• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    1456162 Thienodiazepines F HOFFMANNLA ROCHE & CO AG 7 Feb 1974 [8 Feb 1973] 05396/76 Divided out of 1456161 Heading C2C Compounds of the general formula (R 1 = halogen, NO 2 , NH 2 , alkanoyl; R 2 = pyridyl or thienyl optionally substituted adjacent to linking position, phenyl, o-trifluoromethylphenyl, o - halophenyl, o,o<SP>1</SP> - dihalophenyl, o - nitrophenyl; R 3 = H, OH, alkoxycarbonyl, alkanoyloxy; R 4 = H, alkyl, alkanoyl, hydroxyalkyl, mercaptoalkyl, alkoxycarbonyl, aminocarbonyl, haloalkyl, alkoxyalkyl, alkylthioalkyl, aralkoxyalkyl, cyanoalkyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkyl, alkylcarbonyloxyalkyl, aminocarbonyloxyalkyl, dialkylaminocarbonyloxyalkyl, CN, alkyl NR 5 R 6 , COO alkyl NR 5 R 6 , CONH alkyl NR 5 R 6 ; R 5,6 = H, alkyl, hydroxyalkyl or NR 5 R 6 = monocyclic saturated 5-6 membered ring optionally containing an oxygen or further nitrogen atom ; n = 0, 1) are prepared by standard methods, e.g. condensing the corresponding 5- aryl - 1,3 - dihydro - 2H - thieno[2,3-e] - 1,4- diazepine-2-thione with R 4 CONHNH 2 .
    公开号:SU1060115A3
    申请号:SU782633846
    申请日:1978-06-10
    公开日:1983-12-07
    发明作者:Хеллербах Йозеф；Целлер Пауль；Биндер Дитер；Хроматка Отто
    申请人:Ф.Хоффманн-Ля Рош Унд Ко,Аг (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new thienotriazolodiazepine derivatives possessing valuable pharmacological properties. There are 6-o-halo-phenyl-4-H-si triaolo {3,) -thieno (2, 3-e) -1, zepins of the general formula in -4 where R is -C2-alkyl; p -H, -alkyl, having anticonvulsant and tranquilizing effects of C1. However, the anxiolytic activity of these compounds is practically absent. The purpose of the invention is to obtain new compounds that expand arsenic of effects on a living organism by synthesizing the C 2 direct halogenated reaction based on the known reaction. . This goal is achieved by the fact that according to the method of obtaining new derivatives of thienotriazrlodi. . LAe.J Rj - chlorine or bromine; Rj is o-chlorophenyl, R, is methyl or dimethylaminomethyl, or their acid addition salts, a compound of the general formula rO. p-jf- with where R2 and Rj have the indicated values, are chlorinated or brominated with elemental halogen, respectively, in chloroform medium in the presence of pyrridine or glacial acetic acid from to room temperature, followed by isolation of the target product in free form or in acid form -additive salt. The compounds of formula (.1) can be reduced to the corresponding salts by treatment with inorganic or organic acids, and pharmaceutically applicable salts are of great importance. Acidic forming pharmaceutically applicable salts include hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, tartaric, citric, maleic, ascorbic, formic, acetic, amber, methane, benzene. And p-toluenesulfonic acid. The starting materials of formula (i) can be obtained from the corresponding thienodiazepine derivatives of the general formula I p Sv-i-cf. g 1D 2 in which has the indicated meanings. The first step is to react a compound of formula (w) with a sulfide, such as phosphorus pentasulfide, and a compound of the general formula S-vir (IV) is formed. I where R has the indicated meanings. . In this reaction, sulfide is preferably used in excess. The reaction is carried out predominantly in an inert organic solvent, for example, pyridine, xylene and the like (i), at a temperature in the range of from about 40 ° C to reflux temperature of the reaction mixture, preferably at reflux temperature P. The preferred solvent for this reaction is pyridine. The compound of formula (iXf) is then reacted with an organic acid hydrazide of the total foryule H., N-NH-CO — RJ where Rj has the indicated value. The thion of the formula (y) with an acid hydrazide of the formula (v) is condensed in an inert organic solvent, preferably in an alkanol, for example methanol, ethanol, 1- or 2-propanol, 1- or 2-butanol, at 60-120 ° C, preferably at the reflux temperature of the reaction mixture. According to a preferred embodiment, the acid hydrazide uses a two-fold excess of the theoretically required amount. The reaction time depends on the reaction temperature and ranges from a few minutes to 48 hours, preferably 1-24 The crude product thus obtained is in most cases derived from the compound of the formula "H-WH-CORj LJT" n, 2, and Kj have the indicated meanings, and the cyclized compound of the formula (m). This mixture can be divided (due to the different solubility of these compounds) in organic solvents, for example, in methylene chlorite, chloroform, carbon tetrachloride, ethyl acetate, etc., the compound of formula (VI) after separation can be converted by the method described to the compound of formula (0) By a simpler method a mixture of compounds of formula (P) and (VI) but about converted into a homogeneous product formulpl (H) by heating according to the aforementioned method. The reaction of reacting a compound of formula- (1 with an acid hydrazide of formula (v) is preferably carried out by passing an inert gas, preferably nitrogen, through the reaction mixture in such a way that the resulting hydrogen sulfide is constantly removed. Hydrazide acids of the formula (9) are known compounds and can be easily obtained, for example, by heating an ether complex of the formula R-COO-alkyl with hydrazine hydrate to a reflux temperature, for example, in methanol. Compounds of formula (III) can be easily obtained, for example, from2-amino-3-arryl-thiophene derivatives by reacting with ha / shgenic anhydride oC-halogencarboxylic acid, for example chloroacetyl chloride, by treating the compound obtained with ammonia and subsequent cyclization. According to another variant of the method, compounds of the formula (b) like that can be obtained from compounds of the general formula 1 Uld 1 jL-Vit &amp; where R has the indicated meanings, by reacting with a carboxylic acid of the formula R -COOH-, where R has the indicated value, or with a reactive derivative it is an acid. Suitable reactive derivatives of these carboxylic acids are, for example, ZFIROPs, anhydrides, halides, amides, imioethers, amidines, and orthoesters, and especially preferred are orthoesters, for example, orthoacetic acid trimethyl ether, orsthymetras, as well as the word text patterns, or acys- orthoformic acid, triethyl ester of orthopropionic acid, or triethyl ester of oro-butyric acid. The reaction of the compound of formula (L1) with the carboxylic acid or its reactive derivative is preferably carried out in the presence of an inert, organic solvent and an acidic catalyst, for example, hydrohalic acids, for example hydrochloric acid, p-toluenesulfonic acid. alkanols are suitable as solvents, for example methanol, ethanod, ether 1), for example tetrahydrofuran, diethyl ether and the like, dimethyl sulfoxide, dimethyl formamide. The temperature for the successful implementation of this reaction step is not critical, however, elevated temperatures, i.e. ranging from about EO ° C to the boiling point: the reaction mixture, particularly preferably at reflux temperature. In another embodiment of the process, compounds of the formula (vi) can be obtained from compounds of the general formula, lfH-AlK, where Rj is as defined by reaction with an acid hydrazide of the formula (V). The reaction is carried out in an inert, organic solvent, e.g. alkanols, e.g. ethanol, propanol, butanol, dimethylformamide, ether, e.g. diglyme or methoxyethanol, in the presence of a strong base, e.g. amines, e.g. tertiary amines, e.g. triethylamine, methylpiperidine at elevated temperatures. stages, preferably at the boiling point of the reaction mixture. The compounds of the formula {VHl) can be easily obtained from the corresponding compounds of the formula d) by reacting a соедин-compound of the formula (w) with an alkylmin in the presence of a Lewis acid, for example titanium tetrachloride. Compounds of formula (VnI can be obtained from the corresponding compounds of formula (yT |). By reacting the compound of formula (III) with nitrogenous acid to form the corresponding louiero N -nitroso compounds. By reacting the M-nitroeo compound with hydrazine, the compound forms G / 1ULA IViii is obtained). a compound of formula (Ttl) - can be obtained by veaimodeystVIYa compound of formula (c gidraennom Compounds of general formula (|) and their farmatsenticheski applicable acid addition salt thereof in addition to anticonvulsant, anxiolytic, relaxes constituent muscles and tranquilizing properties have bright vyragkenilL anxio lytic action Problematic test... on a test apparatus - skin box with a button to dispense feed pills. During three one-hour preliminary experiments, hungry female rats practice pressing The button of the feed pill sensor for receiving the cortex pitches (each press of the button increases). In the third preliminary experience, the crimsons press the button 150–200 times per hour. In the fourth preliminary experiment, the award was called by the button, Caught with this conflict situation / rats first press the button about 5-10 times, and then stop pressing with fear. In the fifth preliminary experiment, rats may again press the button of the forage sensor sensor without receiving an electric shock, and the rats again press the button 150–200 times per hour. In the sixth preliminary experiment, a special group of test animals is selected. Half an hour before the start of this experiment, the test animals received 10 mg / kg oz of iazepoxide orally, and the rewarding of the pill was again associated with electric shock on the legs. Only those krshoy that, in this preliminary experience, press a button at least 20-50 times, are suitable control animals for testing for possible anxiolytic action. In the main experiment, 8 rats are used per substance and dose. The untreated control group is not needed, as each test animal serves as a control. The test substances dissolved or suspended in a mixture of distilled water (10 ml) and Tween-80 (2 drops I, were administered to animals by animals with a stomach probe half an hour before the one-hour main experiment. During the main experiment, in which Hc1 pilling at each pressing the button is associated with an electric shock, the number of button presses per hour is recorded. The first significantly anxiolytically effective dose is determined by testing Wilcoxon (comparison of pairs), directly comparing the number of button presses in the main experiment (electric shock on the legs, after the pretreatment of the tested substances {vomj with the number of button presses in the control experiment (electric shock on the legs, on the bar, after the pretreatment of salt pacTBOpoivi). The known compound is 2-ethyl-4-0-chlorophenyl-9-methyl-6H- thieno 3,2-L-triazolo C4,3-a) (1,4 diazepine (compound A and the proposed compounds: -2-chloro-4- / o-chlorophenyl-9-methyl-CH-thieno-3,2 - / J- J-triazolo (4, 4 diazepine / compound B), -2-bromo-4-o-chlorofens-9-methyl-bH-thieno (3,2 - /) - j-triazolo (4, 3-a) (l, 4j diazepine (compound B and -2-HLOR-4- (o-chlorophenyl / -9-dimethylaminomethyl-bN-thieno (3,2-f) - triaz olo (4,3-a / (l, 4j-diazepin (the compound icj is subjected to the above-mentioned conflitt. to the test ... The results are shown in the table.
    BUT
    (
    Filthy
    +16 (sedation- + E (H3) (re-He Nia exophthalide) laxaci
    exophthalmos,
    fleece wool /
    About 1.0
    1.0 o Note: PZD pzrva, NZ - insignificant Underlined significant but. The table clearly shows that all tested new compounds are more adaptable and / or more selective with anxiolytic efficacy and a much less prominent side effect than the known substance. The compounds of general formula (D) and their pharmaceutically acceptable 1-addition acid addition salts can be processed according to well-known methods to pharmaceutical preparations, for example, tablets, pills, suppositories, capsules, solutions, suspensions, emulsions. In addition to the usual pharmacologically indifferent fillers, for example, lactose, starch, talc, magnesium stearate, water, raster oils, polyalkylene glycols, etc., these preparations may contain preservatives, stabilizers, wetting agents or emulsifiers, salts for altering o. . . . . Whose pressures, buffers, or other therapeutically valuable substances. When . If necessary, the above preparations can be sterilized or other treatment methods customary in the pharmaceutical industry. A suitable pharmaceutical unit dose may contain about 1-50 mg of the compound according to this invention. Suitable daily allowance
    Table continuation
    + 37
    +44
    +66
    normal
    (weak mustache (normal behavior, rest / behavior)
    +30
    38
    +48
    (normal relaxation;
    (normal behavior) behavior is clearly anxiolytically effective with an 11 anxiolytic effect; The increase in shock is indicated by the lyolithic effect of peroralld oral administration in mammals containing approximately 0.1-30 mg / kg, and for parenteral administration approximately 0.1-10 mg / kg. These doses are only examples, the specific dosage should be adapted to individual needs. I. Example 1. A. Obtaining raw materials. 0.95 g (0.0034 mol of I 5- (o-chlorophenyl) -1,3-dihydro-2H-thieno (2,3-e) -1,4-diazepin-2-she is dissolved in 25 ml of diethylene glycol dimethyl ether at 80 ° C. A finely triturated mixture of 1.6 g and 1 g of sodium bicarbonate is added to the solution, the reaction mixture is strongly foamed. After the addition is completed, stirring is continued for 50 minutes at (D) the solvent is concentrated to 10 ml and 120 yi of water. The precipitated product is sucked off, washed with water. and dried at room temperature. L- (o-chlorophenyl -1,3-dihydro-2H-thieno (2, 3-e 1-1,4-diazepin-2-thione) is obtained. After recrystallization from methanol, yellow crystals with t at 200 ° C. To a solution of 0.5 ml of hydrazine hydrate in 50 ml of absolute tetrahydrofuran was added 2.0 g of 5- (o-chlorophenyl) -1,3-dihydro-2H-thieno- (| 2, 3 - e | -1, 4-diazepin-2-thion. After 10 minutes, a red solution is obtained, which is continued to stir for another 20 minutes at room temperature. By adding ether BtTM, the reaction product is brought to crystallization. each with ether and dried to give 5- (o-chlorophenyl / -2-hydrazino-3H-thieno (2, 3-e:,) - 1,4-diazepine with mp. ITS-ieo C, which is recrystallized from tet rahidrofuran / ether. This gives crystals with a melting point of 179-180 s, 2 g (0.0069 mol / 5- (o-chlorophenium JI: -2-hydrazino-3H-thieno 2, 3rd) 1, 4-diazepine is weighed into 200 hl of dry methylene chloride and then 10 g of sodium bicarbonate is added. The reaction solution is cooled ;; yield 0.8 ml of acetyl chloride with stirring. After 45 minutes, filter the reaction solution from the solid and extract it twice by shaking it with 100 MJI of water. After drying over sodium sulfate, the organic phase is evaporated, 100 butanol is added, and then 20 m) of 1 butanol is evaporated under reduced pressure. The reaction solution is heated under reflux for 8 hours and evaporated in vacuo. After triturating the oily residue with ethanol, the resulting crystals are boiled with a small amount of ethanol and crystallized in a refrigerator, sucked off and dried. Get 4- (o-chlorophenyl | -9-methyl-bN-thieno (3, 2-f) -sim. -Triazolo- (4, 3-a) (1,4 diazepine with so pl. , B. Obtaining the desired product. J g (O, 0032 mol) 4- (chlorophenyl / -U methyl-bH-thieno (3,2 -) - 5-triazolo (4, 3-a} 1,4-diazepine solution 100 ml of absolute chloroform is cooled to 0 ° C and 1 ml of pyridium is added (4-fold molar excess of 7. Chlorine gas is slowly passed through the solution for 2 h. The solution is evaporated and the precipitate is dissolved in methylene chloride and one jpas of 0.1N hydrochloric acid is passed through. The product is extracted with 4N hydrochloric acid, and to the phase methylene chloride and ether is added so that it floats to the top. After neutralizing the hydrochloric acid phase with solid sodium carbonate, the product is dissolved in methylene chloride. The methylene chloride phase is dried with sodium sulfate, evaporated and triturated with a small amount of ethyl acetate .. The crystallized product is recrystallized from ethano, using a tive coal, with (than get 2-hldr-4- (o-chlorfeN-9-methyl-6H-thieno il3,2-f -5-triazolo- (4,3-a) -1,4-diazepine with t .pl. 205 .206 ° C. Yield 0.7 g (63%). Calculated: C 51.59: H 2.89, N 16.04. CigH ,, oN4CV-1 t Found (average of two nvotf, C from 51.60; H 2.63; N 15.85. Mol. Mass 349.24. I. Example 2. A. Preparation of the starting material. Dissolved 0.95 g 0.0034 Mo; jib 5- (o-chlorophenyl -1H-thieno- (2, 3-e) (1.4B-diazepine-2 (ZN} -one in 25 MII diethylene glycolDimethyl ether at 80 ° C. A finely milled mixture of 1.6 g of hemispheric sulfide sulphide and 1 g of sodium bicarbonate is added to the solution. After the addition is complete, the mixture is stirred for another 50 min at 80 ° C, the solution is concentrated to 10 ml and 120 ml of water are added. The precipitated product is sucked off, washed with water and dried at room temperature. 1.05 g of 5 - (o-chlorophenyl / -1H-thieno (2, 3-e | (1,4) -diazepine-: (3N) -thion. This product is dissolved in 50 ml of glacial acetic acid and 20 MP of methanol is heated with 2 g of dimethylammonium chloride and acetic acid and heated for 1 h. After evaporating the solvent, 150 gdl of 5% sodium bicarbonate solution is added to the oil and the solvent is extracted in portions with just 150 ml of methylene chloride. After drying, the solvent is removed with sodium sulfate. The resulting oil was boiled for 1 hour under reflux in 50 m of 1 glacial acetic acid. The solvent is evaporated and the residue is partitioned between 100 ml of sodium bicarbonate solution and 100 ml of methylene chloride. After evaporation of the organic phase, the resulting 4- {o-chlorferyl | -9-dimethylaminomethyl-4H-thione (3,2-f) -5-triazolo (4,3-a) (1,4) diazepine is digested with 100 ml of ethyl acetate, filtered off in hot conditions from pollution and concentrated to 20 MP. The precipitated product is recrystallized from ethyl acetate. 0.42 g (33% J of product, mp. 210212 ° C) is prepared. Obtaining the desired product. About 2 g of this product is dissolved in 30 ml of absolute chloroform, 0.2 ml of absolute pyridine is added and cooled to-B%. Dry chloride gas is injected into the solution slowly. After 3 hours, no starting material can be set. After evaporation of the solvent, the mixture of the chromatographic chromatography is purified on a column (silica gel, ethanol solvent). (o-chlorophenyl-E-dimethylaminomethyl-4-thieno, (3,2-f) -5-gtriazolo (4,3-a) -diazepine, mp 203-205 ° C. Yield 50%.
    Calculated: C 52.05; H 3.85; N 17.85.
    .
    Found: C, 52.26, - H, 3.49; M 17.89
    Example 3. 1.57 g of 4- (o-chlorophenyl) -9-methyl-6H-thieno (3,2-f) -S-triazolo U, 3-a) (.1.4) -diazepine are dissolved in 50 tJUi of glacial acetic acid. To this solution is added a solution of 1.7 ml of bromine in 5 ml of glacial acetic acid over 30 minutes with stirring at room temperature. The reaction, the mixture is stirred overnight at room temperature, and then poured onto excess sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate. The ethyl acetate extracts are dried and evaporated. The residue was dissolved in chloroform and chromatographed with 60 g of silica gel. First, a small amount of byproducts are eluted with chloroform. 2-bromo-4- (o-chlorophenyl) -9-methyl-bH-thieno (3,2 -) - 5-triazolo (4,3-a) 1,4) diazepine is eluted with chloroform + 0.5% methanol. Finally, the unsurpassed source material
    elute with chloroform + 1% methanol.
    It was impossible to isolate the desired 2-bromo-4- (o-chlorophenyl) -9-methyl-bH-thieno (3,2-f) -5-triazolo- (4,3-a D1,4) diazepine in completely pure the form. However, it was possible to identify it according to the concomitant
    chromatography and mass spectrum. (Approximately yield)
    According to the thin-layer chromatogram, this compound is identical to the sample with elementary analysis;
    Calculated: With 45.76; H 2.56; . N 14.23.
    C gH N ClBrS.
    Found: C, 45.81; H 2.56 / N, 14.42.
    0
    A pier, mass. 393.69.
    Mass spectrum: as is typical for a bromo-chloro compound, a triplet can be clearly established based on the ratio of isotopes:
    five
    nineteen
    C1 C1
    Vg
    392
    79
    37
    Vg
    394
    81 81
    35 C1 Bg Vg
    37:
    C1 396
    0
    Example 4. 2-Chloro-4- (o-sslopornyl J-9-dimethylaminomethyl-bH-thieno (3,2-f) -5-triazolo (4,3-a; (1,4) diazepine is translated into the corresponding hydrochloride with the aid of ethanol hydrochloric acid, which melts at 224 ° C with decomposition.
    In a similar manner, the following salt is obtained: 2-chloro-4 (o-chlorophenyl) -9-dimethylamino-6H-thieno methanesulfonate (3,2 | -5-triazolo (4, 3-a / ())
    177 C (with the decomposition of diazepine, T. em).
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives of thienotriazolodiazepine of the general formula ly x
    V "/
    Ί1 N / N 2 .
    I
    .... * 2
    where is chlorine or bromine /
    - o-chlorophenyl, *
    - methyl or dimethylaminomethyl,
    or their acid additive salts, characterized in that the compound of General formula
    CH,
    C = K X 2
    <2 and denied
    de H 2 and
    values are syringed or brominated with elemental halogen, respectively, in chloroform medium in the presence of: iridine or glacial acetic acid at a temperature of from -5 ° C to cometary, followed by separation of the product in free form or in the form of an acid additive salt.
    811 „.1060115
    one
    1060115
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    引用文献:
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    US3904641A|1971-06-18|1975-09-09|Yoshitomi Pharmaceutical|Triazolothienodiazepine compounds|AT338799B|1974-03-02|1977-09-12|Boehringer Sohn Ingelheim|PROCESS FOR PREPARING NEW SUBSTITUTED 6-ARYL-4H-S-TRIAZOLO--THIENO--1,4-DIAZEPINE AND THEIR SALTS|
    DE2531678C3|1975-07-16|1979-06-28|C.H. Boehringer Sohn, 6507 Ingelheim|Thieno [2,3e] triazole [3,4c] 5,6-dihydro-1,4-diazepines and processes for their preparation|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH179973A|CH584223A5|1973-02-08|1973-02-08|
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