JPS62234064A - N-cyanoisothiourea derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (A is aromatic ring containing one N or O, e.g. pyridine, furan or indole; n is 1 or 2). EXAMPLE:N-Cyano-S-methyl-N'-(2-pyridylmethyl)isothiourea. USE:An antiulcer agent. PREPARATION:A dimethyl N-cyanodithioiminocarbonate expressed by formula II is reacted with an amine expressed by formula III in a solvent, e.g. alcohol, ether, pyridine, etc., preferably at room temperature to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to N-cyanoisothiourea derivatives useful as anti-ulcer agents.

[Conventional technology]

Various drugs have already been developed as therapeutic agents for peptic ulcers such as gastric ulcers and duodenal ulcers.

Among them, cimetidine is widely used clinically because it blocks histamine H2 receptors in gastric mucosal parietal cells and strongly and continuously suppresses gastric acid secretion.

[Problem that the invention seeks to solve]

However, cimetidine has a gastric mucosal protective effect.
Because it promotes a decrease in the amount of GE, it often causes flare-up/recurrence of peptic ulcer after discontinuation of administration.

In addition, side effects include a decrease in neutrophils, psychiatric symptoms, headaches, and gynecomastia, so it cannot necessarily be said to be a safe drug.

Therefore, the present inventors conducted intensive research to develop safer and more effective anti-IS drugs. As a result, they discovered a new compound that achieves the intended purpose and completed the present invention.

Means for Solving Problem c] The novel compound of the present invention, an N-cyanoisothiourea derivative, is represented by the following general formula.

(In the formula, A represents an aromatic ring containing a nitrogen atom or one oxygen atom, and n represents 1 or 2.) As A in the general formula (1), a pyridine ring, an indole ring, a furan ring, etc. can be mentioned.

The bonding position may be any of the 2-position, 3-position, and 4-position in the case of a pyridine ring, and the 3-position is preferable in the case of an indole ring, and the 2-position is preferable in the case of a furan ring.

The compound (1) of the present invention can be produced by reacting dimethyl N-cyanodithioiminocarbonate [■] with an amine compound (I[+]) as shown in the following reaction formula.

[11] [I] In the formula, A
and n have the same meanings as above. ) Suitable solvents used in the reaction are alcohols such as methanol, ethanol, propatool or ethylene glycol, ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or ethylene glycol diethyl ether, pyridine, acetonitrile, etc. It is.

The reaction temperature may be from 0° C. to about the boiling point of the solvent; however, if the heating conditions are too strong, a di-substituted product may be produced as a by-product, resulting in a decrease in yield.

Therefore, it is preferable to continue the reaction at about room temperature until compound (n) disappears.

In addition, the molar ratio of amine [■]/compound (n) is 1 to
About 1.5 is preferable.

After completion of the reaction, treatment can be carried out according to conventional methods, and the target product can be easily isolated and purified.

Example I N-cyano-5-methyl-N'-(2-pyridylmethyl)isothioureadimethyl N-cyanodithioiminocarbonate)16.
2 g (0,111 mol) was added to 30 ml of acetonitrile, and while stirring, 12 g of 2-(aminomethyl)pyridine was added.
After dropping 60 ml of an acetonitrile solution of (0,111 mol), the mixture was stirred in the chamber for 12 hours, and the precipitated crystals were collected by filtration. The obtained crystals were sequentially washed with a small amount of acetonitrile and ether, and dried to obtain 19.5 g (yield: 85.2%) of colorless prism crystals with a melting point of 116-117°C.

Elemental analysis values C, H,. Theoretical value (χ) for N and S: C, 52, 4L L 4.89
N, 27.16 Actual value (χ): C, 52,361+
, 4.71 N, 27.21■ Rshi Hue, °
'cm-': 3250 (Nll),
2170 (CN) NMR (DMSOdh, δ)
: 2.72 (3H.

s, 5-CHs), 4.65 (2H, s, CHz
N).

MS m/z: 206 (M”) Example 2 N-cyano-8-methyl-N'-(3-pyridylmethyl)isothioureadimethyl N-cyanodithioiminocarbonate 2'2
g (0.15 mol) was added to 40 ml of acetonitrile, and while stirring, 16.2 g of 3-(aminomethyl)pyridine was added.
(0.15 mol) was added dropwise. After the dropwise addition, the mixture was stirred with room salt for 6 hours, and the precipitated crystals were collected by filtration.

The obtained crystals were sequentially washed with small amounts of acetonitrile and ether, and dried to obtain 28 g (yield: 91.5%) of colorless prism crystals with a melting point of 155-156°C.

Elemental analysis value Cq Ht. Theoretical value (χ) for N and S:
C, 52, 41H, 4, 89N, 27.16 Actual value (χ”): C, 52, 30H, 4, 90N, 27.
23IRvQgQ"cm-': 3200 (II
I), 2200 (CM) NMR (DMSOdb,
δ): 2.61 (3H.

s, S CH3) , 4.51 (2H, S, CH
zN).

MS m/z: 206 (M') Example 3 N-cyano-8-methyl-N'-(4-pyridylmethyl)isothioureadimethyl N-cyanodithioiminocarbonate) 22 g
(0.15 mol) was added to 40 ml of a7tonitrile,
While stirring, 16.2 g of 4-(aminomethyl)pyridine (
80 ml of an acetonitrile solution of 0.15 mol) were added dropwise. After stirring at room temperature for 12 hours, the precipitated crystals were collected by filtration, washed, and dried to give colorless prism crystals 26 with a melting point of 167-168°C.
．． 5g (yield 86.6%) was obtained.

Elemental analysis value CqH+. Theoretical value (χ) for N and S: C, 52,411+, 4.89
N, 27.16 Actual value (χ): C, 52,3011
,4,78N, 27.23I Rv Qgp"c
m-': 3270 (NH) + 2150 (C
N) NMR (DMSO-d6.δ): 2.70
(3H.

s, S CH3), 4.54 (2H, s, CH
zN).

MS m/z: 2Q6(M”) Example 4 N-cyano-8-methyl-N-furfurylisothioureadimethyl N-cyanodithioiminocarbonate 14.
6g (0.1 mol) of acetonitrile solution'/e130
ml, under stirring, add 9.7 g of furfurylamine (0,
50 mff of acetonitrile sine (1 mol) was added dropwise. After stirring at room temperature for 12 hours, the precipitated crystals were collected by filtration, washed, and dried to obtain colorless scales 1 with a melting point of 134-135°C.
7.5 g (yield 89.7%) was obtained.

Elemental analysis value c, H, N3O3 theoretical value (χ): C, 49, 22H, 4, 65N, 2
152 actual measurement value (χ): C, 49, 08H, 4°71
N, 21.43IRv company j, "cm-': 3
250 (NH), 2180 (CN) NMR (DMS
O-d,, δ): 2. 61 (3H.

s, S CH3), 4.48 (2H, s, CHz
N).

MS m/z: 195 (M”) Example 5 N-cyano-5-methyl-N'-(2-(pyridine-2
-yl)ethyl]isothioureadimethyl N-cyanodithioiminocarbonate 11.7 g (0.08 mol) was added to a solution of 2-(2
-aminoethyl)pyridine 9.76 g (0.08 mol) in acetonitrile solution 4 Qmj! was dripped. After stirring at room temperature for 12 hours, the precipitated crystals were collected by filtration, washed, and dried to yield 13.5 g of a colorless prism product with a melting point of 97-98°C (
A yield of 76.7% was obtained.

Elemental analysis value Theoretical value (χ) as C1゜H+□N4S:
C, 54, 52H, 5, 49N, 25.43 Actual value (χ): C, 54, 39) 1.5.51 N, 2
5.28IRvmgA"cm-': 3280
(Nll) + 2170 (CN) NMR (DMSO-
d&, δ): 2. 59 (3H.

s, 5-CHx), 3. 69 (2H,S,
CFTxN).

Ms m/z: 220 (M") Example 6 N-cyano-8-methyl-N'~[2-(indole-
A solution of 8.76 g (0.06 mol) of 3-yl)ethylisothioureadimethyl (N-cyanodithioiminocarbonate) in 30 mA of acetonitrile was added with stirring under stirring.
9.6 g (0.06 mol) of 2-aminoethyl)indole dissolved in acetonitrile was added dropwise. After stirring at room temperature for 5 hours, the precipitated crystals were collected by filtration, washed, and dried. Colorless powder with a melting point of 169-170°C 13.5
g (yield 87.2%) was obtained.

Elemental analysis value C13H1aNa S Theoretical value (χ)
: C,60,4411,5,46N, 21.69 Actual value (χ): C,60,25I+, 5.61 N
, 21.55 [R, HAOL Cm: 340
0 (NH), 3240 (N11) 2160 (CN) NMR (DMSO-d,, δ) 1.57 (3H
.

s, S CHff) , 3.62 (2H,5,C1
hN).

MS m/z: 258 (M”) [Action and effect] The compound (1) of the present invention exhibits excellent anti-ulcer activity and has low toxicity. Therefore, it is useful as a treatment or prophylaxis for gastric ulcers and duodenal ulcers. .

The compound of the present invention is preferably administered orally in the form of a solid preparation such as a tablet, powder, or capsule.

The dosage varies depending on age, body weight, symptoms, etc., but is usually increased or decreased as appropriate within the range of about 300 to 1000 mg per day for adults.

(Pharmacological experiment: Suppressive effect on gastric juice secretion) SD male and female rats were fasted for 24 hours, and then under ether anesthesia, a small incision was made along the midline of part 111 of the rat, the abdomen was opened, and the pylorus was ligated. After 3 hours, the gastric juice accumulated in the stomach was collected and centrifuged at 8000 rpm for 10 minutes. After measuring the volume of the supernatant, a portion of it was taken and its acidity was measured (neutralization titration).

The test drug is 0.5% carboxymethyl cellulose! 200 mg/Kg of the prepared solution was administered into the duodenum at the time of pylorus ligation.

The gastric juice secretion suppressive effect (%) was determined as a significant difference from the control group (vehicle alone administered).

The results are listed in Table 1.

(Margin) Table 1 Test drug Suppression of gastric juice secretion (no examples) Effect (%) (Toxicity experiment) The test drug was suspended in 0.5% carboxymethyl cellulose in DDY-type mice weighing 20-25 g. Orally administered. Based on the cumulative mortality rate up to 7 days after administration, Lichfield-Wilcoxon
xon) method, 50% lethality Ji (LDsa) was calculated.

The results are shown in Table 2.

Table 2 Test drug: LDS.

(Example Arashi) (mg/Kg) 1 >1000 5 >1000

Claims (5)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A represents an aromatic ring containing one nitrogen atom or oxygen atom, and n represents 1 or 2.) N- Cyanoisothiourea derivative. (2) The compound according to claim 1, wherein in the general formula, A represents a pyridine ring. (3) The compound according to claim 1, wherein in the general formula, A represents a furan ring. (4) The compound according to claim 1, wherein in the general formula, A represents an indole ring. (5) The compound according to claim 2, wherein in the general formula, A is a 3-pyridyl group and n is 1.