• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    This invention relates to new compounds corresponding to the general formula: <IMAGE> I R1 represents a C3-C10 cycloalkyl group substituted by C1-C6 alkyl radicals, a C3-C19-cycloalkyl-C1-C4 alkyl group which may be substituted by C1-C6 alkyl radicals, a C6-C8 bicycloalkyl group, a C6-C8 bicycloalkyl-C1-C4 alkyl group, a C6-C10 tricycloalkyl group, a C6-C10 tricycloalkyl-C1-C4 alkyl group, a C6-C9 tetracycloalkyl group or a C6-C9-tetracycloalkyl-C1-C4 alkyl group, R2 represents hydrogen, a C1-C6 alkyl group, a phenyl-C1-C4 alkyl group or a C1-C6 alkyl group which is substituted by halogen atoms, nitro groups, hydroxy groups, C2-C6 alkanoyloxy groups, C1-C4 alkoxy groups, C1-C4 alkoxy carbonyl groups or carboxy groups, R3 represented hydrogen, the 2-[5-(dimethylaminomethyl)-2-furyl-methylthio]-ethyl group, a C1-C18-alkyl group, a C3-C6-cycloalkyl group, a C3-C6-alkenyl group, a C3-C6-alkinyl group, an amino-C1-C4-alkyl group, a C2-C6-alkanoylamino-C1-C4-alkyl group, a mono-C1-C6-alkylamino-C1-C4-alkyl group, a di-C1-C6-alkylamino-C1-C4-alkyl group or a C1-C18-alkyl group, which is substituted by halogen atoms, nitro groups, hydroxy groups, C2-C6 alkanoyloxy groups, C1-C4 alkoxy groups, C1-C4 alkoxycarbonyl groups or carboxy groups, A represents a nitrogen atom or a methine group, B represents a cyano radical or a nitro group, and X represents an oxygen atom or a sulphur atom, and salts thereof. The compounds inhibit the secretion of gastric juice. Moreover, they have an ulcer-inhibiting and stomach-spasmolytic effect.
    公开号:SU1222196A3
    申请号:SU833663583
    申请日:1983-11-21
    公开日:1986-03-30
    发明作者:Эмиг Петер；Шеффлер Герхард；Тимер Клаус；Вайшер Карл-Хайнрих
    申请人:Дегусса Аг (Фирма)；
    IPC主号:
    专利说明:


    The invention relates to a process for the preparation of new compounds, 2-aminomethyl-5-thiomethylfuran derivatives, which have prolonged antihistamines, such as H-blocking agents.
    The aim of the invention is to obtain new. Derivatives of 2-aminomethyl-1-5-thiomethylfuran, possessing biological activity.
    Example 1, Y-2 - /// 5- / Tricyclo / 2,2,1,0 / -hept-3-yl-aminomethylTyl / - 2-furanyl / -methylthio / -ethyl / -K -methyl- 2-nitro-1,1-ethylenediamine.
    Suspension of 37.2 g of CH- / 2 - // 5- / tricyclo-2.2.1. (-hept-3-yl-aminomethyl / 2-furanyl) -methyl-Thio / -ethyl (-1- / methyl-thio / -2-nitroethylene) in 1 liter of ethanol is mixed with 50 ml of methylamine and stirred for 4 h at 0 ° C until a clear solution is formed. Then it is concentrated under vacuum at room temperature and the residue is dried under high vacuum at 40 ° C. The yield is 38.5 g of Rf 0.26 (solvent chloroform: methanol: concentrated ammonia 90J10: G Hydrochloride.
    A solution of 38.5 g of base in 280 ml of ethanol prepared at 45 ° C is mixed with 23.2 ml of a 4.36 N hydrochloric acid solution while cooling with ice and stirring. The hydrochloride is left overnight to allow complete precipitation. Then sucked off, optionally washed with pre-cooled ethanol and dried in vacuum. Recrystallization is carried out in a mixture of ethanol and methanol solvents (3: 2), Yield 31.1 g, m.p., 174 ° C,
    Preparation of precursors, A, 5-Tricyclo / 2.2.1 .0 - / -hept-3-yl-aminomethyl / - / 2-furansh1 / -methanol. 96 g of tricyclo (2.2.1.0.) -Hept-3-yl-amine hydrochloride and 64.7 g of (2-furanyl) -methanol in 580 ml of ethanol heated under nitrogen to approximately 40 ° C. mixed with 30 g of paraformaldehyde and heated for 3 hours at 70 ° C. For completeness of the reaction, 10.2 g of paraformaldehyde is added and heated for 4 hours at 70 ° C. Then concentrated in vacuo, the residue is dried in vacuum at 40 ° C until complete removing the solvent, after which it is dissolved in 450 ml of water, the pH is adjusted to 6-7 in the solution and to remove from 22196
    The excess amount of (2-furansh1) -methanol solution is extracted three times with ether. In the visible phase with sodium hydroxide solution
    5, the pH is adjusted to 10-11 and extracted four times with n-butanol. The butanol extracts are dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Remainder
    10 is purified in ethanol solution using active carbon and silica gel, filtered, concentrated in vacuo and the product obtained is dried at, Yield 94.5 g, Rf 0.47 (solution) 5 solvent. chloroform: methanol: concentrated ammonia (90: 10: 1),
    B, 2 - // 5- / Tricyclo / 2.2. hept-3-yl-aminomethyl / -2-fz wounded / -methylthio / -ethanamine
    20 A solution prepared under ice-cooling with 94.59 g of 5- (tricyclo) / / 2,2,1,0 / -hept-3-yl-amino /, -methyl / - / 2-furanst / -methanol in about 200 ml of concentrated hydrochloric.
    25 Acids at O - 5 C, while stirring, are mixed dropwise with a solution of 49 g of cysteamine hydrochloride in 220 ml of concentrated hydrochloric acid. The mixture is stirred for 1.5 hours in an ice bath, it is drained, then cooled with ice with sodium carbonate and then alkalinized with 32% sodium hydroxide solution. Vodny. the alkaline solution is extracted four times with 150 MP each n -butanol and the combined butanol extracts are dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gives an oily residue, which is subjected to acid-base purification, then treated in an ethanol solution with active charcoal and silage gel, which gives the target compound in pure form. Yield 72g, RfO, 43 (dissolve. Chloroform: methanol: concentrated ammonia 85: 15: 1).
    B, K- / 2 - // 5-Tricyclo / 2.2.1. / - hept-3-yl-aminomethyl / -2-furanyl / -methyl-ILHIO / -ethyl / -1- / methyl thio / -2-nitro50 ethyleneamine.
    A solution of 50 g 2 - // 5- / tricyclo / 2.2. (2,2, 1, 0) -hept-3-yl-aminomethyl (-2-furanyl) -methylthio) -ethanamine in 1 liter of isopropanol and stirred with 38.6 g. Of 1-nitro-2.2-5is - (methyl mercapto) ethylene and heated for 3.5 hours at 70 ° C. Methyl mercaptan formed during the reaction in a stream of nitrogen
    35
    40
    45
    passed into an aqueous solution of sodium hypochloride. The reaction solution is then concentrated in vacuo, the residue is dried intensively in high vacuum at 30 ° C, purified in ethanol solution over activated charcoal and silica gel, the solution is filtered, concentrated again in vacuum and the residue is recrystallized from isopropanol. Suction of the crystalline precipitate, washing with cooled by ice
    Jtl
    L-CHa O CH.
    212221964
    isopropanol and drying at 40 ° C gives a homogeneous, according to thin layer chromatography, compound (solvent: chloroform / methanol / concentrated ammonia 90: 10: 1). Yield: 47.4, m.p. 94 ° C.

    lo
    EXAMPLE j) 2. L-C2-C 5-tricyc- (2.2,1,0) -heptyl-3-aminomethyl - 10 2-furanyl-methylthio} -ethyl-N-methyl- 2-nitro-1,1-etenediamine
    N0
    sn
    P
    -CHr | .CH2-NH-C- iHCH3
    18.9 cyclo (2,2,1, o) -heptyl-3-aminomethyl -2-furanyl-methylthio-ethyl-1-methoxy-2-nitroethenamine suspension in 400 ml of ethanol under rapid stirring at 0 ° C 40 ml of methylamine are added and the mixture is stirred for 5 hours at 0 ° C. Then, at room temperature under vacuum, the mixture is concentrated for 2 h and the precipitate is dried under high vacuum at a yield of .. 16.3 g. Rf 0.26 (carrier chloroform: methanol: concentrated ammonia 90: 10: 1).
    Comparative testing.
    The antisecretory activity with respect to pentagastrin-stimulated acid secretion in Gosh and Schild rats was determined as follows.
    Male white rats (SIV5 /; Ivano-vas, Kiplegg / Allgau) weighing 180–200 g who were fed for 48 hours but given enough water, anesthetized, injected intraperitoneally with 1.5 g / kg urethane. Animals were cannulated into the duodenum, esophagus, trachea, and jugular vein. The body temperature was maintained at 36-37 C. Isotonic saline (37 ° C) was injected through the esophagus into the stomach at a rate of I ml / min. Flowing through the exit of the duodenum fluid was collected.
    Gastric secretion samples collected in 15 minutes were titrated with 0.01 N NaOH to pH 7. Acid secretion was calculated by the amount of 15 minutes. After determining unstimulated acid secretion, it was carried out using pentagastrin, which was injected (60 and g / kg / h) into the strap vein through a catheter. The volumetric rate with the introduction of the drug 2 ml / h.
    After a constant secretion rate was established, animals were injected intravenously with a test compound in an amount of 1 ml / kg.
    Inhibition of acid secretion for
    each sample was calculated as a percentage of the value of stimulated secretion.
    The table shows the doses at which 50% inhibition (LDgo) of pentagaster stimulated acid secretion was observed.
    Determination of toxicity.
    Toxicity was determined in mice by intravenous administration of the test compound. The table shows the values representing the dose, with the introduction of which killed 50% of the animals. LDgo is determined by the conventional method of Miller and Taiter.
    45
    50
    55 From the data in the table it follows that the proposed compound inhibits the secretion of acid more than twice as much as comparative connection. In addition, the comparative methyl-thio-ethyl-N-methyl-2-nit-compound (renithidine formul -N-f2-ro-1,1-ethylenediamine) is significantly b-Ctt5- (yiMyo a a hno) -methyl-2 -fyranil is more toxic than proposed.
    权利要求:
    Claims (2)
    [1]
    'METHOD: · PRODUCTION OF DERIVATIVES
    [2]
    2-AMINOMETIP-5-THIOMETHYLFURANA of the formula
    CH 2 -CH g -MH-C-bHHH2 or their salts, characterized in that the compound of the formula
    H 4 NR 4 where R 2 has the indicated meaning, and the desired product is isolated in free form or in the form of a salt; ,
    2221
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    引用文献:
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