WO1992017462A1

WO1992017462A1 - N-cyanoimino heterocyclic compound

Info

Publication number: WO1992017462A1
Application number: PCT/JP1992/000412
Authority: WO
Inventors: Toshihisa Ogawa; Tomomi Ota; Minoru Taguchi; Misa Yoshimura; Katsuo Hatayama
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1991-04-04
Filing date: 1992-04-03
Publication date: 1992-10-15
Also published as: JP3136609B2

Abstract

Object: a novel type of a compound having a vasodilatory action is provided. Constitution: an N-cyanoimino heterocyclic compound represented by general formula (I) and a salt thereof, wherein X represents oxygen or sulfur; and A represents C1 to C5 alkylene which may be substituted by nitroxy.

Description

Specification

N-cyano mino heterocyclic compound

Technical field

The present invention relates to an N-cyanino heterocyclic compound having a vasodilatory effect. Background art

Conventionally, vasodilators such as nitroglycerin, isosorbide dinitrate, diltiazem, verapamil, diphedivine, and nicorandil are known, but none of the compounds of the present invention have a similar structure.

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

Disclosure of the invention

The present invention uses the formula — A— ON 0 _{2 τ} ,

(In the formula, X represents an oxygen atom or a sulfur atom, and Α represents an alkylene group having 1 to 5 carbon atoms substituted with an alkylene group having 1 to 5 carbon atoms or a nitroxy group.): And a salt thereof.

In the present invention, an alkylene group having 1 to 5 carbon atoms refers to a direct group such as a methylene group, an ethylene group, a trimethylene group, a 1-methylethylene group, a 2-methylethylene group, a tetramethylene group, a benthamethylene group, and the like. It refers to a chain or branched chain. In addition, the alkylene group having 1 to 5 carbon atoms substituted by a nitroxy group means that an alkylene group having 1 to 5 carbon atoms is replaced with a 1 ^^ dinitrooxy group at any position. What is

The compound of formula (I) has two types of geometric isomers, anti-type and syn-type, and the present invention includes both anti-type, syn-type, and mixtures thereof. The compound of (I> has the formula

Wherein X is as defined above, and a compound represented by the formula:

. ) Can be produced by reacting the compound represented by the formula (1) in an organic solvent in the presence of a base.

Here, the halogen atom means a chlorine atom, a bromine atom or an iodine atom. Examples of bases include sodium hydroxide, hydroxide hydroxide, potassium carbonate and other salts, dimethylamine, getylamine, disopropylamine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, Amines such as morpholine, organic metals such as n-butyllithium and lithium diisopropylamide, alcohols such as sodium methoxide and sodium ethoxide, and sodium hydride can be used. As organic solvents, methanol, ethanol, dichloromethane, chloroform, N, N-dimethylformamide, tetrahydrofuran, dioxane, benzene, toluene and the like can be used. The reaction temperature is 5 to: L 0 C, and the reaction time is 2 to 5 hours.

The compound of formula (I) thus obtained can be converted into a hydrochloride, a nitrate, a P-toluenesulfonate or the like by a conventional method, if necessary.

The compounds of the present invention can be administered orally or parenterally in conventional dosage forms. Dosage forms include tablets, capsules, injections, ointments, tablets and the like, all of which can be manufactured by conventional methods. When used as an antianginal agent or an antihypertensive agent for humans, for example, the dosage varies depending on the condition, administration route and the like, but is usually 20 to Lmg per day.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples. Example 1 2-(: N-cyanomino) -1-3-nitroxetylthiazolidy'C compound 1)

Dissolve 6.35 g (0.05 mol) of N-cyano minothiazolidine and 8.50 g of 2-2 trooxoshetchylebamide (0.05 mol C) in 30 ml of N, N-dimethylformamide and then 8.28 g of lithium carbonate ( 0.06 mol), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and extracted with dichloromethane. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 1), and the obtained crude crystals were recrystallized from a mixed solution of tanol and ether to give the title compound 1 1.80 g were obtained.

m.p. 88 ~ 90 ° C

^ -NMRC CDC lg, 200 MHz) ό "p p m;

3.43 (2H, t, J = 8Hz), 3.81 (2H, t, J = 5Hz),

4.00 C 2 H, t, J = 8 Hz),. 78 (2H, t, J = 5 Hz)

The following compounds were obtained in substantially the same manner as in Example 1 except that the corresponding compound of the formula (1) was used in place of 2-nitrooxhetylpromide in Example 1 described above.

2- (N-cyanomino) 1-3-2 N-cyclopropylthiazolidine (compound 2)

m. p. 30-32. C (Dichloromethane-isopropyl ether; the solvent in parentheses after the melting point indicates recrystallization from that solvent.)

^ -NMRC CDC lg, 200 MHz) p p m;

2.08 (2H, m), 3.47 (2H, t, J = 8Hz),

3.58 (2H, t, J = 6 Hz), 3.96 (2H, t, J = 8 Hz),

4.55 C 2 H, t, J = 6 Hz)

2— _ (N-cyanomino) -1 3— (41-2 trooxy-1-n-butyl) thiazoli C compound 3) _{NMR (CD C 1 3, 2} 0 OMH z) ^ ppm;

1.79 C 4 H, m), 3.44 (2 H, t, J = 8 Hz),

3.52 [2H, t, J = 5 Hz), 3.92C2H, t, J = 8Hz),

4.5 3 (2 H, t, J = 5 Hz)

2- (N-cyanoamino) -1-3-[— 2-nitrooxyprol) thiazolidine m.p. 125-127. C (Methanol-Jetylether)

_{1H-NMR (DMSO- d 6,} 2 0 0 MHz) ^ ppm;

1.31 (3H, d, J = 6Hz), 3.49 (2H, t, J = 8Hz),

3.72C2H, m), 3.98 (2H, m), 5.39 (lH, m)

2- (N: cyanamino) -1- (2,3-dinitrooxypropyl) thiazolidine

m.p. 122-124. C (dichloromethane-diethyl ether)

^ -NMRC CDC lg, 200 MHz) δ p pm;

3 4 6 C 2 H, t, J = 6 Hz)

3. 73 C 1 H d d, J = 14 Hz 8 Hz),

3.88 C 1 H d d, J = 1 H z 5 Hz),

4.01 C 2 H t, J = 6 H z),

4.5 5 C 1 H d d, J = 12 Hz 5 Hz),

4.95 C 1 Hdd, J = 12 Hz 4 Hz), 5.55 (lH, m) Example 22- (N-cyano-imino) -l 3-nitroxoxyloxy Lysine (compound)

To 20 ml of N, N-dimethylformamide was added 1.32 g (0.055 mol) of sodium hydride at room temperature under a nitrogen stream, and the mixture was stirred for 30 minutes. N-Cyanoyminoxazolidine (5.56 g C, 0.05 mol) dissolved in 10 ml of N-dimethylformamide was added dropwise, and the mixture was further stirred for 1 hour. In this solution After dropping 2-2 trooxoshethyl bromide (8.50 g C, 0.05 mol), the mixture was further stirred at the same temperature for 5 hours. Water was added to the reaction solution, and extracted with dichloromethane. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 1), and the obtained crude crystal was recrystallized from a mixture of dichloromethane and dihydrobutyl ether. 3.20 g of the title compound were obtained.

m. p. 86-88. C

_{½ - NMR (CDC l 3,} 200MHz) ^ ppm;

3.73 C 2H, t, J = 5 Hz), 3.91 (2H, t, J = 8 Hz),

4.68 (2H, t, J = 8Hz), 4.70 (2H, t, J = 5Hz)

In the above Example 2, the following compound was obtained in substantially the same manner as in Example 2, except that the corresponding compound of the formula (BI) was used in place of 2-2-troxoxetyl bromide.

2- (N-cyanomino) -1-3-toxoxyproviroxaxolidine (compound 5)

m. p. 72-74 ° C (dichloromethane-ethyl ether)

^ -NMRC CDC lg, 200 MHz) ^ p p m;

2.09 C 2 H, m), 3.49 (2H, t, J = 5 Hz),

3.82 (2H, t, J = 8Hz), 4.56 (2H, t, J = 5Hz),

4.66 (2H, t, J = 8Hz)

2- (N-cyanomino) -1 3- (4-Nitrooxy-1-n-butyoxazolidin (Compound 6)

^ -NMRC CDC lg, 200 MHz) S p pm;

1.77 C 4 H, m), 3.40 (2H, t, J = 5 Hz),

3.80 (2H, t, J = 8Hz), 4.53 (2H, t, J = 5Hz),

4.64 (2H, t, J = 8Hz) Reference Example 1 N-cyano minothiazolidine

To 500 ml of ethanol was added 146.24 g (1 mol) of S, S'-dimethyl N-cyanodithioiminocarbonate and 7.15 g (1 mol) of 2-aminoethanethiol for 3 hours. The mixture was heated under reflux with stirring. After the completion of the reaction, the resultant was cooled to room temperature, and the precipitated crystals were removed. The obtained crystals were washed with ethanol and dried to obtain 85.25 g of the title compound.

m.p. 1 56.3-1 56.9 ° C

_{½- NMR (DMS O- d 6,} 2 0 0 MH z) S ppm;

3.36 (lH, br.s), 3.56C2H, t, J = 6Hz),

3.79 C 2 H, t, J = 6 Hz) Reference Example 2 N-Cyanoy-minoxoxazolidine

To ethanol 500 ml, S, S'-dimethyl N-cyanodithioiminocarbonate 146.24 g (lmol) and 2-aminoethanoylyl 61.08 g (lmol) were added. The mixture was heated under reflux for 3 hours with stirring. After the completion of the reaction, the resultant was cooled to room temperature, and the precipitated crystals were removed. The obtained crystals were washed with ether and dried to obtain 72.35 g of the title compound.

mp 1 1 2.0—1 13.3 ^e C

½-Band R (DMS O-d _fi , 200 MHz) ppm;

3.38 (lH, br.s), 3.70 (2H, t, J = 8Hz),

4.64 C 2 H, t, J = 8 Hz) Industrial applicability

The compound of the present invention exhibits a strong vasodilatory effect, has a long lasting property, and has a good absorbability, and is therefore useful as an antianginal agent or an antihypertensive agent.

Hereinafter, the effect of the compound of the present invention will be described with reference to a fiber example. Test Example 1: Vasodilator Fiber:]

N. Miyata et al. [Gen. Pharmac., Vol. 21, No. 5, pp. 665-669 (1990)], the following tests were conducted. Male dipper rats (weighing 250-400 g) were subjected to the test as 3-4 animals per group. After removing the thoracic aorta from this rat, the adipose tissue attached to the removed blood vessels was removed, and a spiral strip of 2-3 nm x 20 nm was prepared. A gas mixture of 95% oxygen and 5% carbon dioxide was aerated 37. A nutrient tank containing 5 ml of Krebs-Henseleit¾ (KH solution) of C was suspended and fixed under a load of 1 g. The KH solution was changed every 20 to 30 minutes and left for 60 to 90 minutes to stabilize the sample. The composition (mM) of the KH solution is as follows.

Na C 1 1 18.0, KC 1 4.7, NaHC03 25.0, C a C 12 1.8, Na H2PO4 1.2, Mg S O4 1.2, dextrose 11.0

Become helical in the rat aorta and Noruebinefurin 10 one ⁷ M or blow static Grange emissions F _2Tit known as compounds that have a vasoconstrictor action in the nutrient tank which is suspended to a concentration of 10 ^_6 M So added. Thereafter, a sample (the compound of the present invention and nicorandil for comparison) was dissolved in dimethyl sulfoxide, and calo was added to the solution to give a concentration of 10 to ¹⁶ M. Norepinephrine or brostaglandin F. The effect of suppressing vasoconstriction was examined. The contraction force was guided to a strain pressure amplifier (AP-621G, Nihon Kohden) using an FD big up (TB-612T, Nihon Kohden) and measured isometrically.

The results are shown as shrinkage suppression rates and are summarized in Table 1.

Claims

The scope of the claims

( 1 set

(In the formula, X represents an oxygen atom or a sulfur atom, and A represents an alkylene group having 1 to 5 carbon atoms substituted with an alkylene group having 1 to 5 carbon atoms or a nitroxy group;) An N-cyano amino heterocyclic compound represented by the formula: