JPS58213768A - Furan derivatives and their addition salts, manufacture, drug composition, use for therapy - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is useful for clinical purposes such as the treatment of duodenal dysfunction and all symptoms caused by or accompanied by acid secretion.
(A novel furan derivative with therapeutically interesting applications,
Processes for making them and their physiologically acceptable salts;
It relates to pharmaceutical compositions containing these derivatives and/or their salts, and to the therapeutic use of these compositions.

According to the present invention, there are provided compounds having the general formula ζ in which R is a straight-chain or branched alkylene group having from 1 to 6 carbon atoms, and physiologically acceptable salts thereof. Ru.

Physiologically acceptable salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, or with organic acids such as mono- and dicarboxylic acids such as acetic acid, oxalic acid, malic acid, fumaric acid, etc. included.

The above compounds and their salts can be administered orally or parenterally.

In pharmaceutical compositions, these compounds are generally accompanied by suitable excipients. The dosage form for oral administration may be a capsule, a tablet, or a syrup.

The daily dose for oral administration is 100 Tn of active ingredient in the form of unit doses containing 20 to 2 oom9. Or x, 2gc
be.

Parenteral administration may be by injection at intervals or by continuous infusion. The injection solution contains 10 to 1001n of active ingredients.
y/mε.

The active ingredient Fi may be accompanied by other therapeutic agents depending on the specific condition of the disease being treated.

All compounds of formula (I) are tautomeric and clonic is intended to include all tautomeric forms. Optical isomers may also exist, and clonics are intended to include all optical diastereomers and optical enantiomers.

A preferred method for preparing the compounds of the present invention is to react a compound of the following formula with a hydroxyalkylamine of the general formula) (R-Nlj2Gll) (wherein R has the meaning given above) in a suitable solvent. It consists of making 6.

The chemical reactions that occur in this method can be abbreviated as follows.

CH, (1) slightly less than the 1:1 molar ratio of the stoichiometric reaction (5-1
5 H) It is recommended to use excess hydroxyalkylamine in a suitable solvent such as methanol, ingropanol, chloroform, etc. or mixtures thereof.

The process is carried out at temperatures between 0°C and the boiling point of the solvent used, with a range of 40-7°C (-1°C being recommended).

The product obtained is isolated from the reaction medium in the usual manner and treated with a solvent such as Impropatol, A7).
It can be purified by crystallization in IJL, ethyl acetate, etc., or mixtures thereof.

In another method for producing compounds of general formula (1), compounds of general formula It is reacted with a compound of the formula:

Another method for preparing compounds of the general formula (I) is to react a compound of the above formula with a compound of the general formula in which R has the meaning given above.

The substance of formula (IV) can be prepared by converting the corresponding hydroxyalkylamine ([1) into 1,1-bis(methylthio)-2 by a conventional method.
- Can be prepared by reaction with ditroethane.

The compound of general formula (I) has the following formula: The compound with the general formula %formula% A compound or general formula (wherein X is a halogen atom) It can also be produced by reacting with a compound of

Similarly, the compound of the general formula (I) is a compound of the general formula (in which Y is preferably a \rogen atom, and may be -OH or an acyl group); metal salts, such as AIL Cu
.

It can also be produced by reacting with Zn or PLI salt.

Finally, compounds of general formula (I) can also be prepared by reacting nitromethane with a compound of general formula (wherein is a group to be eliminated). Examples of leaving groups include formula-8R
', -OR', etc., in which R/ is a straight or branched alkyl chain having 1 to 6 carbon atoms, optionally substituted by a phenol residue.

Some detailed examples are provided below to illustrate, but not to limit, the objects of the present invention.

Example 1 α) 12.2 g (0.2 mol) of 2-aminoethano-y were dissolved in N-(2-[:((
5-(:(dimethylamino)methyl]-2-furanyl)
Methyl]thio]ethyl]-1-methylthio-2-nitro-1-ethenamine 3! 1.1.9 (0.1 mol)
solution over a period of 1 hour.

After the addition, the mixture was kept at 35° C. for 5 hours, the solvent was evaporated off under vacuum, water 501Re was added and then extracted with chloroform (2×50111). The organic extract was dried, treated with activated carbon, filtered, and concentrated to dryness to give the following formula (%) thyl]-2-furanyl)methyl]thio]ethyl]-N'
28 g of -(2-hydroxyethyl)-2-nitro-1,1-ethenediamine was obtained as a yellow oil, which was recrystallized from isopropyl alcohol, soluble in methanol and chloroform, melting point 108-109°C, 23
A crystalline white solid 25, SF, which exhibits a maximum absorption in the ultraviolet region of 0 to 320 yn was obtained. The IR spectrum showed among the most specific and significant absorption bands:

: 3400.3150.2950.2830.279
0.1620.1560°1460, 1405.138
5.1350.1220.1180.1130.106
0°1050, 1010.980.940.900.8
20.800.760 cm-”.

Elemental analysis' Cukb4N+048 (Molecular lid: 3
44,44).

1 [Calculated value: C: 488ch; H near, 02%; N: 1
626%; S: So, 60%.

Actual measurement: C: 48.7; f (near, 1; N:
17.1ch; S: 9.18ch.

b>N-[2-[[(5-((dimethylamino)methyl]-2-ranyl)methyl]thio]ethyl]-N'
A sample of -(2-hydroxyethyl)-2-nitro-1.1-ethenediamine 20 & (58 mmol) was dissolved in 13 ynl of ethanol (99-100%) and 58 mmol of hydrochloric acid was added.
25 mA of isopropyl alcohol containing mmol was added slowly. The mixture was left under stirring overnight, and a solid precipitate was collected, washed with ethanol, dried, and N-
(2-(((5-[(dimethylamino)methyl]-2-
18 g of furanyl)methyl]thio]ethyl]-N'-(2-hydroxyethyl)-2-nitro-1.1-ethencyamine hydrochloride was dissolved in water and methanol with a melting point of 11.
Obtained in the form of white crystals with a temperature of 9-122°C.

The IR spectrum showed among the most specific and significant absorption bands: 3600-2500.1610゜1570-1460.1410.1340.1225,
1040, 1005, 970゜930, 79 too, 750
and 695cTII.

Elemental analysis” *4HtaC7N404S (molecular weight:
380.89) Calculated value: C: 44.14ch; H: 6
．． 61 inches; N: 14.7 inches; S: BAlTo.

Actual measurement: C: 44.31 inches; H: 6.8 inches; N
:14/$chi;S:86chi.

Example 2 2-Amine Ethanol 78117 (1.3 mol) was gradually added to 1.1 in toluene 500 $11/2 over half an hour.
-His(methylthio)-2-nitroethene 95g (0,
57 mol) at 80°C. After the addition, the mixture was kept at 80 °C for half an hour, cooled to room temperature, and the resulting solid was separated, washed with chloroform (1001 × 2), dried, and N,N'-bis(2-hydroxy ethyl)-2
-107 g of ditro-1,1-ethenediamine (yield: 97
-98 t) was obtained in the form of yellow crystals with a melting point of 145-146°C.

A sample of the above solid recrystallized from water and methanol exhibited the following physical and chemical properties.

White crystals, melting point 148-149°C, slightly soluble in methanol and ethanol, soluble in water. The methanol solution exhibits an absorption maximum at 320 fLm.

The IR spectrum (KBr tablet) showed among the specific and significant absorption bands:

3300, 3000.2920.1620.1580.
1480.1400.1350°1290, 1260.
1220.1060.1010.870.825.76
0°730, 695 and 660cIrL.

Elemental analysis: CaHtsNsO+ (molecular weight: 19
119).

Calculated value: C: 37.69%; H: 6.85%;
N: 21.97 chi.

Actual value: C: 37.50%; H: 6.79%;
N: 21.82%.

Example 3 The following compounds were similarly prepared from the corresponding hydroxyalkylamines by the method described in Example 2.

α)(:)-N,N'-bis(2-hydroxypropyl)-2-nitro-1-ethenediamine Melting point: 129-131°C 1, R,: 3250.2950.2920.1610
．． 1570.1460°1400, 1260.1210
．． 1120.1080.1000゜930, 910.8
40.750.690 cm-'.

Elemental analysis' CaH+yNs04 (molecule t: 219
．． 24).

Calculated value: C: 43.83%; H near, 81ch; N: 19
．． 17%.

Actual value: C: 45.90%; I■ Near, 78%; N:
19.14%.

b) N,N'-bis(3-hydroxypropyl)-2-
Nitro-1,1-ethenediamine melting point: 94-96°C.

1. R: 3300,2940.2850,160
5,1570°1460.1400.1340,125
0,1210°1190.1050,1030,100
0,940°740s (i90 Cl11-'.

Elemental analysis' CaH17NaC included (Molecular lit 2
19.24).

Calculated value: C: 43.83%; H near, 81 minutes; N:
19.17%.

Actual value: C: 43.78%; H near, 88%; N
:19.05 yen.

c) (2-N,N'-bis[(1-hydroxymethyl)propyl]-2-nitro-1,1-ethenediamine Melting point: 165-136°C 1, R,: 3250.2950.2860,160
0,1580°1420.1350.1240.120
(1,1150°1110, H140,1000,94
0,920°840.760,690,630 m-
1゜Elemental analysis' Cl0H21N304 (molecule t
247.30).

Measurement value: C: 48.5-7 chi; H: 8.56 rice; N
:17.00%.

Actual value: C: 48.49%; H: 8.63 axe; N:
16.92%.

d) (-)-N, N'-bis[(1-hydroxymethyl)propyl]-2-nitro 1.1-ethenediamine Melting point: 133-165°C ■, R,: 3250, 2950, 2930.286
0,1600°1580.1460,1410,134
5.1245°1200.1'1150,1005.9
95,940°910.750,690,630
.

Elemental analysis' Cl0H21N304 (molecule i
247.50).

Calculated value: C248.57ch; H:8.5<Sch; N:
17.00%.

Actual value: C: 4B, 629b; H: 8.50min; N
:17.13 Thiro Example 4 21.5 g (0.1 mol) of 2-[[(5-dimethylamino.)methy)v-2-furanyl]methyl]thio]ethanamine was added slowly over 1 hour to N in 1007 of water,
'N'Nbi(2-hydroxyethyl)-2-nitro-
1,1-ethenediamine 21.96,! ii'(0,
115 mol) at 80° C. in a round bottom flask equipped with a stirring and reflux system. After the addition, the resulting mixture was kept under reflux for 3 hours. It was then cooled and treated with chloroform (200rne + 2X
10 Qml). The organic extract was evaporated to dryness, and the resulting oil was subjected to thin layer chromatography (chloroform: meth, 7-l: ammonia, 75/25/1
) was washed with toluene remaining in the soil showing a single spot of R,7'0.42.

The residue was dissolved in inopropyl alcohol, treated with activated carbon, filtered and concentrated to dryness to give N-[2-[((5-[(
dimethylamino)methyl2-furanyl)methyl]thio]ethyl')-N'-(2-hydroxyethyl)-2
20 g of nitrolff-1,1-ethenedimine' were obtained as a yellow oil. This was crystallized from inopropyl alcohol to give a white solid 17.9 with the same properties as the product prepared according to section 2, Example 1a).

Example 5 The following compounds were similarly prepared according to the methods described in Examples 1 and 4.

a) (±1-N-'(2-[:[(5-(:(dimethylamino)methyl2-furanyl)methyl]thio]ethyl')-N'-(2-hydroxypropyl)-2-nitro -1,1-ethenediamine hydrochloride Melting point: 119-1
21°C0 1, R,: 3700-2500.1610,157
0,1460°1400.1350,1230,113
0,1010°975.935,800,755,69
5 cut.

Elemental analysis: C,,H2,N,O,5-HCl (molecule 1
394.92).

Calculated value: C: 4562chi; ) I: 6.89%; N
H14, 19th; 8: 8.12%.

Actual value: C: 45.49 饅; H: 6.7B%; N
: 14.23chi; S: 8.18%.

b) N-[2-[[(5-[(dimethylamino)methy#
]-2-';'jranyl)methyl]thio]ethyl]-N
'-(3-hydroxypropyl)-2-nitro 1.1
-ethenediamine hydrochloride Melting point: 280-82°C 1, R: 370 (+-2500, 1605, 15
70,1460°140 (1,1350,1225,1
120,1005°970.930,790,750,
690 cIIL-Desk elemental analysis: C,, H26N40
4S.HCl (molecular weight 394.92).

it #: (Direct: C245<S2%; H:6.
89%; N: 14.19%; S: 8.12%.

Actual measurements: C: 45.45%; H: 671%; N:
14.10%; S near, 98 yen.

C) (1-N-[2-([(5-[(dimethylamino)methylio2-furanyl)methyl]thio]ethyl]'
-N'-C('1-hydroxymethyl)propyl]
-2-2) l"1',]-ethenediamine hydrochloride melting point = 98.~102°.

LR,: 3700-2500.1 (i05.15
75.1470°1410.136i), 1305.1
240,1200°1135.1045.1tH5,9
80,945°870.800,760,700,63
0,600an"-foot cumulative 1'l" C+n:HzaN
404S-HCl (molecular ffl 408.95).

Calculated value: c; 4Zoo%; ) [Near, 15%; N:
13.70%; S near, f14'le.

Actual 611J value: C: 4Z15%; n: 702%; N
: 13°61cm; S near, 77cm.

d) (-)-N-[:2-([:(s-[(dimethylamino)methyl]-2-furanyl)methyl]thio]ethyl]-N'-((1-hydroxymethyl)propyl 1) −
2-nitro 1.1-edenediamine hydrochloride Melting point: 99-103°C0 T, R,: 3700-2450.1605,157
5,1470°1410.1360.1305.124
0.1200°1135.1045.1015,980
,945°870,soO,760,700,630,
600C1i-1゜Elemental analysis: C16H2sN404
S-HCl (molecular weight 408.95).

Calculated value: C: 47.00 excellent; H near, 15%; N:
13.70 inches; S near, 84 inches.

Actual positioning: C: 47.15%; H near, 02chi; N:
13.61ch; S near, 77%.

Example 6 2-([[(5-dimethylamino)methyl-2-furanyl]methyl]thio]-ethanean 21.5,!i/
(0.1 mol) gradually over 1 hour with 60 nt5 of water.
N-(hydroxyethyl)-1-methylthio-2-
It was added to a solution of 17.8 g (0.1 mol) of nitro-1-ethenedimole. After the addition, the mixture was held at 68°C for 8 hours. This was extracted with chloroform (2x51:HJ) and the organic extract was dried over anhydrous magnesium sulfate, treated with activated carbon, filtered and concentrated to dryness.
[(5-[(dimethylamino)methyl]-2-furanyl)methyl]thio]ethyl)-N'-(2-hydroxyethyl)-2-nitro-1,1-ethenediamine 269
was obtained as a yellow oil. This was crystallized from isopropyl alcohol to give a crystalline white solid 21 with the same properties as the product prepared according to Example 10).

Example 7 A solution of 2.24,9 (40 mmol) of potassium hydroxide in 15 m of water was dissolved in 5-[(dimethylamino)
Methyl]-2-furanmethanethiol oxale) (
1:1) 2.61,110 mmol) and N-(2-
chloroethyl)-N'-(2-hydroxyethyl)-2
-Nitro-1,1-ethenediamine2. (19,9(1
0 mmol) at 45°C under nitrogen atmosphere with stirring.

The solution was stirred at 45° C. for 2% and at room temperature for 15 hours. Air was bubbled through the mixture for 15 minutes, and it was mixed with ether (2X
15 m/) and the aqueous fraction was evaporated under vacuum.

This was filtered with 7 Qtxl of tetrahydrofuran, excess of anhydrous sodium carbonate, and C1 added to the activated charcoal residue, and the organic phase was separated by decantation and concentrated in vacuo to give 1.91 kg of a yellow oil. This was crystallized from inglovir alcohol-ethyl ether, Example 1α)
N-(2-[
[(5-C(dimethylamino)methyl]-2-furanyl)methyl]thio]ethyl)-N'-(2-hydroxyethyl)-2-nitro1.1-diamine 1.69
I got it.

Example 8 15 mj of ethyl ether and excess anhydrous sodium carbonate were dissolved in 0.131 mj of 5-[(dimethylamine)methyl]-2-furanmethanethiol oxalate (1:1) in water.
0.5 mmol), 0.05 g of sodium dithionite and 0.15 g of anhydrous sodium carbonate.

The mixture was filtered once and the liquid was evaporated under vacuum. Remaining VC
N-(2-hydroxyethyl)-α-tromethylene)
-1-aziridinemethanamine 0.0879 (0.5 mmol) and methanol 41 were added. The mixture was evaporated to dryness, heated to 95-100°C for 1 hour and chromatographed on silica (methanol-
0,88N) et al; 79:1). Evaporation of the appropriate eluent under vacuum gives N-[2-[[(5-[(dimethylamino)methyl]-2-furanyl)methyl] with the same properties as the product prepared according to Example 1α). thio[ethyl]−
W-(2-hydroxyethyl)-2-nitro-1,1-
Ethendiamine 0.129 was obtained.

Example 9 N-(2-([(5-[(dimethylamino)methyl]-2-furanyl)methyl]thio]ethyl)-N'-(2-hydroxyethyl)-8-metalisothiourea 2I in 8 g of nitromethane The mixture was heated to 98-100°C for 22 hours. The mixture was evaporated under vacuum and the oily residue was dissolved in isopropyl alcohol 8-0 proof, treated with activated charcoal, filtered once and cooled to 5°C. 1-1 to precipitate N-(2-[(
(5-[(dimethylamino)methyl]-2-furanyl)
1.6 g of methyl]thio]ethyl)-N'-(2-hydroxyethyl)-2-nitro-1,1-ethenediamine was obtained.

Example 10 A solution of 5-[(dimethylamino)
Methyl]-2-chloromethylfuran hydrochloride 2.1.11
0 mmol) and N-(2-hydroxyethyl)-N
'-(2-mercaftethyl)-2-nitro-1,1-
A solution of 2.07 JF (10 mmol) of ethenediamine (with stirring) was slowly added to K at 45° C. under a nitrogen atmosphere. The solution was stirred at 45° C. for 2 hours and at room temperature for 5 hours.

Air was bubbled through the mixture for 15 minutes, it was extracted with ether and the aqueous phase was extracted with chloroform (2X25m).

Dry the chloroform extract over anhydrous sodium sulfate,
Treated with activated charcoal, filtered and concentrated under vacuum. The residue was dissolved in 8-proof isopropyl alcohol and placed in the refrigerator. ,
N-(2-(((5-((dimethylamino)methyl))-
2-furanyl)methyl]thio]ethyl]-N'-(2-
0.9 g of hydroxyethyl)-2-nitro-1,1-ethenediamine was precipitated. The product had the same properties as the product prepared according to Example 1α).

Example 11 This example shows the compound N-(2-(((5-[(
dimethylamino)methyl]-2-furanyl)methyl]thio]ethyl)-N'-(2-hydroxyethyl)-2-
The present invention relates to the preparation of several pharmaceutical compositions containing nitro-1,1-ethenediamine hydrochloride as an active ingredient.

α) each of the above compounds (Example 1, h)) 165
．． 1000 gelatin-■ capsules containing 899 were prepared.

The composition was as follows.

Compound (Example 1, b)) per 1000 capsules - 165,8
9, V microcrystalline cellulose ------------
54,11#Silicon dioxide-----1-
---3,00y magnesium stearate ---
--, -z, ooy These ingredients were sieved and thoroughly mixed, and the resulting powder was filled into gelatin capsules using an appropriate filling machine.h) Each compound (Example 1.h)>165.89M9 1000 tablets containing the following were prepared from the following ingredients:

Compound per 1000 tablets (Example 1, h')) ------165,89,i
9 Finely knotted madder cellulose-1-----1----1
18.11g silicon dioxide
---1-'-'' 12.00 g Magnesium stearate, ---, ----1, 4.00 g The above compound (Example 1, b)) was mixed with microcrystalline cellulose and silicon dioxide. Mixed with magnesium stearate.The mixture was homogenized and compressed in a press.
Each of the above compounds (Example 1, b)) 165.891n
1000 tablets containing y were molded.

C) Syrup IOJ containing 165.89# of compound (Example 1, A)) for each 5me dose was prepared from the following ingredients:

101 compounds (Example 1, h)) -, -, ,,, -,, -35
1,789 sucrose -,, -2---m-～---
--------,7,000,00,9 glycerin U,
S, P, -, -----------500,
00# Sodium chloride --, ---, so, oogp
-Methyl hydroxybenzoate---,, -io, oo
, pp-hydroxybenzoic acid isopropyl-2,00,
9 Sorbic acid −−−−−−−−−−−−−−−−−
--io, ooy sodium hydroxide---m---
--- Appropriate amount of sweeteners and flavoring agents ---
1----Appropriate amount of distilled water-----1---------
-------, i o z Amount of p-hydroxybenzotmethyl isopropyl p-hydroxybenzoate and norbic acid is heated gently and then dissolved in an appropriate amount of distilled water with the remaining substances excluding the flavoring agent. did. Flavoring agents should be mixed in after the syrup has cooled and before the final filling.

d) 55.299 compounds for each 5d dose (Example 1,
1000 injection ampoules containing bJ) were prepared from the following ingredients:

Compound (Example 1, A))-----,----55,2
99 Sodium chloride----------------------
,55,,00,9 Water for injection----1------
The compound (Example 1, b)) and sodium chloride were dissolved in a suitable amount of water for injection under stirring, then filled to 51, filtered and sterilized.

Example 12 The pharmaceutical composition of Example 11 was prepared in the same manner from the corresponding compound of Example 5.1 Pharmacological Description The compound of the present invention mainly has histamine H2 receptor mediated activity, suppresses gastric acid secretion, prevents gastric ulcers, etc. It has the effect of

It has very low toxicity and is well tolerated.

Rat Uterus 11□ Receptor Engagement Activity This experiment compared Example 1 to ranitidine. This was carried out to determine the selectivity of the product b) for histamine H2 receptors.

Rats in oestrus were administered 1 o mcg of stilbestrol by intramuscular injection 30 hours before hysterectomy. Uterine horn on the day of the experiment
Extract the organ and place it in the organ bath (1) e Jalon
) i, maintained at 28°C, 95% 0. and 5% CO6 was bubbled through. Thereafter, sustained uterine contractions were induced by adding KC/solution to the organ bath at a concentration of 4.2~/me, ie 10 times that of Desjaron serum. The uterus was relaxed by adding the amount of histamine necessary to obtain a good response.

The same experiment was carried out by adding the product of Example 1, b) or ranitidine before the addition of histamine and then adding the same proportion of histamine as in the control trial.

K by 5.45 x 10-5 M histamine in organ bath
The contraction caused by C/ was inhibited by 74.5%.

By pre-adding the compound of Example 1, b) or ranitidine at 11i&, the histamine-induced response was antagonized to a degree proportional to its concentration.

The obtained results are shown in the following table.Similarly to 1, the obtained results are shown in the attached graph.

In the graph, 1 is the concentration, Z is the antagonism (depending on the rate of decrease), the solid line is the product of Example 1, b), and the broken line is ranitidine.

From the results obtained above, it can be seen that the degree of goodness () which is effective in producing 5D% antagonism of the histamine response! :C50) for the product of Example 1, h) under the experimental conditions described above.
5 x 10 M, 825 x for ranitidine
1 [J M .

Therefore, in this experiment, 11. t for receptors! 11. It was possible to show that the product of b) has a selective effect and that the substance is more active than ranitidine since its EC,o is 50 degrees lower than that of ranitidine.

Pyloric ligation The method of Pichel et al. (J, Pharma
cExp, Tber, 110. 188.
1954).

Male Wistar rats weighing 250 to 300 g were used. Animals were divided into groups of 10 and fasted for 24 hours before the start of the experiment. However, water was freely available.

These rats were anesthetized with ethyl ether and underwent laparotomy [7, and the pylorus was ligated. The abdominal incision was then sutured.

The procedure was performed before suturing the abdominal incision: VCB-1) intravenously via the femoral vein; B-2) intraduodenumally.

Three hours after pylorus ligation, the volume of gastric juice was measured and the pH was measured using a Beckman Centiury-88-1 ipH meter.

The obtained results are shown in Tables B-1 and B-2.

Its total acidity is 0. Determined by titration with IN-NaOH.

Table B-1 - Product of Example 1, b), volume, pH and total acidity (o, titrated with IN·Nd0n) compared to the corresponding control values for animals treated intravenously with ranitidine or cimetidine
Changes (%) in Table B-2: Volume, pH and total acidity (0,1N- From the results obtained above, the activity of the product of Example 1, h) after intravenous and intraduodenal treatment is very high, the volume of both fluids decreases and T)H is observed to increase. When compared to ranitidine, the product of Example 1, h) is found to have substantially the same activity when administered intraduodenally and a significantly higher activity when administered intravenously.

The product of Example 1, b) also has higher activity than cimetidine both intraduodenally and intravenously, with acute toxicity in rats and mice, as shown in the following table:
The acute toxicity of the product of h) is low.

[Brief explanation of the drawing]

The figure shows the antagonism of the histamine-triggered response (denoted by Z, percentage decrease in Chi) by adding beforehand various concentrations (M) of the product of Example 1, b) or ranitidine to the rat uterus contracted by MCI. The solid line represents the product of Example 1, b) and the dashed line represents ranitidine. Patent applicant: Inc. Société Anonymous (4 others)

Claims (1)

[Scope of Claims] (1) Furan derivatives having the general formula (wherein R is a linear or branched alkylene group having 1 to 6 carbon atoms) and pharmaceutically acceptable thereof; Acid addition salts with acids. (2) it is -cti2-c)1! The furan derivative according to claim 1, which has the general formula when -. (3) The product is N-[2-[[(5-((dimethylamino)methyl]-2-furanyl)methyl]thio]ethyl"
l-N'-(2-hydroxyethyl)-2-nitro 1
．． Claim tIA2 which is 1-ethenediamine
Furan derivatives described in Section. (4) A method for producing a furan derivative according to claim 1, wherein a hydroxyalkylamine of the general formula % (wherein R has the meaning shown in the same paragraph) is prepared as follows in an appropriate medium: A method comprising reacting with a compound of formula. (5) A method for producing a 7-run spindle according to claim 1, comprising a compound of the general formula (wherein R must be equal to each other and have the meanings shown in the same paragraph) A method comprising reacting in a suitable medium with a compound of the formula: (6) In the method for producing a furan derivative according to claim 1)), a compound of the general formula % formula %) (wherein R has the meaning shown in the same paragraph) is prepared in an appropriate medium. (7) A method for producing a 7-run Ippou conductor according to claim 1, which comprises reacting a compound of the following formula with a compound of the general formula (in the formula (8) A method for producing a furan derivative according to claim 1, comprising: A method comprising reacting a compound of the following formula with a compound of general formula (4) C-CH-No./CH2 (in the formula, R has the meaning shown in the same paragraph). (9) Claims No. A method for producing a furan derivative according to item 1, wherein a compound of the general formula '' (in the formula, Y is a halogen atom, and may also be -011 or an acyl group) (10) A process for producing a furan derivative according to claim 1, comprising: , a method comprising reacting nitromethane with a compound of the general formula (wherein is a group to be eliminated and R has the meaning given in the same paragraph). (11) An amount effective for the application as claimed. Any condition involving gastric or duodenal ulcers and acid secretion containing an active ingredient selected from the compounds listed in items 1 to 3 of the scope together with excipients and/or other pharmaceutically acceptable active ingredients. (12) The pharmaceutical composition according to claim 11, further comprising an active ingredient in a state suitable for oral or parenteral administration. (13) Furan derivatives and the like. addition salts, their preparation, pharmaceutical compositions, and their therapeutic use.