JPS59196879A - Novel 1,3,4-thiadiazole derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (A is group shown by the formula II or formula III; X is O, or S; R is -SH, -S- lower alkyl or -NH- lower alkyl; m is 2, or 3; n is 0, or 1). EXAMPLE:2-N-{3-[3-( 1-Piperidinylmethyl )phenoxy]propyl}amino-5-mercapto-1,3, 4-thiadiazole. USE:An inhibitor for secretion of acid in the stomach. PREPARATION:A corresponding bithiourea or thiocarbamyldithiocarbazinic acid ester as a starting raw material is condensed through ring closure to give the desired substance (R' is as shown for R or -NH- phenyl).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 1,3,4-thiadiazole derivative represented by the following and a gastric acid secretion inhibitor containing the same as an active ingredient.

The compound of formula (1) is a novel substance that was synthesized for the first time by the present inventors and found to be useful as a gastric acid secretion suppressant having excellent histamine H2 receptor antagonism.

Also, the compound of formula (1) is:

In the structural formula, the following tautomerism occurs at the thiadiazole site, and therefore, these tautomers are naturally included in the present invention.

Conventionally, compounds with histamine H2 receptor antagonism are:
Many drugs are known, including cimetidine and ranitidine, but they generally have many side effects.

Since the effect of suppressing gastric acid secretion is temporary, there are problems such as the large dosage and frequency of administration, and they are not always satisfactory.

The present inventors synthesized a large number of compounds and conducted intensive research to solve these problems.

A new compound that exhibits remarkable effects on suppressing gastric acid secretion (
We succeeded in creating 1).

The compound (1) of the present invention can be easily produced by appropriately combining known methods for producing similar compounds.

For example, as a typical manufacturing method for "unexploded" compounds.

The corresponding videoureas or thiocarbamyldithiocarbazates are used as starting materials.

A method of ring-closing condensation can be mentioned.

This method can be shown by the reaction formula below.

A (CI4z)n -X -(CH2)m-NC80NH2NH-C-R' (However, in formula 2, A, X, R, n
and m have the same meaning as above, R' is the same as R or -
Indicates NH-phenyl. ) In order to specifically explain the manufacturing method of the following two compounds of the present invention,
First, the manufacturing method of the starting materials will be shown as a reference example.

Reference example 1 N-3-[3-(]-piperidinylmethyl)phenoxy]propyl-N'-meter-viteaurea N-3-(3-(1-piperidinylmethyl)phenoxy]propyl-isothiocyanate 2 .037 and 4-methyl-3-thiosemicarbazide 0.745' were stirred in ethanol 2O- for 3 days at room temperature, then the reaction solution was concentrated to dryness under reduced pressure, and ethyl ether was added to the residue and collected by filtration. death,
Obtained written knowledge of 2.06r.

Reference Example 2 To-3-[3-(1-piperidinylmethyl)phenoxy]propyl-N/yenylubithiourea N-3-[3-(1-piperidinylmethyl)phenoxy]propyl-isothiocyanate 2.03 ml of 4-phenyl-3-y-osemicarbazide 1171 was added to 2 liters of ethanol, stirred at 50° C. for 8 hours, and then concentrated to dryness under reduced pressure. The residue was purified using a silica gel column (eluent: 3 thiemethanol and chloroborum) to obtain the substance listed in title 2, 2.007.

Reference Example 3 N-3-(3-(1-piperidinylmethyl)phenoxy]propyl-thiocarbamyldithiocarbazic acid methyl ester N-3-[3-(]-piperidinylmethyl)phenoxy]propylinch 450■ and methyldithiocarbazinate 189Iny were added to 51nL of tetrahydrofuran, and after stirring at room temperature for 20 hours, the solution was evaporated to dryness under reduced pressure, and the residue was diluted with chloroform-ethyl ether (1:1). Solution U was added and collected by filtration to obtain 592m9 of the title compound.

Reference Example 4 ゜N-2-[(5-dimethylaminomethyl-2-furanyl)methylthio]ethyl-N'-meter-viteone-a corresponds to the same manner as in Reference Example 1. Obtained from isoteothiae and thiosemicarbazide.

Reference Example 5°N-2-[(5-dimethylaminomethyl-2-furanyl)methylthio]ethyl-N'-phenylbitiocrea corresponds to the same manner as in Reference Example 2. Obtained from isothiocyanate and thiosemicarbazide.

Next, the method for producing the compound of the present invention by ring-closing condensation of the above starting materials will be specifically explained using production examples.

Production Example 1 2-N-(3-C3-(1-piperidinylmethyl)phenoxy]propyl)amino-5-mercap) -1,3
,4-thiadiazole and 2-N-(3-[3-(1-
piperidinylmethyl)phenoxy]propyl)amino-
5-Methylamino-1,3,4-thiadiazole Obtained by the procedure of Reference Example 1. i'l-3-C3-(1-
Vipe9 di(methyl)phenoxy]propyl=N'-methyl-bithiourea 1.55r.

3N-Hanawa 1151nl and heated at 95-100°C for 3 hours.

After heating and stirring, the mixture was concentrated to dryness under reduced pressure. A small amount of water was added to the residual solution to dissolve it, and while cooling with water, potassium carbonate was added until the pH reached 9, extracted with chloroform, the extract was dried over magnesium sulfate, and then concentrated to dryness at 2M pressure F'.

Using a silica gel column, remove the candy-like residue from methanol
When eluting with chloroform containing 5%, 2% is present in the first two fractions.
-N-(3-43-(1-piperidinylmethyl)phenoxy]propyl)amino-5-mercapto-1,3,4
4111!9 (yield 29.0%) of -thiadiazole was obtained.

IR to N (CL) CL3) δ: 1.10 to 1.76 (61-f, m) 1.9
7 (2f-1, t, J=6Hz)2.
2C1~2.73 (4H, m)3, ], IJ~3.
65 (4H, m )4.00 (2H,t
, J=6I-Iz)6.66~7.57 (4H,
m ) MS m/z 364 (M+) Continue elution to obtain 2-1tl-(3-[3-(1-piperidinylmethyl)phenoxy]propyl)amino-5
-Methylamino-1,3,4-thiadiazole 456■
(yield 32.4%).

NMR(CDCl2) δ2 1.1 0~1.8 0 (6
H, m) 1.9 (J~2.63 (6H, m)
2.93 (3H, s) 3゜26~3.73 (4Pl, m) 4, (J
2 (2H, t, J=6Hz) 4.70~
6.20 (2H,s, disappeared in heavy water)+3cNMR(
4so-C16) δ: 23.895 (L), 25.
421 (L) 28.415 (1,30,646
(q)40, gBO(t), 53.778
(t)62.644 (t), 64.875
(L) 112.663 (d), 114
．． 659 (d) 120°826 (d),
128.928 (d) 139.904 (s)
, 158.4.53 (S)159.457
(s), 160.3:31 (S)MS
mlz 36] M" Production Example 2 200 m9 of N-3-[3-(1-piperidinylmethyl)phenoxy]propyl-N'-phenyrubithiourea obtained by the method of Reference Example 2 was added to 10 ml of 2N-hydrochloric acid. In addition,
After heating and stirring at 100 to 105°C for 1 hour, it was condensed to dryness under reduced pressure, water was added to the remaining candy-like substance to dissolve it, and then potassium carbonate was added under water cooling until the pH reached 9, and i! I'l
: Extracted with acid ethyl ester, dried the extract over magnesium sulfate, and concentrated to dryness under reduced pressure to obtain a candy-like substance.

This was purified using a silica gel column (common solution: chloroform containing 50% of methanol) 1- and 2-N-(3-[3
-(1-piperinylmethyl)phenoxylopropyl)
118 mg (yield: 742) of amino-5-mercapto-1,3,4-thiadiazole was obtained.

Production Example 3 200 drops of N-2-[(5-dimethylaminomethyl-2-furanyl)methylthio]ethyl-N'-metelubithymeurea obtained in Reference Example 4.

The mixture was added to 2N hydrochloric acid solution, heated and stirred at 95 to 100°C for 1 hour, and then concentrated to dryness under reduced pressure. The residual candy-like substance was dissolved in a small amount of water, and under water cooling, potassium carbonate was added until the pH reached 9. After extraction with chloroborm, the extract was dried over magnesium sulfate.

The dried extract was concentrated to dryness under reduced pressure, and the residual candy-like substance was purified and eluted with a silica gel column (eluent: chloroform containing 5 g of methanol).
-N-(2-[(5-dimethylaminomethyl-2-furanyl)notylthio]ethyl)amino-5-mercap)
-1,3,4-thiadiazole 79m9 (yield 43.4
φ).

N M, J < (CD C13) δ: 2.
40 (6H,s)2.5U~3.00 (
2H,,m)310~3.83 (6)-L,m)6
．． 00-6.30 (2H, m) M S mlz 330 (M+) Continue elution to obtain 2-N-(2-[(5-dimethylaminomethyl-2-furanyl)methylthio]ethyl)amino-5- Methylamino~1. :3.4-Thiadiazole 49I (yield: 27.3) was obtained.

NMR(CD(23)δ: 2.27(61(,S)2.
60~3.10 (5H, m) 327~3.62
(41(,m)373 (2H,s) 6.15 (2H,s) M Srn/z 327 (B4+) Production Example 4 Obtained according to Reference Example 5. N-2-[(5-dimethylaminomethyl -2-Furanyl)methylthio]ethyl-N'-phenylbithiourea 1°85 ?Total 2H hydrochloric acid 307
After heating and stirring at 100 to 105°C for 1 hour, the mixture was concentrated to dryness under reduced pressure. Add water to the residual candy-like substance to dissolve it, add water-cooled solution, and potassium carbonate until the pH reaches 9.
Extracted with chloroform. The extract was dried over magnesium sulfate and then concentrated to dryness under reduced pressure to obtain a candy-like substance.

This candy-like substance was purified using a silica gel column (eluent: chloroform containing 5 g of methanol).

2-N-(2-[(5-dimethylaminomethyl-2-furanyl)methylthio]ethyl)amino-5-mercapto-1,3,4-thiadiazole 419 μ (yield 29.1
N-3-(3-(1-
490η
The reaction mixture was added to 15 ml of propatool and heated under reflux and stirred for about 6 hours, and then the reaction mixture was concentrated to dryness under reduced pressure using Fla. The residual candy-like substance was purified by silica column chromatography (eluent: chloroform containing 4 parts of methanol) and recrystallized from benzene-hexitine to obtain colorless needle-like crystals of 2-N-(3-[ 3-
(1-Piperidinylmethyl)phenoxy]propyl)amino-5-methylthio-1,3,4-thiadiazole 342~ (yield 753) was obtained. River, p. 106
~1075℃N&LR(CJ)Cl3) δ:1.25~1.90 (6H, m)2.16
(2H,,t, J=6Hz)2.3:3
~2.80 (7H, m)'3.35~3.80
(4H,rn)4.15 (214,t,
J=6)1z)6.10~6.71J (IH,S
, broad and disappeared by adding static water) 6.70 to 7.50 (4i-(,rn)M S
ITI/2 378 (M+) Next, the excellent histamine 11□ receptor antagonism and gastric acid secretion suppressing effect of the compound of the present invention will be explained using test examples.

Experimental Example 1 Histamine H2 Receptor Antagonism Test After the head of a Hartley guinea pig (male: 300 to 350 f) was bruised and blood was exsanguinated, the heart was removed.

Oxygen-saturated Rock Lin detaches the atrium in one fluid;
Attach a thread to both ends. Contains lock linker liquid maintained at 37°C, mixed gas (0295%, CO25
The atrium was suspended in a Magnus tube (30 m) with a tension of 500 m using threads attached to both ends. A strain gauge (manufactured by Nikifukou'tun) measures the contraction of the atria.
From TB-612'L'')i2.

Also, measure the output using a tachometer (Nihon Kohden" 11 + A
Heart rate was measured via a T-600G).

Histamine (used in the form of dihydrochloride, same hereafter) was added at doses of 1 x 10"8 M to I
Histamine was added cumulatively into the Magnus tube at 10-'M 7h degrees and a histamine dose-response curve was obtained. After rinsing the intramedullary tube several times and stabilizing the atrium for 30 minutes, the above procedure was repeated again to obtain a histamine dose-response curve.

After washing the inside of the Magnus tube several times and stabilizing the atrium for 30 minutes, the test compound was added to the Magnus tube and 10 minutes later, a dose-response curve of histamine in the presence of the test compound was obtained.

From the second histamine dose-response curve and the third histamine dose-response curve in the presence of the test compound, J, M'
1- Van Rossum's method (Arch, in
t, Pb-armacodyn, 143.2
99.1963), calculate the PAz value of the test compound (the negative number of the logarithm of the molar concentration of the test compound required to double the histamine concentration in Magnus Sparrow to cause a certain reaction). did.

The results are shown in Table 1.'3-6 Table 1 However, in Table 9, H233, -ru.

1-i2-33: 2-N-(3-C-3-(1-piperidinylmethyl)propyl)amino-5
-Methylamino-1,3,4,-thiadiazole ■1°-37: 2-N -[3-[3-(1-piperidinylmethyl)phenoxy]propyl) amino-5-mercapto-1,3, 4-Thiasiazole H2-41: 2-N-(3-C3-(1-piperidinylmethyl)phenogysi]propyl) Amino-5-methylthio-1,3,4-thiadiazole Test Example 2. Gastric acid secretion suppression effect test J) Onryu male rats (210-230 y)
After fasting for 48 hours, the abdomen was opened under ether anesthesia, and the pylorus was ligated.

Immediately after administering the test drug into the duodenum, tji4
The abdomen was closed.

Six hours after drug administration, the stomach was removed using the same anesthetic knife and gastric juice was collected.

The gastric juice was centrifuged, and the liquid volume, acidity, and pepsin activity of the supernatant were measured.

Ite 0 for acidity high heel. pH 7 with IN NaOH
, (J), and the amount of acid discharged per hour was calculated based on the amount of each liquid.

Pepsin activity was measured using the Anson method (J, gen, Ph
ysiol, 21.79°1938).

This test was carried out using the compounds of the present invention, 11□-33 and l-42-3.
7, with cimetidine as the comparative drug.

A weight loss test was conducted using two doses of 6.7 kg/3 liters of 9.201B and 60 cm/chest, respectively.

In the test of 142-33, the test compound had a stripe of 0.
After dissolving in INHCt, pH 6-7 with 0.1NINaOH
Made by Nini^j.

In the H2-37 test, the test compound (05% CM
To C-Na! ¥! , and used it. The test results for H2-33 are shown in Table 2, and the test results for H2-37 are shown in Table 3.

However, the results in Table 1 are expressed as the average value of 5 animals per group.

Table 2 Table 3

Claims (1)

[Claims] (1) A 1,3,4-f adiazole derivative represented by the general formula (1) % formula % (1). A 1.3°4-thiadiazole derivative according to claim 1. A q-acid secretion inhibitor comprising a 1,3,4-thiadiazole derivative represented by the following as an active ingredient. (4) The gastric acid secretion inhibitor according to claim 3, which contains a 1,3,4-thiadiazole derivative represented by general formula (II) as an active ingredient.