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    • 专利摘要:
    . The method of obtaining 3-amino-1-benzoxepine derivatives of general formula IV .. in R where R and Rj independently of one another are hydrogen, C-C-alkyl, unsubstituted or substituted by phenyl, or C-C-alkyl containing the ends as substituents methoxyl residues, or one of Rxj and R j is hydrogen or C-C-alkyl, and the other of Li is C2-Ca-alkyl, having at the end as a substituent the group - In which K and Rg are independently from a friend — hydrogen or C — Cc-alkyl, or R and R, together with the nitrogen atom to which they are bound, form a pyrrolidine, piperidine or mor olinovoe ring; one of H3 and R4 is hydrogen, and the other of them is hydroxy,. or both R and R together - oxygen; Rg- and R independently of each other are hydrogen or halogen, C-C-alkyl, or C-alkoxy, or their stereoisomers, or their salts, which is tl and h a and with the fact that the 3-amino derivative 1-benzoxepinone-5
    公开号:SU1017170A3
    申请号:SU802953852
    申请日:1980-08-01
    公开日:1983-05-07
    发明作者:Олендорф Хайнрих-Вильхельм；Вольф Клаус-Ульрих；Каупманн Вильхельм；Хайнеманн Хеннинг
    申请人:Кали-Хеми Фарма Гмбх (Фирма)；
    IPC主号:
    专利说明:

    Li-tri-7C / -butylborohydride in a neutral medium or sodium cyanoborohydride in a strong acidic range of pH values and the desired product is isolated in free form or as a salt,
    or as stereoisomers, or a compound of Form I, where R and Rg are hydrogen, are converted to Compound 1, where R-, is hydrogen. or C — C — alkyl and Rg — C — Cc — alkyl.
    The invention relates to a luce method. new compounds: 3-amino-1-benzoxepine derivatives of the general formula where R, and 5 are independently hydrogen, C-C5 alkyl, unsubstituted or substituted by phenyl, or C-C-alkyl, containing at the ends as methoxyl residues, or one of R ;, and R ,,, is hydrogen or C is C-alkyl, and the other of them is C2 C-alkyl, and ixcii at the end as a substituent group in which Rf and K g independently of one another are hydrogen or C - Cd - alkyl or R and R together with the nitrogen atom, with which they are bound, form a pyrrolidine, piperidine or morpholine ring about; one of R and R is hydrogen, and the other of them is a hydroxy group, or both Rt- and R together oxygen; Rg - and R independently of one another - hydrogen or halogen, C C -f alkyl or C - C4 alkoxy group, or their stereoisomers, or their salts. These compounds have pharmacological activity, having a good effect on the mobility of the muscles of the stomach. A known method for producing 2-ethyl-4-oxychromane or 2-ethylchroman by catalytic reduction of 2-ethylchromene in the presence of Rene G nickel. The purpose of the invention is the preparation of new 3-amino-1-benzoxepine derivatives of general formula I possessing valuable biologically active properties. This goal is achieved in the manner that the Z-amino-1-benzoxepinone-5 (2H) derivative of the general formula "(D). 1 have the indicated RF 6 where H, R values. subjected to reduction with sodium borohydride at pH 4-7 or sodium cyanoborohydride at pH 3-4 at a temperature from ambient temperature or catalytic hydrogenation with hydrogen in the presence of Rene nickel, preferably in a hydrogen pressure of 2-150 bar, in a proton solvent, preferably ethanol or isopropanol, and isolate the desired product of formula I, where R is hydrogen and R. is hydroxy, in free form, either as a salt, or as stereoisomers, or the compound of formula II is subjected to reduction of sodium cyanoborohydride ohm at pH 4-6 at a temperature from (f C to ambient temperature or catalytic hydrogenation with hydrogen, preferably at a hydrogen pressure of 50-150 bar, in the presence of Rene nickel in an aprotic solvent, preferably toluene or benzene, and the desired product is isolated You I, where R and R are together oxygen, in free form or as a salt, or translate it into a compound of formula I, where R is hydrogen and R is hydroxy, by the action of sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium 5k - (2 - methoxyethoxy) -alkmogidrid or lit It’s 7C1-butylborohydride in neutral medium or sodium cyanoborohydride in the strongly acidic pH range and the desired product is isolated in free form, either as a salt or as stereoisomers, or a compound of the formula 1, where R7 and Rg are hydrogen, are translated into a compound of the formula T, where R-, is hydrogen or Q is C-alkyl and R0, is Q-C-alkyl. Derivatives of 3-amino-1-benzoxepine of formula 1, in which one of the two residues R and R represents a hydrogen atom, and the other of them represents a hydroxyl group, can be separated into racemates with and using a configuration of a carbinol residue and amino residual. The compounds of formula 1 contain at least one chiral carbon atom and are in the D-or L-form, and also in racemic form.
    In one stage, the double bond is located at the 3, 4 position, and the 5-keto group is reduced to the hydroxyl group at the 5 position in the case when the compound of formula P is reduced with sodium borohydride. in neutral or weakly acidic medium, especially in the pH range from 4 to 7, or sodium cyanoborohydride S acidic medium / mainly, but with pH values from 3 to 4, for example, dioxane, tetrahydrofuran, dimethylformamide can be used as a solvent , ethylene glycol dimethyl ether or diethylene glycol dimethyl ether. In addition, such molecular molecular alcohols as methyl alcohol, ethyl alcohol and isopropyl alcohol can be used. Organic or inorganic acids, such as, for example, acetic acid, para-toluenesulfonic acid, benzoyl sulfonic acid, hydrochloric acid, or sulfuric acid, can be used to create a pH value that is in the favorable region.
    Simultaneous hydrogenation and reduction also occurs when the compound of formula P is reduced by hydrogen in the presence of Rene nickel in a protic solvent medium, which is preferably
    use ethyl or isopropyl, new alcohol.
    A racemic 2,3,4,5-tetrahydro-3-amino-1-benzoxepinode-5 of formula 1 is thus formed. It can be obtained from the reaction mixture in the form of the free base or in the form of a salt with an acid.
    For separation into the racemates of the scimene, respectively, the / 7 & l-configurations of carbinol residues and amino-residues, the resulting free base or its additive salt with an acidic salt can be subjected to fractional crystallization in a suitable solvent, which can be used, for example, lower alcohol. Preferably, maleic acid, p-toluenesulphonic acid and cyclohexaminosulfonic acid are used as the acid in the preparation of the salt. The separation of MpmjsT isomers should be carried out by chromatography of the free base with a suitable solvent on silica gel or alumina.
    ..- tsga and rats - mind / C-2,3,4,5-tetrahydro-3-amino-1-benzoxepinols-5 of formula I as a result of interaction with a suitable optically active acid, for example tartaric acid, o, (/ - dibenzoyl tartaric acid
    one, almond acid, di-O-isopropylidene-2-oxo-b-gulonic acids, and the subsequent fractional crystallization of the obtained salt can be divided into optically active antipodes. Free bases can be isolated from these salts, which, if desired, can be converted to pharmacologically acceptable salts. By recrystallization from a solvent such as a lower alcohol and / or ether, racemic compounds and their isomers, as well as their acid addition salts, can be purified. 1 hydrogenation of the double bond in position 3, 4 in compounds of formula 11 is carried out in a weakly acidic medium, preferably at pH values from 4 to 6, using sodium cyanoborohydride in a solvent such as, for example, lower alcohol, dioxane, tetrahydrofluran , dimethylformamide, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether. Suitable acids are, for example, acetic acid, para-toluene sulfonic acid, benzosulfonic acid, hydrochloric acid or sulfuric acid. Hydrogenation with hydrogen in the presence of Rene nickel in an aprotic solvent such as toluene or benzene equally leads to the selective hydrogenation of the 3,4-double bond in compounds of formula II. As a result of interaction with the acid in the medium .9 An organic solvent, additive salts of rac-3-amino-3,4-dihydro-1-benzoxepinone-5 (2H) derivatives can be obtained. Separation on. Optically active antipodes can be implemented in the manner described.
    Example. To a cooled ice-bath, 1.88 g (0.1 mol) of 3-methylamino-1-benzoxepinone-5 (2H) in a mixture consisting of 125 ml of dioxane and 125 ml of acetic acid, are added when cooled in small portions, borohydride. sodium to complete the reaction, 0.4 mol pH 4-5. The reaction solution is then poured into ice water, the mixture is made alkaline by the addition of sodium carbonate, after which it is extracted with dichloromethane. The organic solution is washed with a saturated solution of sodium chloride and dried over sodium sulfate. After distilling off the solvent, 16.4 g (85% of theory) of rac. -2j3,4,5-tetrahydro-3- are obtained. -methylamino-1-benzoxepinol-5 c. as an oily residue.
    The melting point of the hydrochloride of the obtained compound was 152-157 ° C (from isopropyl alcohol To separate the isomers, the mash obtained in the manner described was dissolved in isopropyl alcohol and the solution was mixed with an excess of maleic acid. As a result of fractional crystallization of maleate from isopropyl alcohol and the subsequent conversion compounds in hydrochloride receive hydrochloride rats.-chmg-2, 3, 4 5-tetrahydro-Z-methylamino-1-benzoxepinol-5, the melting point of which is l (methyl alcohol) diethyl ether, and rac.-trans -2,3,4,5-tetrahydro-3-methylamino-1-benzoxepinol-5 hydrochloride, the melting point of which is 170173 C (methyl alcohol) diethyl ether. compounds of formula I, which themselves possess valuable pharmacological activity, are intermediate products used to prepare the corresponding 5-hydroxy compounds of formula 1. The keto group can be reduced using conventional reducing agents, for example, in a neutral pH range using b rgidrata sodium, lithium aluminum hydride, lithium borohydride, sodium gYaks- (2-methoxyethoxy) -alyuminiygidrida or tri- 77go / -butilgidrida lithium or e silnokisloy field pH using sodium cyanoborohydride in the solvents indicated and the application of these acids in order to maintain the desired pH . However, by selecting the appropriate solvent and reducing agent, an increase in the amount of the desired racemate can be achieved. EXAMPLE 18.18 g (0.1 mol) of 3-methylamino-1-benzoxepinone-5 (2H) is mixed with 40 g of Rene nickel in 400 ml of ethyl alcohol for 5 hours at a hydrogen pressure of 55 bar. Immediately after this, the catalyst is filtered off from the reaction mixture, the solvent is distilled off from the filtrate, as a result of which 7.7 g (40% of the theoretical) are obtained is happy. -2, 3,4,5-tetrahydro-3-methylamino-1-benoxipinol-5 as an oily residue. By analogy with the described, the obtained compound can be divided into isomers. Example 3: To a solution of 94.2 g (0.5 mol) of 3-methylamino-1-benzoxepinone-5 (2H) in smsi, consisting of 300 ml of dioxane. and 300 ml of glacial acetic acid, while cooling added 18.9 g (0.3 mol) of sodium cyanoborohydrate in small portions in such a way that the temperature of the reaction mixture does not exceed. Immediately after this, the reaction mass is stirred at room temperature until: the reaction is complete, after which the reaction solution is poured into ice with a mixture, the mixture is made alkaline by the addition of sodium carbonate and then extracted with dichloromethane. The organic phase is washed with an overhead sodium chloride solution and dried over sodium sulfate. The rac-3-methylamino 3, 4-dihydro-1-benzoxepinone-5 (2H) hydrochloride is precipitated by introducing hydrogen chloride into the solution of hydrogen chloride, which is immediately filtered off. The yield of the product is 89.9 g (79% of the theoretical), m.p. 184-18bs (methyl alcohol / diethyl ether). Example 4. To a solution of 2.3 g (0.01 mol) of 3- (rt.-butylamino) -l benzocsepinon-5 (2H) in 10 ml of methyl alcohol, traces of bromocresol green are added. A solution of hydrogen chloride in methyl alcohol (3N) was added dropwise to the mixture before the transition of the indicator (pH 4-6). Immediately thereafter, a solution of 0.65 g of sodium cyanoborohydride (0.01 mol) in 10 ml of methyl alcohol was slowly added to the mixture at room temperature, after which the reaction mixture was further stirred for 1-2 hours until the reaction was complete. In this case, by adding a dropwise solution of hydrogen chloride in methyl alcohol, the indicator is yellow. The solution is then evaporated, the residue is extracted with water, the reaction of t) acTBopa is made alkaline by the addition of dimethylamine, followed by extraction with diethyl ether. The ethereal solutions are combined and dried over sodium sulfate. By introducing hydrogen chloride into the solution, rac-3 (and-butylamino) -3,4-dihydro-1-beneoxepinone-5 (2H) hydrochloride is precipitated. The resulting product is filtered and recrystallized. The product yield is. 2.0 g (74.1% of theoretical), so pl. 154-158s (isopropyl alcohol / diethyl ether). Example 5. 27.9 g (0.1 mol) of 3-phenethylamino-1-benzoxepinone-5 (2H) are mixed with 25 g of Rene nickel in 350 ml of toluene for 20 hours under a hydrogen pressure of 150 bar. Immediately thereafter, the catalyst is filtered off from the reaction mixture, the solvent is distilled off from the filtrate, and the residue is extracted with methyl alcohol. 14.6 g (46% of theoretical) of hydrochloride rac. -3-phenethylamino-3, 4-dihydro-1-6eneoxepinone-5 (2H) with melting point (methyl) from methyl alcohol is obtained by introducing hydrogen chloride into the solution of hydrochloride. Example 6. By the methods described in Examples 3-5, 3-Methyl-Mino-7-methyl-1-6-penox-5 {2H) 3-ketilamino-7-ethyl-1-benzoxep non-5 (2H) 3-methylamino- compounds 7-bromo-1-benzoxep non-5 {2H) 3-Methylamino-7-methoxy-1-benzko sepinon-5 (2H) 3-Methylamino-8-methoxy-1-benzoc sepinon-5 (2H) Z-Iirrolidino -Ygbenzoxepinone-5t2H) 3-Matilamino-7,8-dichloro-1-benz sepinon-5 (2H) 3-Methyl amino-7,8-di-methyl-1-ben ksep11non-5 (2H) 3-Isopropylamino-1-benzoxepine-5 {2H) 3-Benzylamino-1-benzoxepinone-5 2H) 3-Dimethylamino-1-benzoxepinone-5 ( 2H) 3-Piperidino-1-benzoxepinone-5 (2H) 3-Morpholino-1-benzoxepinone-5 (3- (PG-Dimethylaminopropylamino) -chloro-1-benzoxepinone-5 (2H) 3- (Dimethylaminopropylamino) -benzoxepinone-5 5 (2H) 3- (| 3-Dimethylaminoethylamino} -1-benzoxepinone-5 {2H) 3-amino-1-benzoxepinone-5 (2H) 3- (1-Metoxyethylamino) -1-benzo pinone-5 (2H) translated into the following compounds: m, pl. , Hydrochloride, rac.-3-methylamino-3, 4-digidro-6-methyl-1-benzoxepinone-5 (2H) 183-185 Hydrochloride, rac.-Zmethylamino-3, 4-dihydro-7-ethyl-1-benzoxepinone -5 {2H) 146-148 Hydrochloride, rac.-3-methylamino-3, 4-dihydro-7-bromo-1-benzoxepinone-5 (2H) 193-195 Hydrochloride, rac-3-methylamino-3,4-dihydro-7 -methoxy-1-benzoxepinone-5 (2H) 178-180 Hydrochloride rac, -3-methylamino-3, 4-dihydro-8-methoxy-1-benzoxepinone-T-5 {2H) 168-170 Hydrochloride rac.-3 -pyrrolidino-3, 4-dihydro-1-benzoxepinone-5 (2H) 128-130 Hydrochloride rac.-3-methylamino-3, 4-dihydro-7, 8-dichloro-1-benzoxepinone-5 (2H) 194 Hydrochloride rats.-3-methylamino-3, 4-d igidro-7, 8-dimethyl-1-benzoxepinone-5 (2H) 206 Hydrochloride, rac.-3-and 3 opropylamino-3,4-dihydro-1-benzoxepinone-5 (2H) 171-175 Hydrochloride, rac.-3- benzylamino-3 ,. hydro-1-benzoxepinone-5 (2H) 141-145 Maleinate rac.-3-dimethylamino-3, 4-dihydro-l-benzoxepinone-5 (2n) 107-109 Rac.-3-piperidino-3 hydrochloride, 4- dihydro-1-benzoxepinone-5 (2H) 154-156 Hydrochloride rats.-3-morpholino-3, 4-dihydro-1-benzoxepinone-5 (2H) 148-150 Dihydrohlrrid monohydrate rac „-3 (y-dimethylaminopropylamino) - 3,4-dihydro-7-chloro-1-benzoxepinone-5 (2H) 150-154 Dihydrochloride rats.t3- (-Dimethylminophenylamino) -3,4-dihydro-1-benzoxepinone-5 (2H): 154-158 Dihydrochloride Rats.-3- ((L-dimethylaminoethylamino) -3,4-dihydro-1-ben. zoxepinone-5 (2H) 150-157 Hydrochloride rats.-3-amino-3, 4-dihydro-1-benzox Pinona-5 (2H) 211 Hydrochloride rats.-3- {L-methoxyethylamino) -3,4-dihydro-1-benzoxepinone-5 (2Я) 133-135 example 7. To a solution of 33.5 g mol) rat dihydrochloride .-Zdimethylaminopropylamino) -3,4hydro-l-benzoxepine-5 (2H) in ml of methyl alcohol while cooling, add sodium orhydride in small portions until pH 7 is complete. The reaction plant is then acidified with added hydrochloric acid and the mixture is dried. The resulting precipitate is extracted with water, the solution until alkaline reaction by
    adding an aqueous solution of ammonia, after which the extraction is carried out with dichloromethane. After washing the organic solution with a saturated solution of sodium chloride, drying over sodium sulfate and evaporation, 23.8 g (90% of the theoretical) rac.-2,3,4,5-tetrahydro-3- (-dimethylaminopropylamino) -1-benzoxepinol are obtained. 5 as an oily residue.
    Using chromatography on silica gel and the subsequent formation of dimaleinate, pau dialmaleate, -i4wr-2,3,4, 5-tetrahydro-3- (y-d-methylaminopropylmino) -1-benzoxepinol-5 with melting point leg-lTO C (methyl alcohol) is obtained. ) and diamaleinate rac.-w / 3 7Wc-2, 3,4,5-tetrahydro-3- (9-dimethylaminopropylamino) -1-benzoxepinol-t5 with a melting point of 157-159s (methyl alcohol).
    Example 8. To a solution of 80 g (0.5 mol) rats.-3-methylamino-3,4-dihydro-1 benzoxepinone-5 (2H) heated to boiling point in a mixture consisting of 550 ml of toluene and 300 ml of hexane 550 ml of 1 M tri-w y-butyl boron hydride a lithium in tetrahydrofuran are added dropwise in such a way that the solution is kept boiling. After completion of the dropwise addition of this solution, the reaction mass is heated at the boiling point for the next hour. After cooling, the reaction mixture is brought to acidic reaction by adding dropwise a methanolic solution of hydrogen chloride, immediately thereafter the methanol phase is separated and the mixture of toluene and goxane is extracted once more with a meter of hydrogen chloride. The extract is evaporated, the residue is extracted with dichloromethane and sodium carbonate solution (10%), the organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. As a result, 67.6 g (70% of the theoretical) rac-2 is obtained, 3.4, 5-tetrahydro-3-methylamino-1-benzoc-, sepinol-5 as an oily residue, containing 32 parts of rac. -C.S-2,3,4, 5-tetrahydro-3-methylamino-1-benzoxepinol-5 and 18 parts rac. fn / yaMC-2,3,4, 5-tetrahydro-3-methylamino-1-benzoxepinol-5. These compounds can be separated and characterized by analogy with that described.
    Example 9. To a solution of 3.9 g (0.02 mol) of rac. - / cghc-2,3,4,5-tetrahydro-3-methylamino-1-benzoxepinol-5 in 80 ml of acetonitrile and 17.1 ml
    aqueous formaldehyde solution (35%), 3.9 g (0.06 mol) of sodium cyanoborohydride is added. Directly thereafter, 2.1 ml of glacial acetic acid was added to the reaction mixture, and the mixture was stirred for 2. h at room temperature. The reaction solution is then diluted with 270 ml of diethyl ether, washed with dilute sodium hydroxide solution, dried over sodium sulfate and evaporated. The residue obtained is dissolved in methyl alcohol, after which the rac-meadows -2, 3,4,5-tetrahydru-3-dimethylamino-1-benzoxepinol-5 is isolated in the form of maleate. The yield of the product is 3.9 g (60% of theoretical), so pl. 157-158 C (methyl alcohol / diethyl ether).
    PRI m e. P 10. By analogy with the described examples from
    3-amino-1-benzoxapinone-5 (2H) 3- (-0thylamino) -1-benzoxepinone-5 (2H)
    Z-Benzylamino-1-benzoxepinone-5 (2H)
    3-Phenethylamino-1-benzoxepinone-5 (2H)
    3-Dimethylamino-1-benzoxepinone-5 UH)
    3-Diethylamino-1-benzoxepinone-5 (2H)
    Z-Pyrrolidino-1-benzoxepinone-5 (2H)
    Z-Piperidino-1-benzoxepinone-5 (2H)
    Z-Morpholino-1-benzoxepinone-5 (2H)
    3-Methylamino-7-ethyl-1-benzoxepinone-5 (2H)
    3-Methylamino-7-chloro-1-benzoxepinone-5 (2H)
    3-Methylamino-8-chloro-1-benzoxepinone-5 (2H)
    3-Methylamino-7-bromo-1-benzoxepinone-5 (2H)
    3-Methylamino-7-methoxy-1-benzoxepinone-5 (2H)
    3-Methylamino-7-chloro-8-methyl-1-benzoxepinone-5 (2H)
      Dimethylaminopropylamino) -7-chloro-1-benzoxepinone-5 (2H) 3- (p, p -Dimethyl-dimethylaminopropylamino) -1-benzoxepinone-5 (2H)
    3- (E-Methoxyethylamino) -1-benzoxepinone-5 (2H) 3-Mutyl "1ino-7gmethyl-1-benzoxepinone-5 (2H)
    3- Methylamino-8-methoxy-1-benzoxepinone-5 (2H)
    3-Methylamino-7,8-dichloro-1-benzoxepinone-5 (2H) 3-Methylamino-7,8-dimethyl-1-benzoxepinone-5 (2H) gives the following compounds: Hydrochloride rat-Cr "; -2, 3, .4,5-tetrahydro-3-amino-1-benzoxepinol-5 Concentrated rac-tycryc-2,3,4,5-tetrahydrc-3-amio-1-6-ene-oxepi-nola-5 toluene-4 sulphonate rac. -4ttc-2,3,4,5 tetrahydro-3- (H, -butylamidio) -1-benzoxepinol-5 Toluene-4-sulphonate rac. -ifpzwc-2, 3,4,5 tetrahydro-3- (N-butylamino) -1-benzoxepinol-5 Meshennat rac. , 3,4,5-tetrahydro-3-benzylamino-1-benzoxepinol-5 Malein rac. -2, E, 4,5-tetragndro-3-benzene amino-1-benzonosepinol-5 Ialeinate rac.H "s-2, 3,4,5-tetrahydro-3-phenethyluthyro-1-braxopenol-5 Malein pau. -2,3,4,5-tetrahydro-3-phenethylamine-1-benzochsepinol-5 Malein rac. -TfUc -2, 3,4,5-tetrahydro-3-dimethylamino-1 -benzoxepinol-5 Maleinate pan. -2,3,4,5-tetrahydro-dimethylamino-1-benzoxepinol-5 Toluene-4-sulfonate rac. -If-2,3,4,5-tetrahydro-3-diethy amino-1-benzoxepic-la-5 Toluene-4-sulphonate rac., 3,4, 5-tetrahydro-3-diethyl amino-1-benzoxepine la-5 Tolurl-4-sulphonate is happy. Number - 2,3,4,5-tet-3- pyropolidine-l-benzo-cyclospinol-5 Toluene-4-sulfonate rac .- "y cwo-2,3,4,5 tetrahydro-3-pyrrolidino-1-benzoxepi-nola-5 Toluene g-4 sulfonate rac., 3,4,5-tetrahydro -3-piperidi no-1-benzoxepi-nola-5 Toluene-4-sulfonate rac. 2,3,4 / 5-tetrahydro-3-piperidino-1-bvneoxepinol-5142-144 Toluene-4-sulfonate rac. -VZffi-2, 3,4, 5-tetrahydro-3-morpholino. -1-benzoxepinol-5154-156 Toluene-4-sulfonate rac .- "/ gals-2, 3, 4, 5-tetrahydro-3-morpholino-1-benzoxepinol-5. 145-146 Hydrochloride of rats.-Chggs-2, 3,4,5-tetragagno-3-methylamino-7-ethyl-benzoksopinol-5138-140 Hydrochloride of rats.-iyb "wc-2, 3,4,5-tetragon -Z-methyl but-7-ethyl-1-benzoxepinol-5197-198 Hydrochloride sd rac. -H "f-2,3,4,5-tetrahydro-3-methylamino-7-chloro-1-benzoxepinol-5172-173 rac. Hydrochloride. -wyW.wc-2, 3,4,5-tetrahydro-3-methylamine-7-chloro-1-benzoxepinol-5242 (decomp.) Rac hydrochloride, -I Zir-2, 3,4, 5-tetra-, hydro-3-methylamino-8-chloro-1-benzoxepinol-5194-195 Hydrochloride. 2,3,4,5-tetrahido-Z-methylamino-8-chloro-1-benzoxepinol-5189-190 Hydrochloride rac. , 3,4,5-tetrahydro-Z-methylamino-7-bromo-1-benzoxepinol-5 186-188 Hydrochloride rac. -W / aAc-2, 3,4,5-tetrahydro-Z-methylamino-7-bromo -1-benzoxepino- la-5 .243 (decomp.) Hydrochloride rac. - fftc-2, 3,4,5-tetrahydro-. gg3-methylamino-7-methoxy-1-benzoxepinol-5198-200 Hydrochloride, rac.-s; Hegles-2, 3,4,5-tetrahydro-Z-methylamino-7-methoxy-1-benzoxepino223-22S Hydrochloride rac, - e {gE 2,3,4,5-tetrahydro-3-methylamino-7-chloro-8-methyl-1233 (de-benzoxepinol-5
    Hydrochloride rats.- l / "zls-2, 3, 4, 5-tetrahydro-3-methylamino-7-chloro-8-methyl-1-benzoxepinol-5
    Dihydrochloride rats.-1 -is-2, 3,4, 5-tetrahydro-3- (T dimethylaminopropylamino) -7-chloro-1-benzoxepinol-5
    Dimaleinat rats.-g ms-2p3, 4,5-tetrahydro-3- (1, (L -dimethyl-dimethylaminopropylamino) -benzoxepinol 5
    Dimaleinat rats.-inpcMC-2, 3,4, 5-tetrahydro-3- (, / -dimethyl-dimethylaminopropylamino) -1-benzoxepinol-5
    Cyclohexylaminosulfonate rac. -2,3, 5-tetrahydrog3- -methoxy-ethylamino) -1-benzoxepinol-5 Cyclohexylaminosulfonate rac-achl 2ls-2, 3,4,5-tetrahydro-3 (-methoxyrtylamino) -1-benzoxepinol-5: - 2, 3,4, 5g of tetrahydro-3-methylamino-7-methyl-1-b; enzoxepinol-5;
    Hydrochloride rac. (, 3,4 ;, 5-tetrahydro-3-methylamino-7-methyl-1-benzoxepinol-5
    Hydrochloride rats.- $ hl: -2, 3,4, 5: -tetrahydro-3-me; type | lamino-8-methoxy-1-benzoxepinol-5 Hydrochloride rats.- g; 5CAC-2, 3, 4 | , 5-tetrahydro-3-methylamino-8-methoxy | -1-benzoxepino / a-5 Hydrochloride | rac. -C-is-2,3,4, | 5-tetrahydro-3-meth; lamino-7, 8-dichloro-1-benzoxepinol-5
    Hydrochloride- | rac, -tf ciHc-l, 3,; 4, 5 tetrahydro-3: -methylamino-7, 8-di; Chlor-l-benzocoxine: Ola-5 Hydrochloride; rac. -IA, tfC -2.3 , 4 5-tetrahydro-3-methylamino-7, 8-dimethyl-1-benzoxepinol-5198 (decomp.)
    Hydrochloride rats.- and / esg; l: -2, 3,4,5 tetrahydro-3-methyl5 amino-7,8-dimethyl-1-benzoxepinol-5 208 (decomp.)
    Example 11. To a solution of 1.9 g (0.01 mol) of 3-methylamino-1-benzoxepine (2H) -one in 10 ml of methanol, a small amount of methyl orange is added, after which a methanol solution of hydrogen chloride is added dropwise to it (3 n.) Before the indicator color changes. To acidified solution slowly at
    A solution of 1.3 g (0.02 mol) of sodium cyanoborohydride in 20 ml of methanol is added at room temperature and stirred for another 6 hours until the end of the reaction. At the same time, to it is added
    drop a methanolic solution of hydrogen chloride in such a way that the indicator was painted red all the time (pH 3-4). The solution is evaporated, the residue is dissolved in water, dimethylamine is added until alkaline, and extraction is carried out with diethyl ether. The ether extracts are combined and dried with sodium sulfate. After the solvent is distilled off, the racemate 2, 3, 4, 5-tetrahydro-3-methylamino-1-benzoxepin-5-one is obtained in the form of an oily liquid.
    Yield 71%, so pl. 152-157 С (after recrystallization from isopropano-la). To separate the isomers, the resulting oily liquid is treated in the same manner as in Example 1.
    The compounds of the formula D or their salts possess valuable therapeutic properties, and above all they exhibit a pronounced activity in the disruption of the motor ability in the gastrointestinal tract.
    c In animal experiments under their influence, the peristaltic wave-like movements of the stomach are amplified, and the frequency of movement is reduced in favor of the occurrence of stronger and more deeply drawn wave-like movements. Similar activity is manifested in improved emptying of the stomach.
    Description of the methods of pharmacological research.
    1. Acute toxicity at 7 days was determined on white healthy NMRI mice after a single injection of the drug intraperitoneally. The LD value was calculated through EDV
    0 through sample analysis.
    2. To determine peristalsis of the stomach of rats weighing 200 g anesthetized with ketamino-hydrochloride (chilazine), were injected into
    5 Vena ugularis catheter and vessel
    the trachea is a tracheal catheter, a stomach probe was introduced into the stomach, which was connected to a pressure sensor (P 23 DB) through a three-way valve .. The pylorus stomach and at the entrance to the stomach were sutured with a ligature thread. The stomach is filled with 3 ml of a 0.9% aqueous solution of sodium chloride. The wavy movements produced by the stomach were continuously recorded by the multi-corrosive Vataiab (MS 641). To determine the activity of the test substances, the latter were dissolved in physiological saline. Sodium chloride Hjm was suspended in tylosis MH50, the administration being administered intraperitoneally at a dose of 20 mg / kg. Then, the amplitudes and frequencies of the wavy movements of the stomach, occurring before and after the administration of substances, were compared. . ,
    The evaluation showed that soon after the administration of the corresponding compounds of formula 1, a significant increase in amplitudes was observed. This effect, in conjunction with a differently increased decrease in frequency, leads to an improved patency of the stomach.
    The following compounds were investigated according to the described procedure:
    A) rac. , 3,4,5-tetrahydro-3-methylamino -1-benzocheapin-5-o,
    A) rac. - ““ / gsg / s-C2,3,4, B-tetrahydro-3-methylamino-1-benzoxepin-5-ol
    B), rac. -; 2,3,4, 5-tetrahydro-3-methylamino-8-chloro-l-enzroxepin-5-ol
    c) rac. -C2,3,4,5-tetrahydro-3-methylamino-8-chlorop-l-benzoccepin-5-pl
    C) rats.-tfUc -2,3,4,5-tetrahydro-3-isopropylamino -1-benzoxepin-5-ol
    c) rac .- (p12is-1 2,3,4,5-tetragyro-3-isopropylamine} -1-benzoxepine
    D) rats.- gglg-2,3,4,5-tetrahydro-3-benzylamino} -1-benzoxepin-5-ol
    D) rac. 2,3,4,5-tetrahydro-Z-benzylamino-1-benzoxepin-5-ol
    E) rac. 2,3,4,5-tetrahydro-3- (3 -dimethylaminopropylamino) J-l-benzoxepin-5-ol
    E) rats. -wfyOHC -12,3,4,5-tetragyro-3- (y-dimethylaminopropylamino) -1-ben. zoxepin-5-ol
    F) a.u., - ifuc-2,3,4,5-tetrahydro-3-diethylamino -1-benzoxepin-5-ol
    F) rac. 2,3,4,5-tetrahydro-3-diethylamino-J-l-benzoccepin-5-ol
    G) Rada-tittc, 3,4, 5-tetrahydro-3-metilimino-7-chloro-benzoccepin-5-ol
    G) rac. -wfiOifc C2,3,4,5-tetrahydro-Z-methylamino-T-chloro-1-benzoxepin-5-ol
    H) rats. -L2,3,4,5-tetragon-3- (| g-butylamino) 3 -1 -b 13oxelin-5-ol
    H) rats. - 7 / gsg., 3,4, B-tetragnd; PO-3- (p - butylamino) -1-benzoxepin-5-ol
    D) rac. , 3,4, 5-tetrahydro-3-morpholino-1-bechzoxepin-5-ol
    3} rac. 2,3,4,5-tetrahydro-3-morpholino -1-benzoxepine -5-ol
    K) rac., 3, 4, 5-tetrahydro-3-pyrrolidino -1-benzoxepin-5-ol
    k) rats..l c-C2, 3.4, 5-tetra-. hydro-Z-pyrrolidinsZ-1-benzoxepin-5-ol
    5L) rac., 3,4,5-tetrahydro-5-phenethylamino3 1-benzoxepin-5-ol
    L) rac. -inpcLHC -2,3,4,5-tetrahydro-5-phenethylamino -1-benzoxepin-5-ol
    0M) pau.-i {-ac-L 2,3, 4,5-tetrahydro.-3-methylamino-7,8-dichloro-1-benzoxepin-5-ol
    M) rats. , 3, 4, 5-tetrahydro-3-methylamino-7, 8-dichloro} -1-ben o5, ksepin-5-ol
    N) rats .-- "le-t2,3,4,5-tetrahydro-3-amino -1-benzoxepin-5-ol
    N) rac .-- fti / OKc- 2,3,4, 5-tetrahydro-3-aminoZ-1-benzoxepin-5-o 0O) rac., 3,4, 5-tetrahydro-3-dimethylamino1-1- benzoxepine
    oI rats.-Sh77a with-2,3,4, 5-tetrahydro-3-dimethylamino-l-benzocoxine
    1) rats.-3-methylamino-3, 4-dihydros -1-benzoxepin-5 (2H) -OH
    2) rats.-3-isopropylamio-3,4-dihydro-1-benzoxepin-5 (2H) -OH
    3) rats.-3-benzylamino-3,4-dihydro-1-benzoxepin-5 (2H)
    4) rac.-3-O-dimethylaminopropyl amino) -3,4-dihydro-1-benzoxepin-5 (2H) -OH
    5) rats.-3-dimethylamino-3,4-dihydro-1-benzoxepin-5 (2H) -OH
    6) rats.-3-SZ-dimethylaminopropyl 5 amino) -7-chloro-3, 4-dihydro-1-benzoxepin-5 (2H) -OH
    7) rac.-3- (c-butylamino) -3,4-dihydro-1-benzoxepin-5 (2H) -OH
    The data taken tja stomach measurements are presented in the table. I.
    The table shows that even small doses of compounds of the formula T or their additive salts with acids cause a significant increase in the peristaltic wavelike movements of the stomach, and the high activity and low toxicity of substances (p.v.) indicate that they are well tolerated by the body. Other
    0 advantage is each: quickly observed activity.
    The observed pharmacological activity can be explained by the fact that the compounds of the formula I eliminate
    5 In humans, gastrointestinal dysfunctions, such as pyloric stenosis, duodenogastric reverse current, as well as atonic conditions. In addition, | a favorable therapeutic effect can be expected in various functional disorders, leading to pain in the upper part of the arm, nausea, a feeling of fullness, other unpleasant sensations. The symptoms in Ulcus ventriculi and ulcus duocleni, in gastritis | and nervous irritation of the stomach. Equally, an increased permeability through the stomach of a contrast agent can be achieved, which is desirable in the X-ray diagnosis of the gastrointestinal tract. |
    Drugs contain compounds of formula G or their pharmacologically acceptable salts as a biologically active substance in combination with the usual pharmacologically acceptable carrier substances; Yami and / or diluents. The drug can be administered orally or parenterally, and it can also be made in the form of tablets, capsules, syrup, dry powder, injection and infusion solutions, or in the form of suspensions. But the drug can also be prepared in the form of a suppository | ev. In most cases, it is preferable that drugs may be introduced into the body through the mouth. |
    The dosage of the corresponding medicinal dosage depends on time9, 6
    4.5
    6.3
    12.5
    7,6
    12.4
    22.9
    personal factors, in particular the type and severity of the disease or the compound used. In most cases, when administered through the mouth, a single dose of 0.1 to 20 mg, preferably 0.5 to 10 mg, is sufficient for satisfactory results to be obtained.
    Example 12. Capsules with 10 mg of rac. -2, 3,4, 5-tetrahydro-3-methylamino-1-benzoxepinol-5, used as a biologically active substance, have the following composition, h:
    Biologically active substance10
    Lactose 65.
    Corn starch, dried 40
    Soluble starch 4 Magnesium stearate 1
    Biologically active substance, see “Sewn with lactose and cornstarch. The prepared mixture is moistened with a 15% aqueous solution of soluble starch and produced, -: granulation. The wet mass is rubbed through a sieve with 1.6 mm holes, the material is dried at 40 s on a trellis shelf, and 0 immediately after this is wiped through a sieve with 1.0 mm holes. After mixing the obtained granulated material with magnesium stearate, the resulting mixture in an amount of 120 mg is processed into capsules so that each capsule contains 10 mg of the biologically active substance.
    200
    83
    272
    664
    92
    113
    664
    191017170
    Table continuation
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives
    3-amino-1-benzoxypine of the general formula I where R + and R t are independently hydrogen, C ^ -C ^ -alkyl unsubstituted or substituted by phenyl, or Cj, is Cy-alkyl containing, at the ends, as substituents methoxy residues, or one of R ^ and R g is hydrogen or C 4 is Su-alkyl, and the other of the C 2 -C 5 alkyl radicals, having at the end as a substituent a group
    - NR 7 Rg, in which R 7 and R are independently hydrogen or C (- Cj-alkyl, or R ^ and R ^ together with the nitrogen atom to which they are bonded form a pyrrolidine, piperidine or morpholine ring; one from R 3 and Rj is hydrogen, and the other of them is an oxy group, or both R 3 and together are oxygen; Ry and Ry are independently hydrogen or halogen, C ^ -alkyl or C ^ C ^ -alkoxy, or stereoisomers or salts thereof, characterized in that the derivative of 3-amino-1-benzoksepinona-5 (2H) and the general formula wherein R., R, R, and R are as defined <2 * value is reduced boron sodium idridom at pH 4-7 or natriytsianborgidrydom at pH 3-4 at a temperature of from 0 C. to e * the ambient temperature or the catalytic Guidry Rovani hydrogen in the presence of nickel Raney nit *, preferably under a hydrogen pressure of 2-150 bar and in a protic solvent , preferably ethanol or isopropanol, and the desired product of formula I is isolated, where R a is hydrogen and R ^ is hydroxy, in free form, or in the form of a salt, or as stereoisomers, or a compound of formula I is subjected to reduction with sodium cyanoborohydride at pH 4-6 at temperatures from 0 ° to ambient temperature or catalytic hydrogenation with hydrogen, preferably at a hydrogen pressure of 50-150 bar, in the presence of Raney nickel in an aprotic solvent, preferably toluene or benzene, and the desired product of formula I is isolated, where Rj HR ^ together is oxygen, in free, in the form or in the form of a salt / or is converted to a compound of formula I, where R ^ is hydrogen and R ^ is an oxy group, by the action of sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium - ^ is- (2-f-methoxyethoxy) aluminum hydride or
    SU, Я1 1017170 lithium tri- ^ wo ^ -butyl borohydride in, neutral medium or sodium cyanoborohydride in. strongly acidic pH range and the target product is isolated in free form, either as a salt, or as stereoisomers, or a compound of formula I, where R 7 and Rg are hydrogen, are converted to compound I, where Rj is hydrogen. or C d is C ^ alkyl and Rg is C 4 is C ^ alkyl.
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    同族专利:
    公开号 | 公开日
    US4279904A|1981-07-21|
    IE50100B1|1986-02-19|
    IL60552D0|1980-09-16|
    PT71600A|1980-08-01|
    AU532394B2|1983-09-29|
    NZ194329A|1982-05-25|
    FI802384A|1981-02-03|
    JPS5649374A|1981-05-02|
    IL60552A|1984-10-31|
    HU181736B|1983-11-28|
    DK333380A|1981-02-03|
    EP0024560A1|1981-03-11|
    PH15870A|1983-04-13|
    ES8104269A1|1981-04-01|
    DK152044C|1988-06-20|
    DE3062741D1|1983-05-19|
    NO802325L|1981-02-03|
    JPS6360750B2|1988-11-25|
    NO155135B|1986-11-10|
    AU6039080A|1981-02-05|
    DK152044B|1988-01-25|
    CA1161857A|1984-02-07|
    DE2931399A1|1981-02-26|
    IE801386L|1981-02-02|
    EP0024560B1|1983-04-13|
    ZA804548B|1981-07-29|
    NO155135C|1987-02-18|
    GR69358B|1982-05-20|
    AT3038T|1983-04-15|
    ES493926A0|1981-04-01|
    DD154018A5|1982-02-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE1593760A1|1967-02-01|1972-06-08|Boehringer Sohn Ingelheim|Process for the production of new benz-epine derivatives|
    US3991082A|1975-03-03|1976-11-09|Warner-Lambert Company|4-Substituted-2,3-dihydro-1-benzoxepin-3,5-diones and tautomers|
    US4153612A|1977-10-31|1979-05-08|The Upjohn Company|2-Benzoxepins|US4556656A|1978-10-23|1985-12-03|The Upjohn Company|2-Benzoxepins|
    DE3440295A1|1984-11-05|1986-05-15|Kali-Chemie Pharma Gmbh, 3000 Hannover|METHOD FOR DIASTEREOSELECTIVE REDUCTION OF 3-AMINO-1-BENZOXEPIN-5-ONES|
    DE3440296A1|1984-11-05|1986-05-15|Kali-Chemie Pharma Gmbh, 3000 Hannover|3-AMINO-2,3-DIHYDRO-1-BENZOXEPINE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    AU597671B2|1986-06-20|1990-06-07|Suntory Limited|2-Phenylbenzoxepin derivative|
    JP2931986B2|1989-02-17|1999-08-09|武田薬品工業株式会社|Aralkylamine derivatives|
    CN103554077B|2013-10-29|2014-12-17|云南烟草科学研究院|Chromone compound as well as preparation method and application thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19792931399|DE2931399A1|1979-08-02|1979-08-02|NEW 3-AMINO-1-BENZOXEPINE DERIVATIVES AND THEIR SALTS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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