JPH04364184A - Hexitol derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound having vasodilating action. CONSTITUTION:A compound shown by formula I [R is H, (lower alkylsubstitutted)cycloalkyl, lower alkenyl, lower alkoxy, lower alkanoyl, piperidyl or group shown by formula II (m)and[n)are 0-3: X, Y and Z are H, lower alkyl, OH, halogen, nitro, etc.)] such as 5-(4-acetylpiperazin-1-yl)-5- deoxy-1,4:3,6-dianhydro-L-iditol 2-nitrate. The compound shown by formula I is obtained by reacting a compound shown by formula III (L is eliminable group) with a compound shown by formula IV in the presence of preferably a base (e.g. sodium bicarbonate, sodium hydride or triethylamine).

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to a nitrate ester of deoxy-1,4;3,6-dianhydrohexitol having a vasodilatory effect.

0002

[Prior Art] As hexitol derivatives having pharmacological activity, isosorbide [The Merck Index 11th Edition 5113 (1989)] is used as a diuretic, and isosorbide dinitrate [The Merck Index 11th Edition] is used as a coronary vasodilator. 5114 (19
1989)] is known.

Further, in connection with the present invention, 5-(4-methylpiperazin-1-yl)-5-deoxy-1,4;3,6-dianhydro-L-iditol 2-nitrate, which exhibits a vasodilatory effect. is disclosed in Japanese Patent Application Laid-Open No. 57-58686.

0004

[Problems to be Solved by the Invention] As a nitrate ester drug, nitroglycerin has long been frequently used during attacks of angina pectoris. However, since nitroglycerin has poor oral absorption, it cannot be used as a preventive drug for angina pectoris attacks, and is always used sublingually as an emergency treatment for attacks. Isosorbide dinitrate is also used to treat angina pectoris and heart failure, but its efficacy and side effects (headache, vomiting, etc.) are not always satisfactory. Furthermore, these nitrate ester chemicals are explosive, so care must be taken when handling them.

According to the present invention, substituted piperazino-1,4;3 which has excellent oral absorption and exhibits strong anti-coronary vasospasm activity
, 6-dianhydrohexitol is provided.

[0006]

[Means for Solving the Problems] The present invention provides formula (I)

00
07]

[Chemical formula 3]

{wherein R is hydrogen, unsubstituted or lower alkyl substituted cycloalkyl, lower alkenyl, lower alkoxy, lower alkanoyl, piperidyl or

000
9]

[C4]

[In the formula, m and n are the same or different and represent integers of 0 to 3, and X, Y and Z are the same or different and represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, lower alkanoyloxy, hydroxyl, halogen or nitro] or a pharmacologically acceptable salt thereof.

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

Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, and acetate, maleate, fumarate, tartrate, and citric acid. Examples include organic acid salts such as salts. Next, a method for producing the compound of the present invention will be explained. Production method 1 Compound (I) can be obtained by reacting compound (II) and compound (III), preferably in the presence of a base.

[0013]

[C5]

(In the formula, R has the same meaning as above, and L means a leaving group.) Examples of the leaving group represented by L include halogen atoms such as chlorine, bromine, and iodine, methanesulfonyloxy, etc. Alkylsulfonyloxy groups such as
Arylsulfonyloxy groups such as phenylsulfonyloxy and p-toluenesulfonyloxy, tert-butoxycarbonyloxy, ethoxycarbonyloxy,
Examples include alkoxycarbonyloxy groups such as isobutyloxycarbonyloxy.

Examples of the reaction solvent include solvents that do not participate in the reaction, such as ethers such as tetrahydrofuran and dioxane, fatty acid dimethylamides such as dimethylformamide and dimethylacetamide, acetone, ketones such as 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.

Examples of bases include sodium bicarbonate,
Alkali metal bicarbonates such as potassium bicarbonate, alkali metal carbonates such as sodium carbonate, potassium carbonate,
Alkali metal hydrides such as sodium hydride, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, ammonium salts such as trimethylbenzylammonium hydroxide (Triton B), organic bases such as triethylamine, pyridine, etc. can be given.

[0017] The reaction is carried out at -30 to 150°C, preferably -
It is carried out at 10 to 100°C and completed in 5 minutes to 20 hours. Raw material compound (III) was prepared according to the method shown in the reference example.
Further, starting compound (II) can be obtained from the corresponding carboxylic acid by a method commonly used in organic synthetic chemistry.

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

[0019]

[C6]

(In the formula, R has the same meaning as 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]

[C7]

Examples of the nitrating agent (wherein R is the same as above) include acetic anhydride-fuming nitric acid, fuming nitric acid,
Fuming nitric acid-concentrated sulfuric acid, etc. are used, and as the solvent, for example, acetonitrile, chloroform, methylene chloride, acetic acid, etc. are 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 compound obtained by the method described in Reference Examples. The intermediates and target compounds in the above-mentioned production methods can be isolated and purified by applying purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography to the reaction mixture. . Further, the intermediate can also be subjected to the next reaction without being particularly purified.

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, or if it is obtained in a free form, it may be purified using a suitable organic solvent. A salt may be formed by dissolving or suspending it in a solution and adding an acid. Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Furthermore, the compounds of the present invention include all possible stereoisomers and mixtures thereof, including optically active forms.

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

[0027]

[Table 1]

[0028]

[Table 2]

[0029]

[Table 3]

[0030]

[Table 4]

Next, the pharmacological effects of representative compound (I) are shown in test examples. Test Example 1 (a) Effect on coronary vasoconstriction model (lysine-vasopressin test) Male Wistar rats weighing 200 to 250 g were used in the experiment. The electrocardiogram (ECG) used in this study was an electrocardiograph (RB
-5; Measured with Nihon Kohden), polygraph (RPM-62)
00; Nihon Kohden).

If the test compound is administered orally, 30 minutes before anesthesia.
In the case of intraperitoneal administration, the rats were administered 20 minutes before anesthesia. After the rats were anesthetized with urethane, they were injected with 0.3 I. lysine-vasopressin (V-2875; Sigma) to produce coronary vasoconstriction. U. /k
g was administered intravenously. After administration of lysine-vasopressin,
An increase in ST-segments was observed in the ECG [
Arznei Mittel Forschung
m. Forsh. ) Volume 36, Page 1454, 198
6 years].

In this study, the attenuating effect of ST-segment elevation after administration of lysine-vasopressin was regarded as anti-anginal activity.
Arzneim. Forsh. ) Volume 36, 1454
Page, 1986], the ST-segment elevation was measured 20 to 30 seconds after administration of lysine-vasopressin to rats in the test compound-treated and non-treated groups. The attenuation rate due to the test compound was calculated using the following formula.

[0034]

[Math 1]

[0035] In this test, a compound that significantly attenuated the ST-segment elevation by 20% or more was defined as effective against a coronary vasoconstriction model, and was defined as a compound having anti-vasoconstriction activity. Furthermore, the minimum dose exhibiting the antivasoconstrictor 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 The animals used were mongrel adult dogs (male and female weighing 8 to 20 kg). Animals were treated with 35 mg/kg of the sodium salt of pentobarbital.
After the animal was anesthetized by intravenous administration of a tracheal cannula and a tracheal cannula was inserted, artificial respiration (for large animals by Takashima Shoten) was immediately started. A left ventricular pressure catheter (Miller Tip 5F) is inserted into the left ventricle of the dog through the common carotid artery, and the left ventricular pressure (LVP) is measured.
), maximum rate of change in left ventricular pressure (Max dp/dt),
Left ventricular end diastolic pressure (LVEDP) was measured with a mirror tip. Blood pressure (BP) was measured by inserting a catheter into the femoral artery.
The heart rate (HR) was measured using a pressure transducer (MPU-0.5; Nihon Kohden), and the heart rate (HR) was measured using a heart rate monitor (
Measured with 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 were stabilized, the dogs were administered propranolol 2 mg/kg intravenously. Thereafter, propranolol (0.05 mg/kg/min) was continuously administered intravenously to create a state of heart failure [Journal of Cardiovascular Pharmacology].
J. Cardiovasc. Pharmacol. )
Volume 6, page 35, 1984]. Continuous administration of propranolol increases LVEDP to 1 as a sign of heart failure.
It increased to 0-15mmHg. After the appearance of heart failure, test compounds were administered intravenously or intraduodenally. LVEDP, LVP, Max dp every 15 minutes after test compound administration
/dt, BP and HR were measured and recorded.

[0038] In this study, LVED was used as an index of heart failure.
P was used, but L increased by propranolol treatment.
A drug that reduced VEDP (10-15 mmHg) by 20% or more 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 test The compound was administered intraperitoneally and orally to male dd-strain mice weighing 20 to 25 g. MLD (minimum lethal dose) was determined by measuring the mortality rate 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 prepared by uniformly mixing an effective amount of Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier. These pharmaceutical compositions are desirably in unit dosage form suitable for administration orally or by injection.

[0043] Any useful pharmaceutically acceptable carrier can be used in preparing the compositions in oral dosage forms. Oral liquid preparations, such as suspensions and syrups, can be prepared using water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, etc.
It can be manufactured using oils such as soybean oil, preservatives such as alkyl parahydroxybenzoates, and flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets contain excipients such as lactose, glucose, sucrose and mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol and hydroxypropyl. It can be manufactured using binders such as cellulose and gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin. Tablets and capsules are the most useful oral dosage units because of their ease of administration. Solid pharmaceutical carriers are used in the manufacture of tablets and capsules. Injectable solutions can also be prepared with carriers consisting of distilled water, saline solutions, glucose solutions, or mixtures of saline and glucose solutions. The effective dose and frequency of administration of Compound (I) or a pharmacologically acceptable salt thereof will depend on the dosage form, age of the patient,
It varies depending on body weight, symptoms, etc., but usually 0.1~ per day.
Preferably, 50 mg/kg is administered in 3 to 4 divided doses.

[0044] Aspects of the present invention will be explained below with reference to Examples, Reference Examples, and Formulation Examples.

[0045]

【Example】

Example 1 5-(4-acetylpiperazin-1-yl)-5-deoxy-1,4;3,6-dianhydro-L-iditol 2-nitrate (compound 1) Compound b obtained in Reference Example 2 2.00g (7.71
mmol) and 30 ml of methylene chloride.
Stir at 0°C, add 0.73 ml of acetic anhydride (7.7
4 mmol) and pyridine 0.62 ml (7.6
7 mmol) were added dropwise one after another. The mixed solution was further stirred at 0°C for 30 minutes. After the reaction was completed, an aqueous sodium bicarbonate solution was added to this solution, and the mixture was 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 to this to dissolve it, and then a saturated hydrochloric acid and ethyl acetate solution was added. This was poured into cold diethyl ether, the precipitated crystals were filtered and dried, and 2.57 g of hydrochloride of compound 1 was obtained.
(yield 99%). Melting point: 137.0 to 140.0°C MS (EI) m/e: 301 (M+) IR (KB
r) cm-1: 1658, 1640, 1434
, 1279, 1083, 856NMR (DMSO
-d6) δ (ppm): 5.44 (1H, m)
, 5.27 (1H, m), 4.84 (1H, m),
2.70-4.65 (13H, m), 2.04 (3
H,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. The same operation as in Example 1 was carried out to obtain Compound 2 as a hydrochloride (yield: 80%). MS (EI) m/e: 315 (M+) IR (KB
r) cm-1: 1660, 1644, 143
5, 1278, 1083, 857 NMR (DMS
O-d6) δ (ppm): 5.44 (1H, m
), 5.31 (1H, m), 4.83 (1H,
m), 2.75-4.75 (13H, m), 2.3
6 (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) in place of acetic anhydride Example 1 except that butyric anhydride was used and the stirring time was changed from 30 minutes to 1 hour and 30 minutes.
Compound 3 was obtained as a hydrochloride by performing the same operation as above (yield 79%). Melting point: 113.5-114.0°C MS (EI) m/e: 329 (M+) IR (KB
r) cm-1: 1657, 1641, 143
1, 1277, 1082, 853 NMR (DMS
O-d6) 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)

00
48 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. Compound 4 was obtained as a hydrochloride by the same operation as in Example 1.
(Yield 87%). Melting point: 140.5-141.0°C Elemental analysis: C14 H23 N3 O 6 ・HC
Theoretical value (%) as l: C, 45.97 H
, 6.61 N, 11.49 Actual value (%):
C, 45.84 H, 6.77 N, 1
1.52IR (KBr) cm-1: 1659,
1644, 1436, 1276, 1089, 9
96, 854 NMR (DMSO-d6) δ (ppm): 5.
44 (1H, m), 5.27 (1H, m), 4.8
4 (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) 2.50 g of valeric acid A mixture of (24.48 mmol) and 60 ml of methylene chloride was stirred at 0°C, to which 4.40 ml (54.40 mmol) of pyridine and 1.78 ml (24.51 mmol) of thionyl chloride 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 compound b obtained in Reference Example 2
(10.80 mmol) and 30 m acetonitrile
1 mixture was stirred at 0° C. and solution A was added dropwise to it. The mixed solution was further stirred at 0° C. for 3 hours, concentrated under reduced pressure, then a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: chloroform/
Compound 5 was obtained by purification with methanol = 50/1).

[0051] Chloroform was added to this to dissolve it, and then a saturated hydrochloric acid and ethyl acetate solution was 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 the hydrochloride of Compound 5. Melting point: 61.0 to 61.5°C MS (EI) m/e: 343 (M+) IR (KB
r) cm-1: 1642, 1432, 127
6, 1086, 852NMR (DMSO-d6)
δ (ppm): 5.44 (1H, m), 5.2
6 (1H, m), 4.83 (1H, m), 2.8~
4.6 (13H, m), 2.34 (2H, t, J=7
．． 3Hz), 1.48 (2H, m), 1.30 (2
H, 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) The same procedure as in Example 5 was performed except that isovaleric acid was used instead of valeric acid, and Compound 6 was converted to hydrochloric acid. Obtained as a salt (yield 5
8%). Melting point: 181.5-183.0°C MS (EI) m/e: 343 (M+) IR (KB
r) cm-1: 1658, 1641, 143
2, 1279, 1087, 851NMR (DMS
O-d6) 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), 1.98 (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) Substituting heptanoic anhydride for acetic anhydride and reaction time of 30 minutes at 0°C for 4 hours at room temperature. Compound 7 was obtained as a hydrochloride by carrying out the same operation as in Example 1, except for changing to the compound (yield: 66%). Melting point: 178.0-178.5°C Elemental analysis: C17 H29 N8 O 6 ・HC
Theoretical value (%) as l: C, 50.06 H
, 7.41 N, 10.30 Actual value (%):
C, 49.87 H, 7.49 N, 1
0.28IR (KBr) cm-1: 1658,
1644, 1433, 1282, 1087, 8
55NMR (DMSO-d6) 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)

00
54 Example 8 5-(4-cyclohexylcarbonylpiperazine-1-
yl)-5-deoxy-1,4;3,6-dianhydro-L-iditol 2-nitrate (Compound 8) The same operation as in Example 5 was performed except that cyclohexanecarboxylic acid was used instead of valeric acid to prepare the compound. 8 was obtained as a hydrochloride (yield 34%). Melting point: 141.0-141.5°C Elemental analysis: C17 H27 N3 O 6 ・HC
Theoretical value (%) as l: C, 50.31 H
, 6.95 N, 10.35 Actual value (%):
C, 50.10 H, 7.15 N, 1
0.32IR (KBr) cm-1: 1651,
1645, 1435, 1283, 1083, 8
58NMR (DMSO-d6) 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 ~ 1.8
2 (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 performed except that compound c obtained in Reference Example 3 was used instead of valeric acid. 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%).

1.80 g (3.83 mmol) of the above compound, 20 ml of ethanol and 20 ml of 1N aqueous hydrochloric acid solution
ml mixture was stirred at room temperature for 6 days. After concentration under reduced pressure, the residue was tritylated with ethyl acetate, and the crystals were filtered and dried to obtain 1.33 g (yield: 78%) of the hydrochloride of compound 9. MS (FAB) m/e: 371 (M++1) IR (
KBr) cm-1: 1642, 1441, 1
278, 1088, 857NMR (DMSO-d6
) δ (ppm): 5.45 (1H, m), 5
．． 31 (1H, m), 4.85 (1H, m), 2.
7-4.6 (18H, m), 1.45-1.95 (4
H, m)

Example 10 5-deoxy-5-[4-(2-methylbutyryl)piperazin-1-yl]-1,4;3,6-dianhydro-
L-iditol 2-nitrate (compound 10) Example 5 except that 2-methylbutyric acid is used instead of valeric acid
Compound 10 was obtained as a hydrochloride by performing the same operation as above (yield 69%). Melting point: 234.0-234.5°C MS (EI) m/e: 343 (M + ) IR (K
Br) cm-1: 1651, 1634, 14
62, 1434, 1278, 1088, 857 NMR (DMSO-d6) δ (ppm): 5.
44 (1H, m), 5.28 (1H, m), 4.8
4 (1H, m), 2.8 ~ 4.7 (13H, m),
2.72 (1H, m), 1.54 (1H, 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) Example 5 except that 2-ethylbutyric acid is used instead of valeric acid
Compound 11 was obtained as a hydrochloride by performing the same operation as above (yield 75%). Melting point: 197.3-197.5°C MS (EI) m/e: 357 (M + ) IR (K
Br) cm-1: 1650, 1641, 14
61, 1436, 1278, 1229, 108
5,998,955,851NMR (DMSO-d
6) δ (ppm): 5.44 (1H, m),
5.30 (1H, m), 4.83 (1H, m), 2
．． 8 ~ 4.4 (13H, m), 2.63 (1H, m
), 1.25-1.65 (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) Compound 12 was obtained as a hydrochloride in the same manner as in Example 5, except that methoxyacetic acid was used instead of valeric acid (yield: 8
9%). Melting point: 126.4-127.5°C MS (EI) m/e: 331 (M + ) IR (K
Br) cm-1: 1657, 1643, 14
39, 1280, 1114, 958, 857 NMR (DMSO-d6) δ (ppm): 5.
44 (1H, m), 5.25 (1H, m), 4.8
3 (1H, m), 4.13 (2H, s), 3.30 (
3H, s), 2.75-4.40 (13H, m)

0
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 5.00g (48.0 mmol)
, 4.98 ml (52.8 mmol) of acetic anhydride, and 60 ml of pyridine were 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 (yield: 100%) of 2-acetoxybutyric acid.

[0061] 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 (K
Br) cm-1: 1735, 1660, 16
45, 1441, 1376, 1279, 124
3,959,856 NMR (DMSO-d6) δ (ppm): 5.
44 (1H, m), 5.15-5.35 (2H, m)
, 4.83 (1H, m), 2.80-4.35 (13
H, m), 2.05 (3H, s), 1.70 (2H
, m), 0.92 (3H, t, J=7.3Hz)

0
Example 14 5-deoxy-5-[4-(2-hydroxybutyryl)
piperazin-1-yl]-1,4;3,6-dianhydro-L-iditol 2-nitrate (compound 14
) 0.65 g of compound 13 obtained in Example 13 (1.
68 mmol), sodium hydroxide 67 mg (1.68
mmol), 10 ml of water and 10 ml of tetrahydrofuran
ml mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent;
Compound 14 was obtained by purification using chloroform/methanol (20/1).

[0063] Ethanol was added to this to dissolve it, and a saturated hydrochloric acid and ethyl acetate solution was added thereto. This was poured into cold diethyl ether and the precipitated crystals were filtered and dried to form compound 14.
0.55 g (yield 86%) of the hydrochloride of was obtained. Melting point: 60.7 ~ 72.7°C MS (EI) m/e: 345 (M + ) IR (K
Br) cm-1: 3415(br), 1641
, 1636, 1439, 1278, 1059,
988, 959, 858NMR (DMSO-d6
) δ (ppm): 5.44 (1H, m), 5
．． 27 (1H, m), 4.84 (1H, m), 2.
7 ~ 4.7 (15H, m), 1.35 ~ 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) Example 5 except that 2-chlorobutyric acid is used instead of valeric acid
Compound 15 was obtained as a hydrochloride by performing the same operation as above (yield 79%). Melting point: 179.7-179.8°C MS (EI) m/e: 363 (M + ) IR (K
Br) cm-1: 1651, 1646, 14
41, 1279, 1086, 957, 857 NMR (DMSO-d6) δ (ppm): 5.
44 (1H, m), 5.28 (1H, m), 4.9
0 (1H, m), 4.84 (1H, m), 2.6 ~
4.3 (13H, m), 1.65-2.10 (2H,
m), 0.96 (3H, t, J=7.3Hz)

00
65 Example 16 5-[4-(4-chlorobutyryl)piperazin-1-yl]-5-deoxy-1,4;3,6-dianhydro-
L-iditol 2-nitrate (compound 16) Example 5 except that 4-chlorobutyric acid is used instead of valeric acid
Compound 16 was obtained as a hydrochloride by performing the same operation as above (yield 75%). Melting point: 159.3-163.9°C MS (EI) m/e: 363 (M + ) IR (K
Br) cm-1: 1766, 1643, 14
38, 1278, 1086, 998, 959,
858 NMR (DMSO-d6) δ (ppm): 5.
44 (1H, m), 5.30 (1H, m), 4.8
4 (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) Example 5 except that 2-bromobutyric acid is used instead of valeric acid
Compound 17 was obtained as a hydrochloride by performing the same operation as above (yield: 82%). Melting point: 180.9-181.2°C MS (EI) m/e: 407 (M + ) IR (K
Br) cm-1: 1650, 1642, 14
40, 1278, 1086, 1000, 958
, 857 NMR (DMSO-d6) δ (ppm): 5.
44 (1H, m), 5.26 (1H, m), 4.9
0 (1H, m), 4.83 (1H, m), 2.7 ~
4.3 (13H, m), 1.70-2.10 (2H,
m), 0.96 (3H, t, J=7.3Hz)

00
67 Example 18 5-deoxy-5-(4-pivaloylpiperazine-1-
yl)-1,4;3,6-dianhydro-L-iditol 2-nitrate (Compound 18) The same procedure as in Example 5 was performed except that pivalic acid chloride was used instead of solution A to convert Compound 18 into hydrochloride. (yield 100%). Melting point: 204.5-204.7°C MS (EI) m/e: 343 (M + ) IR (K
Br) cm-1: 1641, 1631, 14
79, 1421, 1366, 1276, 119
1, 1087, 995, 955,855NMR (
DMSO-d6) δ (ppm): 5.44 (1
H, m), 5.30 (1H, m), 4.83 (1H
, m), 2.8 ~ 4.5 (13H, m), 1.2
0(9H,s)

Example 19 5-[4-(4-bromobutyryl)piperazin-1-yl]-5-deoxy-1,4;3,6-dianhydro-
L-iditol 2-nitrate (compound 19) Example 5 except that 4-bromobutyric acid is used instead of valeric acid
Compound 19 was obtained as a hydrochloride by performing the same operation as above (yield 53%). MS (EI) m/e: 407 (M + )IR (K
Br) cm-1: 1658, 1650, 16
29, 1576, 1447, 1370, 132
2, 1166, 1001, 878, 830,
754NMR (DMSO-d6) 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) instead of solution A The same operation as in Example 5 was performed except for using crotonic acid chloride to obtain Compound 20 as a hydrochloride (yield 91%). Melting point: 175.8-175.9°C MS (EI) m/e: 327 (M + ) IR (K
Br) cm-1: 1655, 1642, 14
32, 1278, 1232, 1082, 961
, 858 NMR (DMSO-d6) δ (ppm): 6.
74 (1H, m), 6.51 (1H, dd, J=14
．． 9Hz, 1.2Hz), 5.44 (1H, m),
5.28 (1H, m), 4.83 (1H, m), 2
．． 6 ~ 4.6 (13H, m), 1.85 (2H, d
d, 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 salt by carrying out 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 (K
Br) cm-1: 2916, 1660, 16
47, 1560, 1471, 1440, 141
7, 1379, 1279, 1234, 1213
, 1145, 1086, 1035, 999,
974, 858 NMR (DMSO-d6) δ (ppm): 5.
44 (1H, m), 5.27 (1H, m), 4.8
4 (1H, m), 4.71 (2H, t, J = 5.7H
z), 3.08 (2H, t, J=5.7Hz), 2
．． 7 ~ 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 2
2) Compound 22 was obtained as a hydrochloride salt by carrying out 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 (K
Br) cm-1: 1651, 1633, 14
27, 1374, 1285, 1241, 109
0, 1033, 965, 848 NMR (DMSO
-d6) δ (ppm): 5.44 (1H, m)
, 5.31 (1H, m), 4.84 (1H, m),
2.9 ~ 4.4 (13H, m), 2.27 (2H
,s), 1.28(9H,s)

Example 2
3 5-deoxy-5-[4-(2,2-dimethylbutyryl)piperazin-1-yl]-1,4;3,6-dianhydro-L-iditol 2-nitrate (compound 2
3) Compound 23 was obtained as a hydrochloride salt by carrying out the same operation as in Example 5 except that 2,2-dimethylbutyric acid was used instead of valeric acid (yield: 86%). Melting point: 197.2-198.0°C MS (EI) m/e: 357 (M + ) IR (K
Br) cm-1: 1641, 1636, 14
17, 1276, 1089, 994, 954,
854 NMR (DMSO-d 6 ) δ (ppm): 5.
44 (1H, m), 5.29 (1H, m), 4.8
3 (1H, m), 2.8 ~ 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 salt by carrying out 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 (K
Br) cm-1: 1658, 1640, 14
66, 1437, 1375, 1277, 119
9, 1067, 992, 956, 852NMR (
DMSO-d 6 ) δ (ppm): 5.43 (1
H, m), 5.26 (1H, m), 5.10 (1H
, q, J=6.4Hz), 4.84 (1H, m),
2.7 ~ 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 obtained by carrying out the same operation as in Example 5 except for using 2-methylcyclopropanecarboxylic acid in place of valeric acid.
was obtained as a hydrochloride (yield 81%). Melting point: 172.7-177.1 °C MS (EI) m/e: 341 (M + ) IR (K
Br) cm-1: 1641, 1637, 14
66, 1433, 1277, 1234, 108
1,988,958,853NMR(DMSO-d
6) δ (ppm): 5.44 (1H, m),
5.29 (1H, m), 4.84 (1H, m), 2
．． 7 ~ 4.6 (13H, m), 1.76 (1H, m
), 1.15 (1H, m), 1.07 (3H, d,
J=5.6Hz), 0.95 (1H, m), 0.5
8 (1H, m)

Example 26 5-(4-cyclopropylcarbonylpiperazine-1-
yl)-5-deoxy-1,4;3,6-dianhydro-L-iditol 2-nitrate (compound 26)
The same operation as in Example 5 was performed except that cyclopropanecarboxylic acid was used instead of valeric acid to obtain Compound 26 as a hydrochloride (yield: 85%). Melting point: 139.5-142.0°C MS (EI) m/e: 327 (M + ) IR (K
Br) cm-1: 1642, 1636, 14
62, 1436, 1381, 1280, 123
5, 1086, 957, 855 NMR (DMSO
-d 6 ) δ (ppm): 5.44 (1H, m)
, 5.29 (1H, m), 4.85 (1H, m),
2.8 ~ 4.6 (13H, m), 2.01 (1H
, m), 0.55-0.95 (4H, m)

Example 27 5-deoxy-5-[4-(2-oxopropionyl)
piperazin-1-yl]-1,4;3,6-dianhydro-L-iditol 2-nitrate (compound 27
) Example 5 except that pyruvic acid is used instead of valeric acid.
Compound 27 was obtained as a hydrochloride by performing the same operation as above (yield 42%). Melting point: 106.0-106.5°C MS (EI) m/e: 329 (M + ) IR (K
Br) cm-1: 1792, 1651, 16
42, 1439, 1280, 1243, 110
3,957,854 NMR (DMSO-d6) δ (ppm): 5.
43 (1H, m), 5.24 (1H, m), 4.8
3 (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) The same procedure as in Example 5 was performed except that vinyl acetic acid was used instead of valeric acid, and Compound 28 was dissolved in hydrochloric acid. Obtained as a salt (42% yield). Melting point: 93.0 to 93.5°C MS (EI) m/e: 327 (M + )IR (K
Br) cm-1: 1640, 1634, 14
40, 1278, 1087, 1002, 961
, 854 NMR (DMSO-d 6 ) δ (ppm): 5.
89 (1H, m), 5.44 (1H, m), 5.2
7 (1H, m), 5.14 (1H, m), 5.08 (
1H, m), 4.84 (1H, m), 3.21 (2
H, d, J = 6.6 Hz), 2.6 ~ 4.7 (13
H, m)

Example 29 5-deoxy-5-(4-methacryloylpiperazine-
1-yl)-1,4;3,6-dianhydro-L-iditol 2-nitrate (compound 29) 0.39 ml (4.63 mmol) methacrylic acid, 2.75 ml (19.85 mmol) triethylamine and 2 -16ml mixed solvent of butanol and acetonitrile (5/1)
The mixture was stirred at 0°C, a solution of 0.60 ml (4.63 mmol) of isobutyl chloroformate in a mixed solvent of 2-butanol and acetonitrile (5/1) was added dropwise, and the mixture was further stirred at 0°C for 5 minutes. . To this was added 1.00 g (3.86 mmol) of compound b obtained in Reference Example 2, and
The mixture was stirred at ℃ for 20 minutes. After concentration under reduced pressure, 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 2.
I got a 9.

Chloroform was added to the solution to dissolve it, and a saturated hydrochloric acid and ethyl acetate solution was added thereto. This was poured into cold diethyl ether, the precipitated crystals were filtered and dried, and compound 2 was obtained.
0.66 g (yield 47%) of hydrochloride of No. 9 was obtained. Melting point: 172.5-173.5°C MS (EI) m/e: 327 (M + ) IR (K
Br) cm-1: 1645, 1635, 14
62, 1433, 1375, 1277, 120
6, 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 salt by carrying out 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 (K
Br) cm-1: 1642, 1633, 14
60, 1427, 1280, 1087, 957
, 854 NMR (DMSO-d 6 ) δ (ppm): 5.
67 (1H, q, J = 6.8Hz), 5.44 (1H
, m), 5.29 (1H, m), 4.84 (1H,
m), 2.7 ~ 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 ) Compound 31 was obtained as a hydrochloride salt by carrying out the same operation as in Example 29, except that 3,3-dimethylacrylic acid was used instead of methacrylic acid (yield: 68%). Melting point: 222.0-225.0°C MS (EI) m/e: 341 (M + ) IR (K
Br) cm-1: 1641, 1633, 14
60, 1427, 1376, 1281, 124
5, 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 (K
Br) cm-1: 2960, 2415, 16
99, 1641, 1468, 1428, 128
2, 1250, 1153, 1089, 963,
853NMR (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 ~ 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 (90.1 mmol), 84.8 g (984.4 mmol) of piperazine, and n-
A mixture of 240 ml of butanol was heated under reflux for 36 hours. After concentration under reduced pressure, the residue was subjected to azeotropy with toluene several times to remove as much piperazine as possible, thereby obtaining the methanesulfonate of compound a as a crude product.

The above crude product is Diaion SP207
(manufactured by Mitsubishi Kasei Corporation) (elution solvent: water to 30% methanol aqueous solution) was subjected to chromatography, azeotropically distilled with isopropyl alcohol, and then crystallized from ethyl acetate to obtain compound a with good purity. NMR (DMSO-d6
) δ (ppm): 5.35 (1H, 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 methanesulfonic acid salt of compound a obtained in the same manner as in Reference Example 1.
A solution was prepared by dropping 5.6 ml of concentrated sulfuric acid while cooling (hereinafter referred to as solution B).

Urea 2.47g (41.1 mmol)
was dissolved in 55.6 ml of concentrated sulfuric acid.
The mixture was added dropwise to 37 ml of fuming nitric acid (86%) while cooling to .degree. Next, solution B was added dropwise thereto at -15°C over 30 minutes to 1 hour, and the mixture was further stirred at the same temperature for 2 hours. After the stirring was completed, the reaction mixture was gradually poured into 300 ml of water with stirring. While cooling, add sodium hydroxide
A mixture of 120 g (3.00 mol) and 370 ml of water was gradually added to neutralize the mixture. This solution was extracted with chloroform 5 to 10 times, 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 (yield: 38%). IR (KBr) cm-1: 3420 (br),
1634, 1278

Reference example 3 1-t-butoxycarbonyl nipecotic acid (compound c)
Sodium hydroxide 1.70g (42.5 mmol)
, 5.00 g (38.7 mmol) of nipecotic acid was added to a mixture of 40 ml of water and 30 ml of t-butanol, and the mixture was stirred and dissolved at room temperature. 8.45 g (38.7 mmol) of di-t-butyl dicarbonate was added to this solution, and the mixture was further stirred at room temperature for 1 hour and 30 minutes. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH to 4, extraction was performed with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 8.87 g of compound c (yield: 88
%)Obtained.

[0088] Formulation example 1 Tablet Tablets having the following composition are prepared by a conventional method.

Compound 1
50mg lactose
150mg potato starch
75mg polyvinyl alcohol 7.5mg magnesium stearate 2.5m
g

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

Compound 1
50mg lactose
750mg

Formulation Example 3
Syrup A syrup having the following composition is prepared by a conventional method. Compound 1
50mg refined white sugar
75 mg p-hydroxybenzoic acid ethyl ester 100 mg p-hydroxybenzoic acid propyl ester 25 mg Strappy flavor 0.25 cc Add water to make a total volume of 100 cc.

Formulation Example 4 Capsules By the usual method,
A capsule having the following composition is prepared.

Compound 1
50mg lactose
500 mg magnesium stearate 12.5 mg This is mixed and filled into gelatin capsules.

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

Compound 1
20mg sodium chloride
Add water to 45 mg to make a total volume of 5 ml (1 ampoule). The water was previously distilled and sterilized in an autoclave.

[0097]

According to the present invention, a novel nitrate ester of deoxy-1,4;3,6-dianhydro-hexitol having a vasodilating effect is provided.

Claims (1)

[Claims] Claim 1: Formula [Formula 1] {In the formula, R is hydrogen, unsubstituted or lower alkyl-substituted cycloalkyl, lower alkenyl, lower alkoxy, lower alkanoyl, piperidyl or [Formula 2] [In the formula, m and n are The same or different numbers represent integers of 0 to 3, and X, Y and Z are the same or different and represent hydrogen,
a hexitol derivative or a pharmacologically acceptable salt thereof;