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    • 专利摘要:
    . The method of obtaining 2-acylamino-TSH1-1H-2,3-dihydro-1,4-benzodiazhegsh-nrvyh compounds of General formula I) -N-4CH2-NH-C- (CH2) nR2 g O. where R is lower alkyl Group; p O or 1; RJ is one of the following groups: X a) -CE-% RT V Rio d) R. R, H R 8 where X is oxygen or sulfur; R is hydrogen, if X is acidic, genus, or is hydrogen or lower alknl, if X is sulfur; - identical shw different and mean hydrogen or lower alkyl; Rg is hydrogen, lower alkyl, lower alkoxy, nitrohalo trifluoromethyl- or. cyano group; R,) o is hydrogen or halide, or Rq and R. are linked to adjacent atoms 9. R-R, R, mi carbon and together mean methylenedioxy; one of the indicated groups a, b or c, where X is oxygen or sulfur, and hydrogen, if X is oxygen, or hydrogen, lower alkyl or halo, if X is sulfur; lower alkyl; hydrogen; hydrogen, lower alkyl, lower alkoxy, or halo; hydrogen or. . are linked to adjacent carbon atoms and together they mean a methylenedioxy group. as well as their optical isomers and their acid addition salts, with the fact that 2-aminomethyl-H-2,3-dihydro-1,4-benzodiazepine compounds of general formula II RS R. RV and RS u 4; ate 1C SL; o s
    公开号:SU1245259A3
    申请号:SU823453651
    申请日:1982-06-18
    公开日:1986-07-15
    发明作者:Цойгнер Хорст；Ремер Дитмар；Бензон Вернер；Липманн Ханс；Мильковски Вольфганг
    申请人:Кали-Хеми Фарма Гмбх (Фирма)；
    IPC主号:
    专利说明:

    R
    | CSN2 n
    R,
    and E have specified
    where R ,, R ,, .. values, are acylated with acids or reactive derivatives of acids of general formula II
    R, - (CH) - CO -V
    2D5259
    where R and n have the specified mean-. neither;
    . V oxy- or aminolitically cleaving the group, in a solvent inert under the reaction conditions, at a temperature between and the boiling point of the dissolving L under normal pressure and in the case; If necessary, the racemate mixtures of the compounds of the formula T are divided into their optical isomers, followed by the separation of the desired product in the free state or in the form of their acid addition salts.
    This invention relates to a process for the preparation of novel 1,4-benzodiazepine-2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine compounds of the general formula T
    CH-SH-C- (CH2) pV2
    about
    (I)
    N
     - lower alkyl group; - n O or 1 y
    where R p RJ is one of the following groups;
    a) S) -O-R
    X
    . . Yat
    C) O d) “9 V Rio
    where X is oxygen or sulfur;
    Rg is hydrogen, if X is oxygen or Rg is hydrogen or lower alkyl, if X is sulfur;
    R and the same or different and mean hydrogen or lower alkyl
    Rg is hydrogen, lower alkyl, lower alkoxy, nitrohalide, trifluoromethyl or cyano;
    hydrogen or halogen or
    Rg and are bonded to adjacent carbon atoms and together are methyl methyl group;
    five
    0
    five
    ABOUT
    five
    R, is one of the indicated groups a,
    b) GSH in,
    where X is oxygen or sulfur, and Rg is hydrogen, if X is oxygen,
    or Rg is hydrogen, lower alkyl or
    halogen, if X is sulfur; R is lower alkyl; Rg is hydrogen;
    R is hydrogen, lower alkyl, low
    sha apkoxy or halo;
    Rr., Hydrogen or
    R and Rg are attached to adjacent carbon atoms and together represent a methylenedioxy group,
    as well as their optical isomers and their salts of acid addition, have a analgesic activity with good therapeutic latitude and low toxicity,
    The purpose of the invention is to obtain new derivatives of 1,4-benzodiazepinone with a different spectrum of biological properties than the known structural analogues, which is achieved by the properties of newly obtained compounds.
    The following examples illustrate the method for preparing the proposed compounds, as well as previously unknown starting compounds.
    Example. 1-Methyl-2- / (furan-.3-carbonyl) -aminomethyl7-5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazhesh. „
    A., 42.6 g of NI - (thiophene-3-carbonyl) - N -methyl-K, -phenyl-2-hydroxy-1,3-diaminopropane in 126 ml of phosphorus oxychloride is boiled with refluxing for 5 hours. Then
    The reaction solution was added to a mixture of 250 g of ice, 250 ml of concentrated hydrochloric acid, and 250 ml of methylene chloride. The methylene chloride phase is separated, washed repeatedly with water and then washed with 30% sodium hydroxide solution until all acidic components have been removed. After that, it is washed again with water until neutral (wash water), dried. Over sodium sulfate, filtered and the methylene chloride is distilled off under reduced pressure. 31.5 g of a mixture of both isomeric compounds 1-methyl-2-chloromethyl-5- (3-thienyl) -Sh-2,3-dihydro-1,4-benzodiazepine and 1-methyl-3- chloro-6- (3-thienyl) -1,2,3,4-tetrahydro-1,5-benzodiazocine.
    B. The resulting mixture was dissolved in 230 ml of methanol and, together with 21.6 g of potassium phthalimide and 6 g of potassium iodide, was boiled under reflux for 12 hours. Then, methanol was distilled off under reduced pressure and the residue was taken up in methylene chloride, filtered and concentrated again. The residue with toluene and methylene chloride is filtered through 300 g of alumina I degree of activity. 30.9 g of 1-methyl-2-phthalium are obtained.
    midomethyl-5- (3-thienyl) -1H-2,3-di-G
    hydrobenzodiazepine, I
    B, the resulting compound together
    With 8.7 g of hydrazine hydrate in 300 ml of ethanol, it is heated at reflux for 4 hours. The solution is then filtered and the solvent is distilled off under vacuum. The residue is taken up in dilute (20%) hydrochloric acid and filtered again. Then extracted with
    the acidic aqueous solution is treated with concentrated sodium hydroxide solution until alkaline, the base is dissolved in methylene chloride, and the solution is washed with saturated sodium chloride solution to neutrality (wash water), dried over sodium sulfate and filtered. Then the solvent was distilled off, the residue (13.4 g) was dissolved in ether. The crystalline 1-methyl-2-aminomethyl-5- (3-thienyl) 1H-2,3-dihydro-I, 4-benzoyl crystalline dihydrochloride was dissolved in ether. -. shchazepine is filtered off under reduced pressure and carefully washed with ethyl acetate and ether, T, mp, 188 (with decomposition), yield 16.9 g
    D. 10.9 g of the above dihydrochloride are suspended in 130 ml of methylene chloride and the suspension is treated with 14.3 ml of triethylamine. While cooling with ice, 4.5 g of furan-3-carbonyl chloride in 50 ml of methylene chloride are slowly added dropwise to it. After addition, the reaction solution is stirred at room temperature. temperature for 2 hours. Then the solution is washed with water, ammonia solution (10%), again with water and sodium chloride solution, dried over sodium sulfate and filtered. The solvent is distilled off under reduced pressure. The remaining 1-methyl-2-; (Furan-3-carbonyl) aminomethyl-ilyT-5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine is dissolved in 1: 1 ethyl acetate and treated with a solution of hydrogen chloride gas in on air. Then, the hydrochloride released as crystals is filtered under vacuum and recrystallized from acetone, T, mp, 200 - 202.5 ° C, yield 7.9 g,
    Examples are p 2, 1-methyl-2- (furan-2-carbonyl) -aminomethyl-5- (2 -furyl) 1 H-2,3-dihydro-1,4-benzodiazepine,
    A, 273 g of II-furan-2-carbonyl-K-methyl-N-phenyl-2-hydroxy-1,3-diamyl-propane in 810 ml of phosphorus oxychloride are refluxed for 1.5 hours. After completion The reactions were distilled off the main amount of POCl (about 750 ml), the residue was poured onto 500 g of ice, 500 ml of methylene chloride was added. The organic phase is separated and washed with water several times. Then, by adding a concentrated solution of sodium hydroxide, the cyclization product is added as a base. After the usual treatment, 249 g of crude product is obtained, which is dissolved in 750 ml of ether, the solution is filtered and the filtrate is treated with a solution of gaseous chloride hydrogen in ether; The crystallized hydrochloride of the cyclization product is filtered off with suction. The crystals are dissolved in water and the base is again obtained by adding a concentrated solution of sodium hydroxide. The base is dissolved in ether, the solution is washed with water, and is evaporated. After distilling off the solvent, 179.9 g of an oily residue are obtained, which consists of a mixture of
    1-methyl-2-chloromethyl-5- (2-furyl) -1H-2,3-dihydro-1,4-benzodiazepine and 1-methyl-3-chloro-6- (2-furyl) -1,2, 3,4 tetrahydro-1, 5-benzodiazocin.
    B. Without separation or further purification, 179.9 g of the above mixture in 1200 ml of methanol together with 130 g of potassium phthalimide and 36 g of potassium iodide are boiled under reflux for 12 hours. Then methanol is distilled off and the residue is taken up in 500 ml of methylene chloride. After the addition of 50 g of Jf-alumina, the mixture is stirred for 4 hours. Then the solution is filtered off with suction from isopatka and concentrated. Obtained as an oily crude product of 1-methyl-2-phthalimido-5- (2-furyl) -1H-2,3-dihydro-1,4-benzodiazaz pin (211.4g) without further purification is used in the subsequent stage reactions, AT . 38.5 g of 1-methyl-2-phthalimido-5- (2-furyl) -1H-2,3-dihydro-1,4-benzodiazepine along with 140 ml of hydrochloric acid (24%) boil t at reflux for 7.5 h. The reaction solution is filtered and the filtrate is extracted with methylene chloride (100 ml). The acidic aqueous phase is treated with concentrated sodium hydroxide solution until it is alkaline and extracted with methylene chloride. The methylene chloride phase is washed with water, dried over sodium sulfate, filtered and evaporated under vacuum. The amine compound remaining as residue (18.5 g) is dissolved in ether and treated with a solution of hydrogen chloride gas in ether. 1-methyl-2-aminomersh-5- (2 -furyl) -1H-2,3-dihydro-1,4-benzodiazepine di-hydrochloride precipitates in the form of orange crystals, which are filtered, washed with hot acetone, filtered under vacuum and dried. M.p. , yield 21.8g.
    G. 32.8 g of 1-methyl-2-aminomethyl-5- (2-furyl) -1H-2,3-dihydro-1,4-benzodiazepine dihydrochloride are suspended in 450 ml of methylene chloro.o; and treated with 46 ml triethylamine. Under ice cooling, 14.4 g of furan-2-carboxylic acid chloride was added to 50 ml of methylene chloride. After conventional treatment, the resulting 1-methyl-2-.1 (furan-2-carbonyl) -aminomethyl-5- (2-furyl) -1H-2,3-dihydro-1, 4-benzodiazepine is isolated in the form of the hydrochloride. T.-pl. 239-241 0 5 (with decomposition), yield 17 g.
    EXAMPLE 3. 1-Methyl-2 Ktiofen-2-carbonyl) -aminomethyl 1-5- (2-cyanyl) -1H-2,3-dihydro-1,4-benzodiazepine. .
    0 A. 203 g (thiophene-2-carbonyl) -N-methyl-N-phenyl-2-hydroxy-1,3-diaminopropane and 410 ml of phosphorus chloroxide are boiled at reflux 20 hours. The reaction mixture is treated as follows. ,
    5 as described in Example 1 or 2. The inorganic cyclization product is dissolved in ether, the solution is filtered and treated with a solution of gaseous hydrochloric hydrogen in ether. Crystals of 1-methyl-2-2 and 1-methyl-5- (2-thienyl) -1H-2, 3-dihydro-1,4-benzodiazepine hydrochloride crystals, which are recrystallized from acetone / isopropanol, are in excess. M.p. 163-164 ,,
    5 exit 98.3 Go
    B. 26.4 g of the above hydro. the chloride in I00 ml of dimethylformamide is heated from 10.4 g of sodium azide to. R and incubated for 3 h at this temperature. Then dimethylformamide is distilled off under reduced pressure, the residue is taken up in 100 ml of toluene and washed with a complete solution of the donated salt. After drying over sodium sulfate and filtering, the solvent is distilled off under vacuum. 20.1 g of 1-methyl-2-azodimets-1-5- (2-tiiish) -1II-2,3-dihydro are obtained. 1, 4-benzodiazepine (IR spectrum 2120cm).
    B. 20.1 g of the azidomethyl compound are dissolved in 100 ml of methanol.
    five
    and after adding 4.4 ml of triethylamine and 10 ml of hydrazine hydrate in 300 ml of methanol, about 10 g of Reye nickel, added in portions, is treated. After 4 hours, the catalyst is separated and the reaction solution is extruded. The residue is dissolved in methylene chloride and the solution is washed with saturated sodium chloride solution. 1 methyl-2-aminomethyl-5- (2-tynyl) -1H-2,3-dihydro-1, 4-benzodiazepine, after the usual treatment, is transferred in a known manner to the dihydrochloride. M.p. 175 ° C (with. Decomposition), yield 16.6 g.
    D. 16.6 g of the indicated dihydrochloride and 20.5 ml of triethylamine are dissolved in 400 ml of methylene chloride and reacted with 7.3 ml of thiophene-2-carboxylic acid anhydride in the usual way, as described in Example 1G or 2G, and after the usual treatment, the resulting 1-methyl-2- (thiophene-2-carbonyl aminomethyl} -1H-2,3-dihydro-1,4-benzodiazepine in the form of hydrochloride is obtained. mp. 173-197 ° C, yield used
    PRI me R 4, 1-Methyl-2-dS-furan-2-carbonyl) -aminomethyl-5- (2-thienyl) -1H-2,3-dihydro-1,4-benzodiazepin,
    A. 20.3 g of 2- (2-aminobenzoyl) -thiophene are heated for 6 hours to 60-70 ° C together with 10.2 g of epichlorohydrin and 6 g of acetic acid. This reaction mixture is then poured into water and is extracted with methylene chloride. The organic phase is separated, washed until neutral, dried, filtered and evaporated. 25 g of 2 - ((3-chloro-2-hydroxypropyl) -amino-benzoyl | -thiophene are obtained in the form of an oily crude product. The latter, without further purification, is heated in a water bath for 2.5 hours with 32 ml of formic acid and 16 ml 37% formaldehyde solution. The solution is then poured onto ice and extracted with chloroform. The organic phase is washed until neutral with a saturated solution of sodium carbonate. Then the chloroform phase is dried, filtered and evaporated. 24 g of 2-J2 -, (3 -chlorop-2-oxy-propyl methylamino-benzyl | -thiophene. The latter is treated with 3.5 g of hydroxide Atri and 6.8 ml of water in 50 ml of dioxane and 50 ml of isopropanol for 10 hours at room temperature. After distilling off the organic solvent, the oily uncleaned product is diluted in methylene chloride under reduced pressure and the solution is washed with water until neutral, dried over sodium sulfate and filter. Methylene chloride is distilled off to give 12 g of 2- {2- | N- (2,3-epoxypropyl) -methine-amino-benzoyl | -thiophene. The latter is cycled with 36 g of ammonia in 1200 ml of methanol by 10 hour heating to 150 ° C in a steel autoclave. After distilling off the solvent, 9 g of 1-methyl-3-hydroxy-6-tin-1, 2, 3,4-tetrahydro-1, 5-benzodiazocin are obtained. By 2 hours refluxing with SOCf, 10 g of crude α-methyl-2-chloromethyl-5- (2-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine hydrochloride are obtained.
    After recrystallization from acetone / isopropanol, 8 g of 1-methyl-2-chloromethyl-5- (2-thienyl) -111-2,3-dihydro-1, 4-benzodiazepine hydrochloride, m.p. 163-164 ° C.
    B. The above indicated 2-chloromethyl
    The compound is converted to the corresponding 2-aminomethyl compound or to its dihydrochloride (m.p.; upon decomposition) according to the procedure described in Example 3.
    at. The resulting 1-methyl-2-aminomethyl-5- (2-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine dihydrochloride salt is reacted in the usual way, as in Example 2G, with furan-2-carboxylic acid chloride . After the usual treatment, 1-methyl-2- (furan-2-carbo-NILE) -aminomethyl, -5- (2-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine hydrochloride is obtained. M.p.
    221-225 ° C.
    EXAMPLE 5 8-Methoxy-1-methyl-2-benzoyl-aminomethyl-5- (3-thienyl) -1H-2,3-dihydro-I, 4-benzodiazepine.
    A. 16 g of 8-methoxy-l-methyl-2-azido-methyl-5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine, obtained analogously to the example ZA - B from K , - (thiophene-3-carbonyl) -N,., - methyl-N - (3-methoxyphenyl) -2-hydroxy-1,3-diaminopropane, dissolved in 200 ml of methanol and subjected to room temperature the interaction of 12 ml of dimercaptopropane and 16 ml of tr ethylamine. The reaction solution is stirred for 48 hours at room temperature. The solvent is then distilled off and the residue is dissolved in 200 ml of ether. The ether solution is filtered and extracted with dilute hydrochloric acid (10%). The acidic aqueous solution is treated with sodium hydroxide solution (20%) until it is alkaline. Then extracted with ether. The ether solution is washed with a saturated salt solution, dried over sodium sulfate, filtered and the solvent is distilled off. 9.9 g of crude 8-tags are obtained. si-1-metsh1-2-aminomethyl-5- (3-year
    NIL) -1H-2,3-dihydro-1,4-benzodiazepine. The crude product can be used for subsequent transformations without further purification. It can be converted to the dihydrochloride in the usual way by treatment with gaseous hydrogen chloride. M.p. dihydrochloride 1.90-211 C (with decomposition).
    B. 9.5 g of 8-methoxy-1-methyl-2-aminomethyl-5- (3-thienyl) -1H-2,3-dihydro 1,4-benzodiazepine and 3.2 g of triethyl amine are dissolved in 120 mp methylene chloride. Then a solution of 4.9 g of benzoyl chloride in 20 ml of methylene chloride is added dropwise to the solution while cooling with ice. The reaction solution is stirred for 2 h at room temperature and washed with water, then with ammonia solution (10%) and again with water. After drying over sodium sulfate, the filtrate is distilled off and the solvent is distilled off under thinning. 9 g of crude 8-methoxy-I-methyl-2-benzoylaminomethyl-5- (3-thienyl), 3-dihydro 1,4-benzodiazepine are obtained as a residue. The crude product is dissolved in a mixture of ether and ethyl acetate (1: 1). Hydrochloride is precipitated out of the solution by adding hydrochloride gas to the solution. Last
    Filtered under reduced pressure and transferred with hot acetone. The output of 7.3 g of hydrochloride, so pl. 233-234 ° C ..
    And Example 6. 1-Methyl-2-G (4-trifluoromethylbenzoyl) -aminomethyl} -5 (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepin.
    A. 10 g of 1-methyl-2-azidomethyl-5- (3 -thienyl) -IN-2, 3-dihydro-4-benzodiazepine obtained from C. phen-3-carbonyl) -N2-methyl- N-phenyl-2-hydroxy-1,3-diaminopropane, analogously to example ZA-B, is dissolved in 200 ml of concentrated hydrochloric acid and reacted with 20 g of tin chloride dihydrate (G1) at a reaction temperature of 0-3 ° C. the mixture is stirred for 30 minutes while cooling with ice and then for 1 hour at room temperature. Then every 2 hours, another 10 g is added each time tin chloride dihydrate. After 7 hours, the reaction solution is extracted with methylene chloride and the methylene chloride phase is then washed with sodium hydroxide solution.
    (20%), dried over sodium sulfate and filtered. The solvent is then distilled off under vacuum. 6.5 g of crude 1-methyl-2-aminomethyl-5- (3-thienyl) -1H-2, 3-dihydro-1,4-benzodiazepine are obtained as a residue.
    B. 6 g of 1-methyl-2-aminomesh1-50 (3-thienyl), 3-dihydro-1,4-benzodiazepine is dissolved in 50 ml of trrolol. Then, 4.4 g of trifluoromethyl benzoic acid and after 30 min 7 g of triethylamine are added. With this stirring, a solution of 1.6 g of phosphorus oxychloride in 20 ml of toluene is added to this reaction solution under stirring, with a sharp increase in temperature by 40-50 ° C.
    0 The reaction mixture is heated for another 1 hour to 80 ° C and then poured into 500 ml of water. The pH is adjusted to 10 by addition of concentrated sodium hydroxide solution. The organic
    Phase 5 and aqueous alkaline phase again. extracted with methylene chloride. The combined organic phases are worked up in the usual way, washing them with water, suction over sodium sulfate,
    0 filter and evaporated. From the crude residue obtained in the form of 1-methyl-2- (4-trifluoromethyl-benzoyl) -aminomethyl} -5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine, the hydrochloride is prepared in the usual way. and recrystallize it from ethyl acetate. Output 7.5 g, so pl. hydrochloride 185-188 C.
    EXAMPLE 7 .1-Methyl-2-, (4-cya-nobenzoyl) -aminomethyl-5- (3-thienyl) -1 H-2, 3-dihydro-1,4-benzodiazepine. , 15.4 g of 4-cyanobenzoic acid is dissolved in 300 ml of methylene chloride, the solution is cooled before and treated with 14.6 ml of triethylamine. Then, over a period of 5–10 min, add dropwise 10 m of M.ti ethyl chloroformate ester and the reaction mixture is stirred for another 30 min at 0–5 ° С. Then 28.5 g of 1-methyl-2-amino- methyl 5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine (for preparation, see Example 1A-B) dissolved in 200 ml of methylene chloride, is added dropwise in such a way so that the temperature of the reaction mixture was kept in the range. Then the reaction solution is stirred for another 4 hours at room temperature.
    0
    five
    temperature After that, the reaction mixture is treated with ordinary em. 37.6 crude solids are obtained. The latter is known in the art to transfer to hydrochloride. M.p. 234-239 s, exit 31 g
    EXAMPLE 8 8-methoxy- -methyl- 2- (4-cyanobenzoyl) -aminomethyl 1-5- (3-thienyl) -1H-2,3-dihydro-1., 4-benzo azazepine.
    12.7 g of 2-chloro-1-methylpyridinium iodide are suspended in 350 ml of methylene chloride with stirring at room temperature. The solution is treated with 14 ml of 15 triethylamine and 9.5 g of 4-cyanobenzoic acid. After 15 minutes, a solution of 14.1 g of 8-methoxy-1-methyl-2-aminomethyl-5- (3-thienyl) -1H-2,3-dihydro-1,4 is added dropwise over 15 minutes. - benzodiazepine - (for example, see example 5A) in 50 ml of methylene sulide. After another 30 minutes, 300 ml of water was added and the mixture was treated with a small amount of aqueous ammonia (20%) 5 until a weak alkaline reaction was reached. After the usual treatment, 23.2 g of crude product is obtained as a residue. This residue is successively chromatographed with ether, methylene chloride and ethanol on 150 g silica gel. The base obtained is converted in the usual manner into hydrochloride, which, after mixing with hot acetone, has, m.p. 256-259 C, output 17.3g.

    EXAMPLE 9 8-Methoxy-1-methyl-2-C (furan-3-carbonyl) -aminomethyl-5- (3-thienyl), 3-dihydro-1,4-benzodiazepine.
    7.5 g of 8-methoxy-1-methyl-2-amino-methyl-3- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine (for preparation, see Example 5A) are dissolved in 50% ml of methylene chloride and treated under nitrogen atmosphere as an inert gas with 10 ml of a 2.5.M solution of trimethylaluminum v-hexane. The reaction solution is stirred at room temperature for 15 minutes. Then a solution of 3.5 g of furan-3-carboxylic acid ethyl ester in 20 ml of methylene chloride is added dropwise. The reaction solution is heated at 35–40 ° C for 50 hours. C. Then the reaction mixture is decomposed by cooling with ice by carefully adding a solution of ammonium chloride and sodium chloride in water. Uoc40
    45
    50
    55

    5 5 o
    0
    five
    0
    five
    7.3 g of hydrochloride 8-methoxy-1-methyl-2 is obtained by conventional treatment. (furan-3-carbonyl) -aminomethyl-5- (3 thienyl) -1H-2,3-dihydro-1,4-benzodiazepine. M.p. 237-238.5 ° C.
    Example 10., 1-Methyl-2 (thiophen-3-carbonyl) -aminomethyl-5- (3-pyridyl) -1P-2,3-dihydro-1,4-benzodiazepine. ,
    A. To a mixture of 123.5 g of N-methyl-anthranranyl acid methyl ester and 42.6 g of acetic acid heated to 60 ° C, is added dropwise 107 ml of epichlorohydrin while stirring. The mixture is stirred for an additional 16 hours
    60 ° C, then an additional 17 ml of epichlorohydrin is added and the mixture is stirred at 60 ° C for another 4 hours. The reaction mixture is then cooled to room temperature, poured onto ice / water and extracted with methylene chloride. The methylene chloride phase is washed with saturated sodium bicarbonate solution and water and dried over sodium sulfate, filtered and evaporated. 218 g of crude N-methyl- (3-chloro-2-hydroxypropyl) -anthranilic acid methyl ester is obtained as a residue.
    B. 218 g of the obtained ester is added to 1.5 liters of dry ether and, with ice-cooling, 51 g of powdered potassium hydroxide are treated. The mixture is stirred for 24 hours at room temperature. Then the solution is decanted, filtered and evaporated. Crude 3-chloro-methyl-1-me-. TyL-1,2-DIHIDRO-3H-5H-1,4-benzodiazepin-5-OH, remaining in the residue, is crystallized from ether and the crystals are dried under vacuum. Output 54.8 g
    B.31.4 ml of 3-bromopyridine is dissolved in 300 ml of absolute ether under conditions that exclude the presence of moisture, and the solution is cooled to -30 ° C. Under a nitrogen atmosphere, 200 ml of a 1.6 M solution of p-butyl lithium in hexane are slowly added dropwise and the reaction mixture is then stirred at -50 ° C for 40 minutes. The solution of 3-pyridine lithium obtained in this way is at a temperature of about -60 ° C 54.2 g of the compound obtained in c. are added dropwise to the solution. P. B, in 400 ml of absolute tetrahydrofuran and then the reaction mixture is stirred for 1 hour at
    . Then, at this temperature, a solution of 20 MP of water in 150 ml of tetrahydrofuran is slowly added dropwise. The reaction mixture is allowed to warm to room temperature and then diluted with about 200 ml of toluene. The organic layer is separated, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. 87 g of crude product remained as residue, which was purified by chromatography on 850 g of silica gel, eluent diclohexane / ethyl acetate 3: 7. 3950 g of 2- {2-1N- (3-chloro-2-hydroxypropyl) methylMino-benzoyl-pyridine are obtained in the form of an oil.
    D. 39 g of the obtained compound is dissolved in 314 ml of dimethylformamide and treated with 32 g of potassium phthalimide and 4.9 ml of pyridine. The reaction mixture is stirred for 2 hours under conditions that exclude the presence of moisture. The dimethylformamide is then distilled off and the residue is taken up in. water and methylene chloride. The organic phase is separated, washed with water, dried over sodium sulfate, filtered and evaporated. In the form of the residue, 51.0 g of 2 - ((3-phthalimido-2-hydroxypropyl) methylamino benzoyl-pyridine is obtained.
    D. 51.0 g of the obtained phthalimide compound in 612 ml of concentrated hydrochloric acid is heated with reflux for 16 hours, and hydrogen chloride is occasionally introduced into the reaction vessel. Then, most of the hydrochloric acid is distilled off, the residue is transferred to water, and, under ice-cooling, the alkaline reaction is established by the action of a dilute sodium hydroxide solution and extraction is carried out with methyl ene chloride. The organic layer is separated, washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated. 29.8 g of crude 2- {2-L- (3-amino-2-hydroxypropyl) -methylamino-Zbenzoyl | -pyridine are obtained.
    E. 29.8 g of the obtained amine is heated in 259 MP of toluene for 8 hours to 90 ° C in an atmosphere of nitrogen. The solution is cooled to room temperature, filtered and evaporated. 27.4 g of 1-methyl-3-hydroxy-6 (2-pyridyl) -1,2,3,4-tetrahydro-1,5-benzodiazocin are obtained as a residue.
    G. 25.8 g of the obtained compound
    3-hydroxybenzodiazocine is dissolved in 161 ml of methylene chloride and 190 ml of carbon tetrachloride and 26.6 g of triphenylphosphine are added. The reaction mixture was stirred at reflux for 3 hours at reflux, and after 1 hour 6.4 g were added and after 1.5 hours another 1 g of triphenylphosphine was added. The solvent is then distilled off and the residue is purified by chromatography on silica gel, e.pu5 ant toluene, then cyclohexane / ethyl acetate 4: 6. 40 g of crude product are obtained which is taken up in 500 ml of ether. In this case, triphenyl phosphine oxide is precipitated as a white precipitate. This precipitate is filtered off under reduced pressure and the solution is concentrated. 23.3 g of a mixture of 1-methyl-2-chloromethyl-5- (2-pyridyl), 3-dihydro-1,4-benzodiazine pin and 1-methyl-3-chlorop-6- (2-pyridyl) are obtained. l, 2,3,4-tetrahydro-1,5-benzodiazocine.
    3. Without separation or further purification, 25 g of this mixture in 205 ml of metiol, together with 18 g of potassium phthalimide and 1.43 g of potassium iodide, are boiled under reflux with stirring
    for 6 hours, with 5 g added after 5 hours, 5 grams of juice, and after 3 hours, another 2 grams of potassium phthalimide. The methanol is then distilled off, the residue is taken up in water / methylene chloride, the organic phase is separated, washed with water, dried over sodium sulfate, filtered and evaporated. 27.5 g of 1-methyl-2-phthalimido-: 5- (2-pyridyl) -1H-2,3-dihydro-1,4-benzodiazepine are obtained.
    And 27.5 g of this compound in 325 ml of ethanol is heated at reflux and stirred for 2 hours with 7.3 ml of hydrazine hydrate and 35 ml of concentrated hydrochloric acid. The ethanol is distilled off, the residue is treated with dilute hydrochloric acid and the resulting precipitate is filtered off from the solution, and the solution is extracted with methylene chloride. Then, while cooling with ice, the aqueous phase is treated with the action of a dilute sodium hydroxide solution until an alkaline reaction is established and extracted with methylene chloride.
    0
    15
    The methylene chloride phase is washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. 12.8 g of 1-methyl-2-aminomethyl-5- (2-pyridyl) -1H-2,3-dihydro-1,4-benzodiazine are obtained.
    K. 4.2 g of the resulting amine is dissolved in 120 ml of methylene chloride and 2.7 triethylamine. While cooling with ice and stirring, a solution of 2.5 g of thiophene-3-carboxylic acid chloride in 5 ml of methylene chloride is dropwise added to the solution. The reaction mixture is treated with water, the methylene chloride phase is separated, washed with dilute sodium hydroxide solution and water, dried over sodium sulfate, filter, and evaporate. 6.4 g of crude product are obtained, which is purified by chromatography on 80 g of alumina (11 / 1I1 activity level) of eluant toluene / methylene chloride. 5,2 1-methyl-2-, (thiophene-3-carbonyl) -ami. Nomethyl-5- (2-pyridyl) -1H-2,3-dihydro-1, 4-benzodiazepine is obtained. 5.2 g of this
    The bases are dissolved in acetone and the solution is treated with a solution of 1.8 g of fumaric acid in ethanol. The solution is concentrated and the residue is dissolved in acetone. The compound fumarate is slowly deposited in the form of crystals. Crystals are dried for 2 days at 60 ° C under vacuum. Yield 3.5 g, m.p. 175-177 ° C. ,
    The methods described in examples 1-10 can also be obtained by acylation of the corresponding 2-amino-methyl-5-heteroacyl-1H-2,3-dihydro-1,4-benzodiazepine compounds 2 acylaminomethyl-5-heteroaryl-1H-2, 3-dihydro-1,4-benzodiazepine compounds of general formula 1, listed in Table 1 (abbreviations accepted: phen, phenyl; fur-furyl; thien. Thienyl; pyrrole. Pyrrolyl; pyrid. Pyri; Dil; HC G - hydrochloride; basic - free base; n-tos. - p-toluene sulfonate; fumes.-fumarate;; (2) - decomposition; (S) - sintering; am-amorph;
    . PRI me R 143. 7-Methoxy-1-metsh-2-2. (4-hydroxybenzo-11p) -aminomers 11-5- (3-thienyl) -1H-2,3-dihydro-1,4-ben zodiazepine.



    sixteen
    0
    five

    five
    0
    0
    five
    0
    Saponification of 5,2 g of 7-methoxy-1-methyl-2- (4-ace.toxybenzyl) -aminomatyl is performed. (3-Thienyl) -1 H-2,3-dihydro-1,4-benzodiazepine with a mixture of 50 ml of 40% soda lye, 50 ml of water and 100 ml of methanol for 15 minutes at room temperature. After the reaction is completed, they are extracted the reaction mixture with methylene chloride. After evaporation of the methylene chloride phase, a crude base is obtained, in the form of a mild residue. It is absorbed in 25 ml of isopropanol and converted with a saturated solution of ethereal hydrogen chloride in its hydrochloride. The resulting salt is filtered and dried. 4.3 g of 7-methoxy-1-methyl-2- are obtained. (4-hydroxybenzoyl) -aminomethylZ-5- (3-thienyl) -1H-2,3-dihydro-1,4-benzdiazepine x 1.1 HC1 x X 0.1 N Oh with so pl. 193-197 ° C.
    Example 144. 7-Chloro-1-methyl-2 (4-aminobenzoyl) -aminomethyl-5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine.
    6,3 .g 7-chloro-1-methyl-2-C (4-acetamidobenzosch1) -aminomethyl1-5- (3-thienyl) -1II-2,3-dihydro-1,4-benzodiazepic x 1.05 HCl x 0.25 in a mixture of 50 ml of 40% soda lye, 50 ml of water and 100 ml of methanol for 1 hour at 65 ° C. After cooling, the reaction mixture is extracted with methylene chloride and the methyl chloride phase is evaporated. The resulting oily residue of the base is introduced into 30 ml of ethanol and converted into ethereal hydrogen chloride solution in hydrochloride. The resulting salt is filtered and dried. 5.5 g of 7-chloro-1-methyl-2- (4-aminobenzoyl) -aminomethyl-5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine X 1.85 are obtained HC1 X 0.5 NO with so pl. 112-116 ° C.
    Example 145. 7-Fluoro-1-methyl-2 (L-cyanobenzoyl) -aminomethyl 1-5-. (3-Thienyl) -1H-2, D-dihydro-1,4-benzo-.
    danaz epin.
    9.3 g of 7-fluoro-1-methyl-2- (4-cyano-benzoyl) -aminomethyl-5- (3-thienyl) -1H-2, D-dihydro-1,4-benzodiazepine hydrochloride is added with cooling with ice in a mixture of 50 ml of 40% soda lye, 50 ml of water and 100 ml of methanol, and the base is immediately released. The reaction mixture is extracted with methylene chloride and pos1
    jlt nypar H-and methylychloro-nfritol desiccation remains in the form of ml: lknis.) residueKsCh. It crystallized from 30 ml of diethyl ether. After filtration and drying, a crystal of 6.0 g of 7-fluoro-1-methyl is obtained -2-y4-cyaiob (anzoyl) -aminomethyl-5- (3-thienyl) H-2,3-dihydro-1, 4-6eii3o-dnazepnna with so pl. .
    Example 146, Racemic separation of 1-methyl-2- (4-cyanobenzoyl) -aminomethyl-5- (3-thienyl) -1H-2, 3-dihydro-1,4-benzodiazepine.
    100 g of the racemate 1-methyl-2- (4-benzoyl) -aminomethyl-5- (3-tie sh1) -1H-2,3-dihydro-1,4-beisodiazepine (for preparation, see example 7) solution 500 ml, and to obtain the salt, mix with a solution of two equivalents of the monohydrate of / - / - 0.0-dibenzoyl-b-tartaric acid in a small amount of ethanol and leave the solution to stand at room temperature until the crystals precipitate. . The crystals are then filtered, washed with a small amount of ethanol and recrystallized from ethanol to the same angle of rotation.
    A free base is separated from the combined mother liquors and re-dissolved in ethanol. This solution is mixed with a solution of two equivalents of monohydrate / + / - 0.0-dibenzoyl-D-tartaric acid in a small amount of ethanol to form the salt. The resulting solution was also allowed to stand at room temperature until crystals precipitated, the precipitated crystals were filtered off, washed with a small amount of ethanol, and recrystallized from ethanol to a constant angle of rotation.
    By treating the salts thus obtained with a dilute solution of sodium hydroxide, the bases are isolated in free form and extracted with methylene chloride. After separating the aqueous alkaline solutions, the methylene chloride extracts are washed with water, dried over sodium sulfate and evaporated. Amorphous bases are obtained as amorphous residues. 1 result of semi 4ajoT 3.9 g / - / - 1-methyl-2- (4-cyano-benzoyl) -aminomethyl-5- (3-thienyl) -1I-2, 3-dihydro-1,4-beisodiazepine- th base and 4.1 g / / -1-methyl-2-1 (4-cyanobenzoyl) -aminomethyl -5- (3

    ABOUT

    0
    59iS
    thienyl) -1 H-2, 3-dihydro-1, 4-be zepine base of the compound with the following physical characteristics.
    / - / - base: optical purity 97%, determined by NMR spectroscopy using chiral reagent (heptafluoropropyloxymethylene) -d-camphorto-europium -1 1 1. oi 1 - 72.6, (from 0.29% in ethanol). 86-92 ° C (amorphous).
    / + / -basis: optical purity
    97%. + 71.5. (from 0.29% in ethanol) m.p. 72-76 ° C (amorphous). Example 147. 7,8-Methylenedioxy-1-methyl-2- (thiophene-3-carbonyl) -aminomethyl-5- (3-thienyl) -1 H-2, 3-dihydro-1, 4-benzodiazepine ( compound of example 17).
    8 g of 7,8-methylenedioxy-1-methyl-2-aminomethyl-5- (3-thienyl) -1H-2, 3-dihydro-1 |, 4-benzodiazepine dihydrochloride are added, they are reacted in the same way as in example 1G with methylene chloride Reed with thiophene-3-chlorohydride of carboxylic acid, the reaction solution is stirred for 6 hours at a temperature of -5 ° C. Then the separation is carried out, as described in Example 1G, and the resulting compound is converted to hydrochloride. Yield 5.2 g, m.p. hydrochloride 276-283 C.
    Example 148. 7-Methoxy-l-methyl-2-benzoyl-aminomethyl-5- (3-thienyl) - iH-2, 3-dihydro-1,4-benzodiazepine (compound of example 38).
    1.2 g of 7-methoxy-methyl-2-aminomegly-5- (3-thienyl) -IN-2,3-dihydro-, 4-benzodiazepine dihydrochloride is subjected to the interaction as in Example 1G with benzoyl chloride.
    The reaction is carried out in tetrahydrofuran at a temperature of -12 ° C, a duration of 8 hours. Then, as described in Example 1G, the separation is carried out and the resulting basic compound is converted to hydrochloride. Exit 7,8. g, so pl. hydrochloride 197-203 ° C.
    Example 149. 8-Methyl-1-methyl-2- (3-thienylacetyl) -aminomethyl 3 - 5- (3-thienyl) -2, 3-dihydro-1,4-benzodiazepine (compound of example 69).
    7.6 g of 8-methyl-1-methyl-2-aminomethyl-5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine dihydrochloride is reacted as in Example 1G 33 methylene chloride with 3- acetic acid chloride, and the reaction mixture is stirred for 12 hours at a temperature. Then, as described in Example 1G, separation is carried out and the resulting compound is transferred to the hydrochloride salt. T. pl. hydrochloride 206-210 C, the output of 4.1 g. .
    Example 150. Preparation of 1-methyl-2- (furan-3-carbonsh1) -aminomethyl} -5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine (compound of example 1 ).
    A. 10.9 g of 1-methyl-2-aminomethyl-5- (3-thienyl) -1H-2,3-dihydro-1,4-ben: zodiazepine dihydrochloride is converted, as in Example 1G, the reaction solution is left for reaction instead of 2 hours at room temperature; re for 1 hour at a boiling temperature (boiling point of methylene chloride) and then the reaction solution is separated, as described in Example 1G. 8.0 g of the basic compound hydrochloride are obtained. M.p. 200-202.5 C.
    B. 10.9 g of 1-methyl-2-aminomethyl-5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine dihydrochloride is converted, as described in Example 1G, tetra is used as the solvent. - rahidrofuran and leave the reaction solution for reaction for 1/2 hour at boiling point (boiling point of tetrahydrofuran 66 ° C). Then a separation is performed as described in Example 1G. 8.2 g of the basic compound hydrochloride are obtained. M.p. 200-202.5 ° C.
    In “10.9 g of 1-methyl-2-aminomethyl-; 5- (3-thienyl) -1N.-2,3-dihydro-1,4-benzodiazepine dihydrochloride is converted
    as described in Example 1H, benzene was used as the solvent and the reaction solution was allowed to react for 45 minutes at the boiling point (boiling point. Benzene, 80 s). Then a separation is performed as described in Example 1G. 6.5 g of the basic compound hydrochloride are obtained. M.p. 200-202.5 ° C.
    G. 10.9 g of 1-methyl-2-aminomethyl-5- (3-thienyl) -1H-2,3-dihydro-1,4-benzodiazepine dihydrochloride is converted as described in Example 1G, however, as a solvent diethyl ether was used and the reaction solution was allowed to react for 1 hour at a boiling temperature (boiling point of ether). A separation is then carried out as described in Example D. 7.5 g of the basic compound hydrochloride are obtained. M.p. 200-202,
    The novel 2-ac1 shaminomethyl-5-heteroaryl-1H-2,3-dihydro-1,4-benzodiazepine compounds and their pharmacologists) 0 acceptable salts differ from the known 1,4-benzodiazepine derivatives with a pharmacologically specific profile of action and have , in particular, clearly expressed detrimental properties with low toxicity.
    Owing to their clearly pronounced analgesic properties, the compounds proposed are useful analics.
    The analgesic properties of the compounds are demonstrated in a pharmacological test on small rodents and monkeys. It has been proven that the compounds of formula I can increase the pain threshold of mammals in animals. of This, in particular, has been proven in two pharmacologically standard test methods for testing the effect of light radiation on mice and the test for arthritis pain in rats. Determination of the minimum toxic dose.
    Male individuals with a weight of 20-25 g
    orally, the maximum dose of the test substance is 300 mg / kg. For 3 hours, symptoms of toxicity in animals are carefully observed. 24 hours after taking the medicine, all symptoms and deaths are additionally recorded. Adverse symptoms are also observed and recorded. If death or a toxic symptom is observed, then the next j moles are continuously diminished. with a dose until no more toxic symptoms occur. The smallest dose that causes a toxic symptom is referred to as the minimum toxic dose.
    Arthritis pain test in rats.
    Male rats of the OFA breed weighing 160-180 g were anesthetized by administering 20 mg / kg i.p. live weight. pentabarbital sodium. 0.1 ml suspension of Mycobacterium Smegmae (S1043)
    in paraffin oil (0.6 mg Musobaster, O, 1 ml oil) were administered internally in the left hind paw. After 14 days, when a pronounced secondary arthritis developed, especially in the right hind paw, the action of the test substances was examined. 30 minutes before the test substance was injected, a control measurement was made in such a way that the ankle joint of the right hind paw was bent three times and the number of sounds made was counted.
    Rats that do not react are separated. Three hours after the administration of the orally tested substances, the folding procedure is repeated. Animals that make a sound only once or do not make any sound at all are rated as protected from pain. Per dose is applied from 9 to 20 rats and the ED is calculated (95% confidence area) according to the method of Litehfield and Wilcoxon (1949). UNIT denotes a dose that protects 50% of the animals that have been treated.
    Light emission test for mish.
    The method is based on the principle of operation described by D Amour and Smith (1941). However, instead of rats, fed male and female individuals of lower weight are applied. 30 minutes before the test substance is administered, each mouse is individually placed in a cylindrical container so that it cannot rotate and move forward there. Her tail sticks out of the cylinder, being laid in a narrow recess. The determined tail point of each animal (at a distance of about 35 mm from the root of the tail) is exposed to the heat of the lamp with a known intensity and temperature of the radiation that is directly under the tail. The time in seconds that the mouse takes to drag the tail out of the light flux is determined twice, once every 30 minutes and a second time 15 minutes before the subcutaneous administration of the test substance (10 mg / kg). Those whose response time deviates by more than 25% are excluded. The reaction times are again measured 15 and 30 minutes after ingestion of the test substance and
    extending the response time to more than 75% of the average value obtained by determining the same substance before taking the test substance is estimated as an anesthetic effect. As the ED (95% confidence area) of each test substance, 30 minutes after taking it, take that dose, which increases the reaction time compared to the time before taking the test substance by more than 75% for 50% of animals. The calculation is made according to the method of Litehfield and Wilcoxon (1949).
    The use of formula I in the described pharmacological tests at doses ranging from 0.1-100 mg / kg has an analgesic effect.
    Table 2 shows the results obtained with the test methods given (the numbers of the examples given for the compounds of formula I refer to the numbers of the examples given in Table 1).
    The compounds of the formula D can be used in pharmaceutical administration forms which contain about 0.1-100 mg of active substance per unit dose.
    The dosage used is adjusted according to the type of treatment to be treated and individual requirements. However, in general, in animal tests, the analgesic effect was obtained at doses of 0.1-100 mg / kg.
    For the treatment of pain in humans and large nutritional supplements, for example, preparations with a content of 0.25-50 mg, in particular 1-50 mg of the active substance in a single dose, are suitable. Parenteral preparations contain, as a rule, less active substance than preparations for; oral administration.
    The compounds of the formula T are used alone or in combination with pharmaceuticals & amphibiously used carriers and / or auxiliary substances in the form of solid or liquid forms. As examples of solid preparations, oral preparations may be mentioned, such as tablets, capsules, powder granules or dragees, or suppositories. Solid preparations may contain inorganic talc-type and / or organic carriers customary in pharmaceuticals.
    23.
    carriers of the type of milk sugar or starch, as well as pharmaceutically common auxiliary substances such as lubricants, such as magnesium stearate. Liquid preparations such as solutions, suspensions or emulsions may contain the usual dilute 1245259
    whether such as water, oils or petroleum jelly and / or suspending agents such as polyoxyethylene glycol and the like. Other additives, such as preservative agents, stabilizers and wetting agents, may also be added additionally.
    40 СНз Н
    41СНз Н
    About 3-Tien .- 3-Tien, About Fen. 3-Tien
    7-CHjO H Base 157-162 7-F N Base 142-145
    27
    49 CHj N
     3-C1-3-Tien, 7-C1H
    - pheno
    50 CH 3 N
    1 2-C1-3-Tien, 7-C1H
    -phen
    51СНдН
    About 3-Tien. 7-c lН
    -phen
    61 CHj N
    About 4-F-3-Tien. -phen
    1245259
    28 Continuation, table 1
    132-137
    187-191
    Base 0.1 HC1
    197
    (CH)
    SNON am
    8-CH
    H
    HC1
    218-222
    29
    CH,
    SNN
    CH; n
    H
     n
    n-CgH, H
    hair dryer
    About 4-CN- 3-Tien, -phen
    About Fen. 3-Tien.
    About A-CF - 3-Tnen. -phen
    About 4-CN-3-Tien. -phen ..
    About 3-Fur. 3-Tnen.
    76. H
    ABOUT ; 4-CN-hair dryer. 3-Tien. 8-F
    77 CH.
    H
    About 4-F-3-Tien. -phen
    -phen -tyen
    1245259
    30 Continued
    0,
    am 131-135
    H
    HCI
    212-216
    HCN. 179-183, 2
    (SNS)
    snon
    SrF
    HC1
    179-201
    HC1 211-214 HC1 200-204
    HC1
    207-213
    HCI
    221-232
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    权利要求:
    Claims (1)
    [1]
    . A method for producing 2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine compounds of the general formula 1 wherein R i is a lower alkyl group; η = 0 or 1;
    -one of the following groups:
    where X is oxygen or sulfur;
    Rg is hydrogen, if X is acid, OR
    R 6 is hydrogen or lower alkyl, if X is sulfur;
    L and R g are the same or different ( and are hydrogen or lower alkyl;
    R 3 is hydrogen, lower alkyl, lower alkoxy, nitrohalo and trifluoromethyl. cyano group;
    R 10 is hydrogen or halogen or
    Rg and D ^ are bonded to adjacent carbon atoms and together represent a methylenedioxy group;
    R 3 is one of the indicated groups a, b or c, where X is oxygen or sulfur, wherein R 6 is hydrogen, if X is oxygen, or
    R 6 is hydrogen, lower alkyl or halogen, if X is sulfur;
    R lower alkyl;
    R g is hydrogen;
    R ^ g hydrogen, lower alkyl, lower-. alkoxy or halogen;
    R 5 is hydrogen or.
    R and R „are bonded to adjacent carbon atoms and together denote a methylenedioxy group, as well as their optical isomers and their acid addition salts, characterized in that 2-aminomethyl-1H-2,3-dihydro-1,4-benzodiazepine compounds general formula II
    SU <„, 1245259 AZ where R ( , R d , and R & have the indicated meanings, acylate with acids or reactive derivatives of acids of the general formula 111
    R, - (SND - CO, where R Q and η have the indicated meanings;
    V is an oxy- or aminolytically cleavable group, in a solvent inert under the reaction conditions, at a temperature between -30 ° C and boiling point, dissolve La at normal pressure and, if necessary, racemate mixtures of compounds of formula I are separated into their optical isomers, followed by isolation the target product in a free state or in the form of their salts of acid addition.
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    同族专利:
    公开号 | 公开日
    DK274082A|1982-12-20|
    NO822037L|1982-12-20|
    PH17911A|1985-01-25|
    PT74971A|1982-06-01|
    DE3266521D1|1985-10-31|
    PT74971B|1983-12-29|
    IE821468L|1982-12-19|
    FI822148L|1982-12-20|
    ES8304564A1|1983-03-01|
    AU8499182A|1982-12-23|
    AU547857B2|1985-11-07|
    FI822148A0|1982-06-15|
    DE3124013A1|1982-12-30|
    GR76499B|1984-08-10|
    HU188178B|1986-03-28|
    US4497740A|1985-02-05|
    NO157420C|1988-03-16|
    FI68049C|1985-07-10|
    IL66076A|1986-03-31|
    CA1188299A|1985-06-04|
    NZ201007A|1985-05-31|
    EP0068240A1|1983-01-05|
    DD202553A5|1983-09-21|
    IE53464B1|1988-11-23|
    JPH0433795B2|1992-06-04|
    EP0068240B1|1985-09-25|
    NO157420B|1987-12-07|
    ZA823780B|1983-03-30|
    US4649137A|1987-03-10|
    JPS58968A|1983-01-06|
    AT15802T|1985-10-15|
    IL66076D0|1982-09-30|
    FI68049B|1985-03-29|
    ES512844A0|1983-03-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US28315A|1860-05-15|Improvement in method of decomposing fats into fatty acids and glycerine |
    NL122319C|1961-06-20|
    USRE28315E|1964-06-15|1975-01-21|Cooc.hi |
    US3560482A|1967-12-08|1971-02-02|Sumitomo Chemical Co|Method for producing benzodiazepine derivatives|
    US3546212A|1968-06-12|1970-12-08|Hoffmann La Roche|Oxidation of benzodiazepines with ruthenium tetroxide|
    US3773765A|1971-08-18|1973-11-20|Upjohn Co|S-triazinobenzodiazepine-1,3-diones|
    US3847935A|1972-04-12|1974-11-12|Upjohn Co|5-substituted 1--2-imidazolidinones|
    DE2265371C3|1972-05-03|1980-12-11|Kali-Chemie Ag, 3000 Hannover|N- anilines|
    DE2353187A1|1973-05-02|1974-11-14|Kali Chemie Ag|2--1,4-benzodiazepines - useful as tranquillisers with only slight musculotropic effect|
    DE2353160C2|1973-05-02|1986-07-17|Kali-Chemie Ag, 3000 Hannover|5-Phenyl-2,3-dihydro-1H-1,4-benzodiazepines, their acid addition salts and medicaments containing these compounds|
    US4244869A|1972-05-03|1981-01-13|Kali-Chemie A.G.|Benzodiazepine derivatives and process of making them|
    DE2314993A1|1973-03-26|1974-10-03|Kali Chemie Pharma Gmbh|5-benzo-1,4-diazepines - sedatives etc. prepd. by cyclisation of N-anilines|
    DE2353165C2|1973-05-03|1983-06-09|Kali-Chemie Ag, 3000 Hannover|1-methyl-3-hydroxy-6- -1,2,3,4-tetrahydro-1,5-benzodiazocine derivatives|
    US3925358A|1973-07-27|1975-12-09|Hoffmann La Roche|1-Lower alkyl-2-substituted-1,4-benzodiazepines|
    US4368159A|1978-05-15|1983-01-11|Hoffmann-La Roche Inc.|Intermediates to produce imidazodiazepines|
    DE2952279A1|1979-12-24|1981-06-25|Kali-Chemie Pharma Gmbh, 3000 Hannover|NEW 2-ACYLAMINOMETHYL-1,4-BENZODIAZEPINE AND ITS SALTS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    HU186760B|1981-03-12|1985-09-30|Gyogyszerkutato Intezet|Process for preparing 3,4-dihydro-5h-2,3-aenzodiazepine derivatives|US4724237A|1984-06-26|1988-02-09|Merck & Co., Inc.|2-substituted-aminomethyl-1,4-benzodiazepines|
    US4899425A|1986-11-14|1990-02-13|Mahlo Gmbh & Co. Kg.|Apparatus for straightening weft yarns in fabrics|
    US6458784B1|1994-06-29|2002-10-01|Smithkline Beecham Corporation|Vitronectin receptor antagonists|
    US5977101A|1995-06-29|1999-11-02|Smithkline Beecham Corporation|Benzimidazoles/Imidazoles Linked to a Fibrinogen Receptor Antagonist Template Having Vitronectin Receptor Antagonist Activity|
    WO2011034144A1|2009-09-18|2011-03-24|三菱瓦斯化学株式会社|Method for producing cyclohexyl alkyl ketones|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19813124013|DE3124013A1|1981-06-19|1981-06-19|2-ACYLAMINOMETHYL-1,4-BENZODIAZEPINE COMPOUNDS, METHODS AND INTERMEDIATE PRODUCTS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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