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    • 专利摘要:
    Neue substituierte 2-Mercaptoimidazole der Formel worin mindestens einer der Reste R1 und R2 eine gegebenenfalls substituierte Heteroarylgruppe und der andere eine gegebenenfalls substituierte Arylgruppe bedeutet, R3 Wasserstoff oder Niederalkyl darstellt, n für 0, 1 oder 2 steht und R4 einen gegebenenfalls substituierten aliphatischen Kohlenwasserstoffrest bedeutet, und pharmazeutisch verwendbare Salze, davon, haben analgetische Eigenschaften, und können als Wirkstoff in analgetisch wirksamen pharmazeutischen Präparaten verwendet werden. Ihre Herstellung erfolgt nach an sich bekannten Methoden.
    公开号:SU991945A3
    申请号:SU802925099
    申请日:1980-05-23
    公开日:1983-01-23
    发明作者:Джоржо Феррины Пьер；Гешке Рихард
    申请人:Циба-Гейги Аг (Фирма)；
    IPC主号:
    专利说明:

    in free form or with N-alkylation of the product C; (-C-lower alkyl halide and separation of the target product or with oxidation of the resulting product with m-chloroperbenzoic acid, the target product of formula 1, where or 2, and the target product of formula I, where, is oxidized with peroxide hydrogen to the compound of formula I, where the pyridyl group R; and / or Kr can be N-oxidized, followed by isolation of the target products in free form or in the form of salts. Example 1. 2.86 g l.-bromobenzyl- (3 pyridyl-ketone hydrobromide and 1 g of S-methylisisothiouronium bromide are weighed into 30 ml of acetone nitrile, then add 3.1 g of N, N-diisopr-pilethylamine and stir overnight.The red-orange suspension is filtered, the filtrate is evaporated under reduced pressure. The residue is dissolved in chloroform, dried by sodium sulfate, evaporated and recrystallized from mixtures of chloroform and petroleum ether to give 2-methylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole, mp 193-194c, yield 84% (from theory). Starting material can be obtained, for example, as follows. To 20 g of benzyl- (3-pyridyl) -ketone in 20 (3 ml of acetic acid, a solution of 17 g of bromine in 150 acetic acid is added dropwise, and then stirred overnight. Looped bromobenzyl- (3-pyridyl) -ketongidro bromide is filtered off (it can be used further without purification.) Similarly, 2-ethylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole is also obtained, mp 19b-198 ° C, yield 81% (from theory), Example 2. In a suspension of 8 g of 2-methylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) -im das ol and in 400 ml of chloroform with stirring dropwise m is added a solution of 6.3 g of 85% m-chloroperbenzoic acid in 70 ml of chloroform. The resulting solution was then incubated overnight and washed with sodium hydrogen carbonate solution and water, dried with sodium sulfate and evaporated to dryness. The residue was recrystallized twice from an isopropanol-petroleum ether mixture to give 2-methanesulfinyl-4 (5) - phenyl-5 (4) - (3-pyridyl) -imidazole, mp 166-169 ° C, yield 69% (from theory). In an analogous manner, starting from 2-ethyltiltio-4 (5) -phenyl- 5 (4) - (3-pyridyl) -imidazole, get 2-ethanesulfonyl-4 (5) -phen l-5 (4) - (3-pyridyl) -imidazole, so pl. 162-164c. Note 3. 1.0 g of 2-ethanesul-4-4 (5) -phenyl- (3-pyridyl) -imidazole is mixed with 8 ivtn of acetic acid and 0.38 ml of 30% hydrogen peroxide and stirred overnight. at. Leave to cool, neutralize with caustic soda solution and suction. 2-ethanesulfonyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole is obtained, m.p. 208-210s. Example 4. 5.6 g of 2-ethylthio-4 (j5) -phenyl-5 (4) - (3-pyridyl) -imidazole are dissolved in 150 ml of tetrahydrofuran, after which 8.5 g of 85% m -chloroperbenzoic acid. Then it is stirred at 70 ° C for 6 hours, the excess peracid is reduced by sodium hydrosulfite or dimethyl disulfide, and it is concentrated strongly under reduced pressure. The precipitate formed is filtered off with suction, washed with water and then graphically purified on 70 g of silica gel. With a mixture of chloroform and ethyl acetate (1: 1). The ethyl acetate eluate is evaporated, the residue is recrystallized from ethanol to give 2-ethanesulfoiyl-4 (5) -phenyl-5 (4) - (3-pyridyl) -imiadsm, m.p. 190-192 ° C. Example 5. 15 g of 2-ethylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole are weighed into 15 ml of ethanol, then acidified with ethanolic hydrochloric acid to pH 1, after which everything dissolves . Diethyl ether is then added until precipitation begins, it is filtered and recrystallized twice from a small amount of ethanol. 2-ethylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole-bis-hydrochloride is obtained, m.p. 174-176 ° C, yield 96% (from theory). Similarly, 2-ethylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole bis-methanesulfonate, m.p. 150 152 ° С (with decomposition), yield 88% (of theory). Example 6.8 g of 2-methylthio-4 (5,) -phenyl-5 (4) - (3-pyridyl) -imidazole is dissolved in 40 ml of methanol and i 16 ml of 2N. caustic soda solution. B, the solution is added dropwise 4.55 g of methyl iodide, stirred for 2 hours at room temperature, 40 ml of water are added, sucked off and taken up in water. A mixture of 1-methyl-2-methylthio-4-phenyl-5- (3-pyridyl) imidazole and 1-methyl-2-methylthio-5-phenyl-4- (3-pyridyl) -imidazole is obtained, which can be separated by chromatography amounted to qie. Thus, on a silica gel column, chloroform was first eluted with 5-fvinyl isomers with mp. 141-143c, and then using a mixture of chloroform and ethyl acetate tO :) - 4-phenyl isomer with so pl. 125-127 ° C. The output of each is about 18% (from theory). From the column, another product can be iluted and again separated. Note 7. Similarly, the following compounds can be obtained: 2- (2-methoxyethylthio) -4 (5) -phenyl-5 (4) - (3-pyridnl) -imidazole, m.p. I8-120Yas, yield 70% (from theory); .2- {2-methylthioethylthio) -4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazol, t. 1b4-168 s, yield 46% (from theory); . 2-IZOPROPYLTIO-4 (5) - (p-methoxyphenyl) -5 (4) - (3-pyridyl) -imidazole m.p. 20b-210 ° C, yield 82% of Hot theory); 2-isopropyl-4 (5) - {p-fluorophenyl-5 (4) - (4-pyridyl); - imidazol, so pl. 263-264 ° C, yield 76% (6 tons of theory); . 2-methylthio-4,5-6is- (2-thienyl) -imkdazol, m.p. 204-206 ° C, yield 88% (from theory); 2-ETHYLTIO-4,5-bis- (2-thienyl) timazole, m.p. 209-210 С, yield 76% (from theory); 2- (2-ethoxyethylthio) -4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole, m.p. 100-102 C, yield 58% (from theory); 2-propylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazole, m.p. 134-144 OUTPUT 63% (from theory); 2-isopropylthio-4 (5) -phenyl-5 (4) - (3-P11rchdyl) -imidazole, so pl. 182 1–4 С, yield 44% (from theory); 2-ethyl-4 (5) -. (P-fluorophenyl) -5 (- (2-thienyl) -imidazo, mp 160 163 ° C, 72% yield (from theory); 2-methylthio-4 ( 5) - (p-fluorophenyl) -5 (4) - (2-thienyl-imidazole, mp. 171-173 ° C, 76% yield (from theory); 2-etansul% finil-4 (5) - (p-fluorophenyl} -5 (4) - (2-thienyl) -imidazole, mp 143-145 ° C, yield 42% (theory). 2-zanesulfonyl-4 (5) - (p-fluorophenyl - 5 (4) - (2-thienyl) -imidazole, T.PL. 180-182 ° C, 39% yield (theoretical); 2- (2-oxystilthio), - 4 (5) -phenyl-5 ( 4) - (3-niridyl) imidazole, mp 128-130 ° C, yield 34% (from theory); 2-OXIS-SYLTIO-4,5-bis- (2-pyridyl) -imidazole-hydrobromide, t. mp 249-250 s, yield 30% (from theory); 2-hydroxyethylsulfinyl-4,5-bis- (2-pyridyl) -imide ash, mp 215 217 C, yield 27% (oT theory); 2-OXYTHYLTIO-4,5-bis- (2-thienyl-imidazole, mp., yield 44% (from theory); 2- benzylthio-4 (5) -phenyl-5 (4) - (Zridyl) -im daz ol ;, melting point 165-167 ° C, 92% yield (from theory); 2-propyrgylthio-4 (5-phenyl -5 (4) - (3-pyridyl) -imidazole, mp 148 149s, yield 69% (from theory); 2-allylthio-4 (5) -phenyl-5 (4) - (3-Pridyl ) -imidazole, so pl. 177-178 ° C, yield 89% (from theory). Example 8: Tablets containing 25 mg of an active ingredient, for example 2-methylthio-4 (5) phenyl-5 (4) - (3-pyridyl) -imidazole, can be prepared as follows. Ingredients (per 1000 tablets), g: biologically active substance 25.0 lactose 100.7t wheat starch 7.5; polyethylene glycol 6000 5.0; talc 5.0; magnesium stearate 1.8 and demineralized water to the desired volume. All solid ingredients are first passed through a sieve with a hole width of 0.6 mm. Then the biologically active substance, lactose, talc, magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water. The resulting starch paste is added to the main amount of the mixture and the mixture, if necessary with the addition of water, is granulated. The granulation is dried overnight when it is passed through a sieve with a hole size of 1.2 mm and pressed into tablets concave on both sides with a diameter of approximately 6 mm. Similarly, tablets containing 25. mg of each of the indicated / in examples 1–4 compounds of the formula 1; Example 9. Chewable tablets containing 30 mg of a biologically active substance, for example 2-methylthio-4 (5) -phenyl-5 (4) - (3-pyridyl) -imidazoline, can be prepared, for example, as follows. Ingredients (for 1000 tablets), g: biologically active substance 30.0} mannitol 267.0; lactose 179.5; talc 20.0; glycine 12.5; stearic acid 10.0; saccharin 1.0 and 5% solution of gelatin to the desired volume. All solid ingredients are first passed through a 0.25 mm sieve. Mannitol and lactose are mixed, granulated with the addition of a solution of gelatin, passed through a 2 mm sieve, dried at 50 ° C and again passed through a 1.7 mm sieve. The biologically active substance, glycine and saccharin are thoroughly mixed, mannitol, granulated lactose, stearic acid and talc are added after this mixing, the whole set is thoroughly mixed and pressed into concave tablets on both sides with a diameter of about 10 mm with a notch on the outside. Similarly, chewable tablets can be prepared, containing, under the circumstances, 30 mg of another of the compounds listed in examples 1 4 of formula I. Example 10. Tablets Containing iOO mg of the active substance biology, for example 2-; giltio-D (5) phenyl-5 (4) - (3-pyridyl) -imidaeol, can be prepared as follows
    Composition (per 1000 tablets), g; active ingredient 100, lactose 248.5, corn starch 17.5, polyethylene glycol 6000 5.0, talc 15.0, magnesium stearate 4.0 and demineralized water to the full volume.
    The solid ingredients are first passed through a 0.6 mm sieve. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are thoroughly mixed. The other half of the starch is suspended in 65 ml and this suspension is added to the boiling solution of polyethylene glycol in 260 ml of water. The resulting paste is added to the porous and spike-like substances, the whole mixture is mixed and the granulation is made when necessary: with the addition of water. The granulate is dried in Tjg .4 © H enochi at 35 ° C, the sieve with aperture size 1,: 2 mm is passed through and pressed into concave with both. sides of the tablet with a diameter of about 10 mm with a notch on the upper side
    Similarly, you can make tablets containing 100 mg of one of the compounds of formula 1 in accordance with examples 1 to 4.
    权利要求:
    Claims (1)
    [1]
    1. ElderfieldF. Heterocyclic compounds. M., Foreign literature, 1954, p. 196-197.
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    法律状态:
    优先权:
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