JP2000226378A - N-cyanoimino heterocyclic compound and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an N-cyanoimino heterocyclic compound having an excellent vasodilation action useful as a vasodilator. SOLUTION: This compound is expressed by formula I (X is O or S; Z is a 1-6C alkyl, phenyl; A is a 1-6C alkyl, pyridyl, phenyl or the like), for example. 3-(1-acetoxy-3-chlorobenzyl)-2-(N-cyanoimino)thiazolidine. The compound of formula I is obtained by reacting a compound of the formula ACHO (e.g.; 3- chlorobenzaldehyde or the like) with a compound of formula II [e.g.; 3- acryl-2-(N-cyanoimino)thiazolidine or the like] under the presence an organic lithium derivative (e.g.; lithiumdiisopropylamide or the like) in a solvent such as tetrahydrofuran or the like, preferably at -80 deg.C to the boiling point of the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to N-cyanoimino heterocyclic compounds, and more particularly to N-cyanoimino heterocyclic compounds useful as vasodilators.

[0002]

2. Description of the Related Art Conventionally, vasodilators such as nitroglycerin, isosorbide dinitrate, diltiazem, nifedipine and nicorandil are known, but none of the compounds of the present invention have a similar structure.

[0003]

It is an object of the present invention to provide a new type of vasodilator having excellent vasodilator action.

[0004]

As a result of intensive studies, the present inventors have found that certain N-cyanoimino heterocyclic compounds have a vasodilatory effect, and that the compounds can be produced by a new synthetic method. And completed the present invention.

That is, the present invention provides

[0006]

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Wherein X represents an oxygen atom or a sulfur atom, Z represents an alkyl group having 1 to 6 carbon atoms or a phenyl group, and A represents a linear or branched chain having 1 to 6 carbon atoms. Alkyl group, pyridyl group, phenyl group, or an alkyl group having 1 to 6 carbon atoms, a halogen atom,
A phenyl group substituted with one or two cyano groups, nitro groups, trifluoromethyl groups, carbamoyl groups, carboxyl groups, alkoxycarbonyl groups having 1 to 6 carbon atoms, phenoxy groups or alkylsulfonyl groups; And an N-cyanoimino heterocyclic compound represented by the formula:

[0008]

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[In the formula, X represents an oxygen atom or a sulfur atom, and Z represents an alkyl group having 1 to 6 carbon atoms or a phenyl group. To the compound of formula ACHO
[In the formula, A is a linear or branched alkyl group having 1 to 6 carbon atoms, a pyridyl group, a phenyl group, or an alkyl group having 1 to 6 carbon atoms, a halogen atom, a cyano group, a nitro group, A trifluoromethyl group, a carbamoyl group, a carboxyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms, a phenoxy group or a phenyl group substituted by one or two alkylsulfonyl groups. The method for producing an N-cyanoimino heterocyclic compound according to claim 1, wherein the compound represented by the formula (1) is reacted.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention can be produced as follows using a compound prepared by the method of C. Iwata et al. (Heterocycls., 27, 323, 1988) as a starting material.

That is, the equation

[0012]

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An aldehyde represented by the general formula ACHO (where A is as defined above) is added to a compound of the formula (wherein Z and X are as described above), an inorganic base (potassium tert-butoxide), and an organic lithium derivative ( n-butyllithium, lithium diisopropylamide), sodium hydride, etc.
A transfer reaction following the addition reaction occurs, and the compound of the present invention can be obtained.

The reaction can be carried out at a reaction temperature of -80 ° C to the boiling point of the solvent, and the reaction solvent is tetrahydrofuran,
Dimethylformamide, hexamethylphosphoramide and the like can be used.

The compound thus obtained is obtained in the form of crystals or oil, and can be purified, if necessary, by operations such as column chromatography and recrystallization.

In the present invention, a salt means a physiologically usable inorganic acid (hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid, etc.) or an organic acid (maleic acid, fumaric acid, tartaric acid, citric acid, oxalic acid, etc.). Acid, benzoic acid, etc.) according to a conventional method, in addition to a salt with an acid, as well as a hydrate.

The compound of the present invention can be administered orally or parenterally, and the dose can be administered in consideration of the age, sex, body weight, etc. of the patient.

[0018]

The present invention will be described in more detail with reference to the following examples.

Example 1 3- (1-acetoxy-3-chlorobenzyl) -2-
(N-cyanoimino) thiazolidine Under an argon atmosphere, a solution of 3-acyl-2- (N-cyanoimino) thiazolidine (4.23 g, 0.025 mol) in anhydrous tetrahydrofuran (30 mL) at -78 ° C was added with hexamethylphosphoric triamide (4.48 g). , 0.025 mol), lithium diisopropylamide
(26.7 g, 0.025 mol, 10 wt.% In hexane) was added dropwise and stirred for 10 minutes. Subsequently, at the same temperature, 3-chlorobenzaldehyde (3.51
g, 0.025 mol) in anhydrous tetrahydrofuran (30 mL), and the mixture was stirred at the same temperature for 2 hours. After the reaction solution was extracted with chloroform, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (2.3 g, 30%) as white crystals.

[0020] _{^{1 H NMR (200MHz, CDCl 3}} ) 2.26 (3H, s), 3.26-3.
62 (3H, m), 3.81-4.00 (1H, m), 7.21-7.49 (4H, m), 7.66 (1H,
s). MS (ESI): m / z 332 [M + Na] ⁺ mp 129-130 ° C.

Example 2 3- (1-acetoxy-2,3-dichlorobenzyl) -2- (N-sia
(Noimino) thiazolidine The title compound was obtained in the same manner as in Example 1 except that 3-chlorobenzaldehyde was replaced with 2,3-dichlorobenzaldehyde.
3%).

¹ H NMR (200 MHz, CDCl ₃ ) 2.23 (3H, s), 3.27-
3.55 (3H, m), 3.88-3.94 (1H, m), 7.25-7.44 (3H, m), 7.55 (1H
H, dd, J = 8.2 Hz, 7.71 (1H, s). MS (EI): m / z 344 (M ⁺ ) mp 154-155 ° C.

Example 3 3- (1-acetoxy-3-trifluoromethylbenzyl) -2-
(N-cyanoimino) thiazolidine The title compound was obtained in the same manner as in Example 1 except that 3-chlorobenzaldehyde was replaced with 3-trifluoromethylbenzaldehyde (38%).

¹ H NMR (200 MHz, DMSO-d ₆ ) 2.32 (3H, s), 3.03
(2H, t, J = 7Hz), 3.87 (2H, t, J = 7Hz), 7.38-7.49 (2H, m), 7.64
(1H, s), 7.66-7.75 (2H, m), 7.85-7.95 (2H, m). MS (EI): m / z 343 (M ⁺ ) mp 137-139 ° C.

Example 4 3- (1-acetoxy-4-methoxycarbonylbenzyl) -2-
(N-cyanoimino) thiazolidine The title compound was obtained in the same manner as in Example 1 except that 3-chlorobenzaldehyde was replaced with 4-methoxycarbonylbenzaldehyde (46%).

¹ H NMR (200 MHz, CDCl ₃ ) 2.26 (3H, s), 3.22-
3.57 (3H, m), 3.81-3.97 (1H, m), 3.94 (3H, s), 7.45 (2H, d, J =
8.5 Hz), 8.10 (2H, d, J = 8.5 Hz). MS (EI): m / z 333 (M ⁺ ) mp 151-153 ° C.

Example 5 3- (1-acetoxy-3-phenoxybenzyl) -2- (N-sia
(Noimino) thiazolidine The title compound was obtained in the same manner as in Example 1 except that 3-chlorobenzaldehyde was replaced with 3-phenoxybenzaldehyde.
%).

¹ H NMR (200 MHz, CDCl ₃ ) 2.19 (3H, s), 3.32
(2H, m), 3.55 (1H, m), 3.88 (1H, m), 6.92-7.45 (9H, m), 7.65
(1H, s) MS (ESI): m / z 390 [M + Na] ⁺ mp 53-55 ° C.

Example 6 3- (1-acetoxypropyl) -2- (N-cyanoimino) thia
Zolidine The title compound was obtained in the same manner as in Example 1 except that 3-chlorobenzaldehyde was replaced with propylaldehyde (66%).

¹ H NMR (200 MHz, CDCl ₃ ) 0.94 (3 H, t, J = 7.5 H
z), 1.82 (2H, m), 2.12 (3H, s), 3.42 (2H, t, J = 6Hz), 3.92 (2H,
t, J = 6 Hz), 6.48 (1 H, t, J = 7.5 Hz). MS (EI): m / z 227 (M ⁺ ) mp 82-84 ° C.

Example 7 3- (1-acetoxypentyl) -2- (N-cyanoimino) thia
Zolidine The title compound was obtained in the same manner as in Example 1 except that 3-chlorobenzaldehyde was replaced with pentylaldehyde (62%).

¹ H NMR (200 MHz, CDCl ₃ ) 0.91 (3 H, t, J = 6 Hz),
1.14-1.49 (4H, m), 1.61-1.97 (2H, m), 2.09 (3H, s), 3.39 (2
H, t, J = 7 Hz), 3.90 (2 H, t, J = 7 Hz), 6.54 (1 H, t, J = 7 Hz) MS (FAB): m / z 256 (M + H) ⁺ .

Example 8 3- (1-acetoxy-isopentyl) -2- (N-cyanoimi
G) Thiazolidine The title compound was obtained in the same manner as in Example 1 except that 3-chlorobenzaldehyde was replaced with isopentylaldehyde (60%).

¹ H NMR (200 MHz, CDCl ₃ ) 0.96 (3 H, d, J = 3.5 H
z), 1.00 (3H, d, J = 3.5Hz), 1.57 (1H, m), 1.69 (2H, m), 3.42 (3
H, t, J = 6Hz), 3.92 (3H, t, J = 6Hz). MS (ESI): m / z 278 [M + Na] ⁺ mp 86-87 ° C.

Example 9 3- (1-acetoxy-2,3-dichlorobenzyl) -2- (N-sia
Noimino) oxazolidine 3-acyl-2- (N-cyanoimino) oxazolidine (3.82 g, 0.
025 mol) and 2,3-dichlorobenzaldehyde (4.38 g, 0.
025 mol) in the same manner as in Example 1 to give 2.81 g (34
%).

¹ H NMR (200 MHz, CDCl ₃ ) 2.23 (3H, s), 3.29
(1H, m), 3.79 (1H, m), 4.55 (1H, m), 4.64 (1H, m), 7.24-7.62
(3H, m), 7.52 (1H, s). MS (EI): m / z 328 (M ⁺ ) mp 162-163 ° C.

Example 10 3- (1-benzoyloxy-2,3-dichlorobenzyl) -2- (N-
(Cyanoimino) thiazolidine 3-benzoyl-2- (N-cyanoimino) thiazolidine (5.7
In the same manner as in Example 1, 6.33 g (62%) of the title compound was obtained from 8 g (0.025 mol) and 2,3-dichlorobenzaldehyde (4.38 g, 0.025 mol).

¹ H NMR (200 MHz, DMSO-d ₆ ) 3.55 (3H, m), 4.14
(1H, m), 7.47-8.23 (8H, m), 7.85 (1H, s) .MS (ESI): m / z 430
[M + Na] ⁺ mp 206-207 ° C.

[0039]

The compounds of the present invention have excellent vasodilatory effects and are therefore useful as vasodilators. Therefore, it has become possible to provide a new vasodilator.

Claims (2)

[Claims] (1) Formula (1) [Wherein, X represents an oxygen atom or a sulfur atom, Z represents an alkyl group having 1 to 6 carbon atoms or a phenyl group,
A represents a linear or branched alkyl group having 1 to 6 carbon atoms, a pyridyl group, a phenyl group, or an alkyl group having 1 to 6 carbon atoms, a halogen atom, a cyano group, a nitro group, and trifluoromethyl. A phenyl group substituted by one or two groups with a carbamoyl group, a carboxyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms, a phenoxy group or an alkylsulfonyl group. N-
Cyanoimino heterocyclic compounds and salts thereof. 2. The formula: [In the formula, X represents an oxygen atom or a sulfur atom, and Z represents an alkyl group having 1 to 6 carbon atoms or a phenyl group. A compound represented by the formula ACHO wherein A is a linear or branched alkyl group having 1 to 6 carbon atoms, a pyridyl group, a phenyl group, or an alkyl group having 1 to 6 carbon atoms. A phenyl group substituted by one or two halogen atoms, cyano group, nitro group, trifluoromethyl group, carbamoyl group, carboxyl group, alkoxycarbonyl group having 1 to 6 carbon atoms, phenoxy group or alkylsulfonyl group. . The method for producing an N-cyanoimino heterocyclic compound according to claim 1, wherein the compound represented by the formula (1) is reacted.