4-methacryloylpiperazine-
3,6-dianhydro-L-iditol 2-nitrate (compound 29) 0.39 ml (4.63 mmol) of methacrylic acid, 2.75 ml (19.85 mmol) of triethylamine and 2 A mixture of 16 ml of a mixed solvent of butanol and acetonitrile (5/1) was stirred at 0 ° C. and mixed with 0.6 ml of isobutyl chloroformate.
0 ml (4.63 mmol) of a mixed solvent (5/1) solution of 2-butanol and acetonitrile was added dropwise, and the mixture was further stirred at 0 ° C for 5 minutes. The compound b obtained in Reference Example 2
1.00 g (3.86 mmol) was added and stirred at 0 ° C. for 20 minutes. After concentration under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 50/1) to obtain Compound 29.

Chloroform was added thereto to dissolve, and a saturated ethyl acetate solution of hydrochloric acid was further added. This was poured into cold diethyl ether, and the precipitated crystals were collected by filtration and dried to give Compound 2.
0.66 g (47% yield) of the hydrochloride salt of 9 was obtained. Melting point: 172.5-173.5 ° C MS (EI) m / e: 327 (M ⁺ ) IR (KBr) cm ^-1 : 1645, 1635, 1462, 1433, 1375, 1277,
1206, 1086, 958, 855NMR ( DMSO-d 6) δ (ppm): 5.44
(1H, m), 5.27 (2H, s), 5.11 (1H, m), 4.85 (1H, m), 2.8-
4.6 (13H, m), 1.87 (3H, s)

Example 30 5-Deoxy-5- [4- (2-methylcrotonyl) piperazin-1-yl] -1,4; 3,6-dianhydro-L
-Iditol 2-nitrate (Compound 30) Compound 30 was obtained as a hydrochloride by performing the same operation as in Example 29 except that 2-methylcrotonic acid was used instead of methacrylic acid (yield 30%). Melting point: 164.5-166.0 ° C MS (EI) m / e: 341 (M ⁺ ) IR (KBr) cm ^-1 : 1642, 1633, 1460, 1427, 1280, 1087,
957, 854 NMR (DMSO-d ₆ ) δ (ppm): 5.67 (1H, q, J = 6.8Hz), 5.44 (1
H, m), 5.29 (1H, m), 4.84 (1H, m), 2.7 to 4.5 (13H, m), 1.
74 (3H, s), 1.67 (3H, d, J = 6.8Hz)

Example 31 5-Deoxy-5- [4- (3,3-dimethylacryloyl) piperazin-1-yl] -1,4; 3,6-dianhydro-L-iditol 2-nitrate (compound 31 The same operation as in Example 29 was carried out except that 3,3-dimethylacrylic acid was used instead of methacrylic acid, to obtain compound 31 as a hydrochloride (yield: 68%). Melting point: 222.0-225.0 ° C MS (EI) m / e: 341 (M ⁺ ) IR (KBr) cm ^-1 : 1641, 1633, 1460, 1427, 1376, 1281,
1245, 1087, 958, 853 NMR (DMSO-d ₆ ) δ (ppm): 5.97 (1H, s), 5.44 (1H, m), 5.
30 (1H, m), 4.84 (1H, m), 2.8-4.9 (13H, m), 1.87 (3H, s),
1.82 (3H, s)

Example 32 5-Deoxy-5- (4-isobutoxycarbonylpiperazin-1-yl) -1,4; 3,6-dianhydro-L-
Iditol 2-nitrate (compound 32) Compound 32 was obtained as a hydrochloride by performing the same operation as in Example 29 except that methacrylic acid was not used (yield: 72%). Melting point: 197.4-197.5 ° C MS (EI) m / e: 359 (M ⁺ ) IR (KBr) cm ^-1 : 2960, 2415, 1699, 1641, 1468, 1428,
1282, 1250, 1153, 1089, 963, 853 NMR (DMSO-d ₆ ) δ (ppm): 5.44 (1H, m), 5.27 (1H, m), 4.
83 (1H, m), 3.82 (2H, d, J = 6.4Hz), 2.8 to 4.3 (13H, m), 1.
89 (1H, m), 0.90 (6H, d, J = 6.6Hz)

Reference Example 1 5-deoxy-5- (piperazin-1-yl) -1,4;
3,6-dianhydro-L-iditol (compound a) 1,4; 3,6-dianhydro-D-glucitol 5-methanesulfonate (JP-A-57-58692) 20.2 g (9
0.1 mmol), 84.8 g (984.4 mmol) of piperazine and 240 ml of n-butanol were heated under reflux for 36 hours. After concentration under reduced pressure, the residue was azeotroped with toluene several times to remove as much piperazine as possible, thereby obtaining a methanesulfonate of Compound a as a crude product.

The above crude product was obtained from Diaion SP207.
(Mitsubishi Kasei Co., Ltd.) (elution solvent: water to 30% aqueous methanol) was chromatographed, azeotropically azeotroped with isopropyl alcohol, and then crystallized from ethyl acetate to give compound a with high purity. NMR (DMSO-d ₆ ) δ (ppm): 5.35 (1
H, m), 4.50 (1H, m), 4.19 (1H, m), 2.2 ~ 4.1 (14H, m)

Reference Example 2 5-deoxy-5- (piperazin-1-yl) -1,4;
3,6-dianhydro-L-iditol 2-nitrate (compound b) 10.6 ml of water was added to 37.8 g of the crude product of the methanesulfonate of compound a obtained in the same manner as in Reference Example 1, and the mixture was concentrated while cooling. A solution to which 5.6 ml of sulfuric acid was added dropwise was prepared (hereinafter referred to as solution B).

[0086] 2.47 g (41.1 mmol) of urea was added to 55.6% of concentrated sulfuric acid.
The solution dissolved in ml was dropped to 37 ml of fuming nitric acid (86%) while stirring and cooling to -15 ° C. Then, the solution B was
The mixture was added dropwise at 15 ° C. for 30 minutes to 1 hour, and further stirred at the same temperature for 2 hours. After completion of the stirring, the reaction mixture was poured into 300 ml of water with gentle stirring. While cooling, a mixture of 120 g (3.00 mol) of sodium hydroxide and 370 ml of water was gradually added to neutralize. This solution is mixed with chloroform for 5-10
The mixture was extracted twice, the chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 10/1 to 0/1) to obtain 8.9 g of compound b.
(38% yield). IR (KBr) cm ^-1 : 3420 (br), 1634,1278

Reference Example 3 1-t-butoxycarbonyl nipecotic acid (compound c) A mixture of 1.70 g (42.5 mmol) of sodium hydroxide, 40 ml of water and 30 ml of t-butanol was added with 5.00 g of nipecotic acid (3
8.7 mmol) and stirred at room temperature to dissolve. To this solution, 8.45 g (38.7 mmol) of di-tert-butyl dicarbonate was added, and the mixture was further stirred at room temperature for 1 hour and 30 minutes. After completion of the reaction, the pH was adjusted to 4 by adding dilute hydrochloric acid, and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was dried with anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain 8.87 g of compound c (88% yield).

Formulation Example 1 Tablet A tablet having the following composition is prepared by a conventional method.

Compound 1 50 mg Lactose 150 mg Potato starch 75 mg Polyvinyl alcohol 7.5 mg Magnesium stearate 2.5 mg

Formulation Example 2 Powder A powder having the following composition is prepared by a conventional method.

Compound 1 50 mg Lactose 750 mg

Formulation Example 3 Syrup A syrup having the following composition is prepared by a conventional method. Compound 1 50 mg Purified sucrose 75 mg p-hydroxybenzoic acid ethyl ester 100 mg p-hydroxybenzoic acid propyl ester 25 mg stroperi flavour 0.25 cc Add water to make up the total amount to 100 cc.

Formulation Example 4 Capsules A capsule having the following composition is prepared by a conventional method.

Compound 1 50 mg Lactose 500 mg Magnesium stearate 12.5 mg This is mixed and filled into a gelatin capsule.

Formulation Example 5 Injection An injection having the following composition is prepared by a conventional method.

Compound 1 20 mg Sodium chloride 45 mg To this is added water to make a total volume of 5 ml (1 ampoule). Water was distilled in advance and sterilized in an autoclave.

[0097]

According to the present invention, there is provided a novel deoxy-1,4; 3,6-dianhydro-hexitol nitrate having a vasodilator action.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-57-58686 (JP, A) JP-A-57-64696 (JP, A) JP-A-3-218381 (JP, A) (58) Field (Int. Cl. ⁷ , DB name) C07D 493/04 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) Formula (1) Wherein R is hydrogen, unsubstituted or lower alkyl-substituted cycloalkyl, lower alkenyl, lower alkoxy, lower alkanoyl, piperidyl or [In the formula, m and n are the same or different and represent an integer of 0 to 3, X, Y and Z are the same or different and represent hydrogen,
Represents a lower alkyl, lower alkoxy, lower alkanoyl, lower alkanoyloxy, hydroxyl, halogen or nitro], or a pharmaceutically acceptable salt thereof.