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    • 专利摘要:
    Trans-(±)-2- and/or -5-permissibly substituted octahy- dro-oxazolo[4,5-g]quinolines, acid addition salts thereof and individual enantiomers thereof, useful as dopamine agonists or intermediates of the preparation of dopamine agonists.
    公开号:SU1421258A3
    申请号:SU853932559
    申请日:1985-08-01
    公开日:1988-08-30
    发明作者:Менерт Шаус Джон；Даниэль Титус Роберт
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new compounds containing the octahydroxazolo (., 5c |) quinoline ring system of the general formula
    where R, - C 1 CZ alkyl
    R is aNfflHorpynnas, with the hydrogen atoms in the 4a and 8a positions having the trans configuration,
    or pgh pharmaceutically acceptable salts with properties to counteract the effects of dopamine. The purpose of the invention is to obtain oxazole analogues of pyrazolo (3, 4) quinoline, which have advantages in the indicated pharmacological properties.
    Below in the examples, the term pulse chromatography is understood as Still's chromatographic method.
    EXAMPLE 1, Preparation of trans- (+) - 2-amkno-5-n-prop1-45 3., 7 8 8-59-octahydroxazolo (4,5q) quinoline
    TdEZ g of trans - (+) - 1-n-propyl-6-oxodecahydroquinoline is dissolved in 25 to glacial acetic acid. To the solution add 2.3 ml of 37 wt.% Hydrogen bromide in glacial acetic acid, after which t drop by drop 0.6 ml of bromine dissolved in 5 ml of glacial acetic acid. The reaction mixture is changed for half an hour after the introduction of all the reactants has been completed. After this, the volatile components of the mixture are removed by distillation in vacuo to give a trans-residue. (: 1-n-propyl-6-oxo 7-bromodecahydroquinol-hydrobromido 10 mM of this salt is dissolved in 10 l of methanol j, then Ij, g of urea is added to the resulting solution.The resulting mixture is heated under reflux for about 24 hours under nitrogen atmosphere. Then the reaction mixture is cooled to room temperature, after which the solvent is removed in vacuum. The residue is dissolved in water and bring the aqueous solution to alkaline by adding a 14N aqueous solution of ammonium hydroxide. The alkaline layer is extracted with several portions of equal volume of methylene chloride8 or.
    The organic extracts are combined and the combined extract is washed with a saturated aqueous solution of chloride,. sodium, then dried over sodium sulfate. After removal of the solvent in vacuo, an oily brown mass containing trans- (±) -2-amino 5-n-ProQ-4, 4a, 5, 6, 7, B, 3a, 9-octagus is obtained , crooxazole 6 (4,5q) quinoline, formed during the described reaction. The residue is dissolved in chloroform containing 5% methanol and traces of ammonium hydroxide, followed by chromatography on silica gel (eluent is chloroform containing 5% methanol and traces of ammonium hydroxide). The fractions containing the required oxazoloquinoline are combined and a yellow viscous oil is obtained after distilling off the solvent, which slowly crystallizes. The crystalline solid trans- (j) -2-ami-no-5-n-propyl-4,4a, 5,6, 7,8,8ar-oct 5 hydroxazolo (4,5q) -quinoline is dissolved in methanol and saturate the resulting methanol solution with HC1 gas. The solvent is removed and the residue is recrystallized from ethanol. The result is 0.2 g of trans - (+) - 2-amino-5-n-propyl-454a} 5,6,758,8a, 9-octahydroxazole (4, 5q) xoлиндлиндлиндшccллратарата, having a melting point of 1e 225 ° C, which gives an ion since May. 235 in the mass spectrum. Elemental analysis results:
    Calculated,%: C 50.65; H 7.52; N 13.63.
    Found,%: from 50.52, H7.28iN 13.34, The described procedure can be repeated using 4a R as the starting material; 8a of R-1-substituted-6-oxodecahydroquinoline. (Synthesis of 1 n-propyl-6-oxodecahydroquinoline, as described in Preparation Example 1 below). 3.9 g of 4a Rj 8a R-1-n-propyl-b-oxodecahehydroquinoline is dissolved in 40 ml of glacial acetic acid, first 4.6 g of ml of 31% HBr in glacial acetic acid is added to the solution acid and then dropwise dilute 152 ml of bromine in 10 ml of glacial acetic acid. After stirring at room temperature for about half an hour, the solvent was removed in vacuo to give a residue, an orange foam containing (-) - 1-n-propyl-6-oxo-7-bromodecahydroquinoline formed during the reaction, Oran0
    0
    five
    0
    3U21258
    chewing foam is dissolved in 30 ml of methane over 225 ° C; molecules of a stray ion and nol are added to the resulting plant, corresponding to a mass number of 235;
     102.0 (,, 0).
    a thief of 1.32 g of urea, after which the reaction mixture is heated to reflux for about 18 hours, after which the mixture is poured onto ice. The acidic aqueous solution is made alkaline by the addition of 14% aqueous solution of ammonium oxide Q hydrate, and the alkaline solution is extracted with several portions of equal volume of methylene chloride, 4a R, 8a R-2-amino-5-n propyl-4, Yes, 5, 6,7,8,8а, 9-octahydroxazole (4,5q) quinoline, is treated in a mixture of 27.8 ml of anhydrous ethanosis in the course of the described reaction, la and 300 ml of tetrahydrofuran. It is semi-insoluble in the aqueous phase and passes into the organic layer. The organic extracts are combined, the combined extract is washed with water and brine, and then dried. After distilling off the solvent, a dark, viscous residue is obtained. The residue is chromatographed on a silica gel using flash chromatography. Above the reaction mixture, methylene dichloride containing 3% of nitrogen is passed through a nitrogen mixture to remove methanol and traces of a 14N aqueous solution of ammonium hydroxide as eluent over a reaction mixture. The fractions containing the desired product, which is checked according to thin-layer chromatography (9: 1 methylene dichloride methanol + traces) j are combined and the solvent is distilled off
    20
    Elemental Analysis Results
    Calculate about,% C 50.65; H 7.52; N13.63,
    Found,% C 50.37; H 7, 70, -N 13.6
    PRI mme R 2. Getting trans- (+) - 2-methyl-5-n-propyl-4,4a, 5,6,7,8, 8a, 9-octahydroxazolo (4,5q) quinoline
    9.9 g of lithium is dissolved in 2 l of anhydrous liquid ammonia, 98.7 g of 4- (3-n-propylamino) propylanisole solution of lithium is slowly added dropwise to the ammonia solution with stirring. After the completion of the dropping, the reaction mixture is stirred for about 45 minutes. Water is then slowly added to the reaction mixture until the blue color of the dissolved lithium disappears.
    thirty
    nor ammonia. An additional amount of water is then added to the reaction mixture to dissolve the resulting salts. The alkaline aqueous solution is extracted with three portions of an equal volume of diethyl ether. The ether extracts are combined and dried. After distilling off the ester, 93.2 g of 1-methoxy-4- (3-n-propylamino) propyl-1,4-cyclohexadiene are obtained, yield 93.5%,
    in a vacuum. The light yellow foam obtained in the residue, containing purified 4a R, Ba K-2-amino-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydroxazole (4 , 5q) xinoline is dissolved in methanol and the resulting solution is saturated with gaseous HC1. The resulting
    nor ammonia. An additional amount of water is then added to the reaction mixture to dissolve the resulting salts. Alkaline water solution eq. they are stratified in three portions of an equal volume of diethyl ether. The ether extracts are combined and dried. After distilling off the ester, 93.2 g of 1-methoxy-4- (3-n-propylamino) propyl-1,4-cyclohexadiene are obtained, yield 93.5%,
    121 g of 1-methoxy-4- (3-n-propylamine) propyl-1,4-cyclohexadiene is dissolved in 1 liter of 15% sulfuric acid.
    The acidic solution is heated in reverse.
    Salt hydrochloride) is recrystallized, by a refrigerator for about 6 hours, from methanol / ethyl acetate {the output is then poured into ice, diluted with 0.25 g (3.9 g of the initial ketone. acidic solution is made alkaline by adding 50 % aqueous solution of sodium hydroxide.
    The salt has the following physical characteristics: melting point above mass spectrum m / e at 45 Aqueous solution, which is now 235; , -103.1 (,, 0). Analysis results
    H 7.52;
    Calculated,% C 50.65; N 13.63,
    became alkaline, extracted with methylene dichloride. The extract in methylene dichloride is dried and the solvent is removed, resulting in 25.6 cis- (±) 1 alkaline, extracted with methyl dichloride. The extract in methylene dichloride is dried and the solvent is removed, resulting in 25.6 cis- (±) Found,% C 50.93; H7.25; N 13.39, 50 n-propyl-7-oxodecahydroquinoline.
    The above procedure is repeated, starting from 4a S, 8a S-1-n-propyl-6-oxodecahehydroquinoline, resulting in 4.a S, 8a 8-2-amino-5-n-propyl-4,4a, 5, 6,7,8,8а, 9-octagno-okroxolol (4,5q) quinoline, which is subjected to purification in the form of a salt (chlorine hydrate), Yield 0.26 g (from 3.9 g of the starting ketone), melting point 23.8 g of the above crude product is dissolved in 300 methanol and 1.3 g of sodium methoxide is added to the resulting solution, the Pe 55 mixture is stirred overnight at room temperature, then diluted with water. The aqueous mixture is extracted with methylene dichloride and the extract is dried in methylene dichloride.
    In a mixture of 27.8 ml of anhydrous ethanol and 300 ml of tetrahydrofuran. Half a night, the reaction mixture is passed through a stream of nitrogen for the night.
    Elemental Analysis Results
    Calculate about,% C 50.65; H 7.52; N13.63,
    Found,% C 50.37; H 7, 70, -N 13.69,
    PRI mme R 2. Getting trans- (+) - 2-methyl-5-n-propyl-4,4a, 5,6,7,8, 8a, 9-octahydroxazolo (4,5q) quinoline,
    9.9 g of lithium is dissolved in 2 l of anhydrous liquid ammonia, 98.7 g of 4- (3-n-propylamino) propylanisole is dissolved in a mixture of 27.8 ml of anhydrous ethanol and 300 ml of tetrahydrofuran. Half a night, the reaction mixture is passed through a stream of nitrogen for the night.
    With stirring, the lithium solution is slowly added dropwise to the ammonia solution. After the completion of the dropping, the reaction mixture is stirred for about 45 minutes. Water is then slowly added to the reaction mixture until the blue color of the dissolved lithium disappears.
    Q in a mixture of 27.8 ml of anhydrous ethanol and 300 ml of tetrahydrofuran. Semi25 Above the reaction mixture, a stream of nitrogen is passed overnight to remove j
    thirty
    nor ammonia. An additional amount of water is then added to the reaction mixture to dissolve the resulting salts. The alkaline aqueous solution is extracted with three portions of an equal volume of diethyl ether. The ether extracts are combined and dried. After distilling off the ester, 93.2 g of 1-methoxy-4- (3-n-propylamino) propyl-1,4-cyclohexadiene are obtained, yield 93.5%,
    121 g of 1-methoxy-4- (3-n-propylamine) propyl-1,4-cyclohexadiene is dissolved in 1 liter of 15% sulfuric acid.
     The aqueous solution that is now
    became alkaline, extracted with methylene dichloride. The extract in methylene dichloride is dried and the solvent is removed, resulting in 25.6 cis- (±) 1-n-propyl-7-oxodecahydroquinoline.
    Approximately 23.8 g of this crude product was dissolved in 300 ml of methanol and 1.3 g of sodium methoxide was added to the resulting solution. The reaction mixture was stirred overnight at room temperature, then diluted with water. The aqueous mixture is extracted with methylene dichloride, the extract is dried in methylene dichloride and
    the solvent is removed from it, resulting in chromatography of 11.4 g of trans- (±) - 1-n-propyl 7 oxodecahydroquinoline.
    IR spectrum (chloroform); 290 51457, 1081 cm
    Proton magnetic resonance spectrum (CDClj, 270 MHz, /) 2.94 (wide signal, 1H,, 0) 2.79 (wide signal, 1H,); 2.61-2.50 (m.p., 1H); 2.42-1.98 (multiplet, 6H); 1.92-1.22 (multiplet, 8H) 1s10-0 ,, 98 (multiplet 1H); 0.82 (triplet, 3N,, 2),
    19.5 g of trans-α- (J) -1-n-propyl-7-oxo-dehydroquinolin are dissolved in 32/3 ml of ethyl formate in 100 ml of hetero-hydrophys / wound. This solution, in turn, is added to a solution of 22.4 g of potassium t-butylate in 400 ml of tetrahydrofuran at a temperature. The reaction mixture is stirred for 1 hour, after which the thin layer chromatography (tetrahydrofuran + traces of ammonium hydroxide) is absent product. Then, a solution of benzenediazonium chloride is obtained by dissolving 9.3 g of aniline in 60 ml of a 1: 1 mixture of 12N hydrochloric acid and water. This solution is rapidly cooled and ice is added to it. Then a solution of 6.8 g of sodium nitrate in 30 ml of water is added to it, and the temperature of the reaction mixture is maintained at about 0 ° C by adding ice to it.
    The pH of the reaction mixture containing formyl ketone is adjusted to about 6 by adding 10% hydrochloric acid thereto, then a solution of 42.4 g of sodium acetate in 100 ml of water is added to the reaction mixture, after which the resulting solution is added. the solution described above for the benzoldiazonium chloride solution. The newly obtained reaction mixture is stirred overnight at a temperature of about 4 ° C. This produces an orange solid which is separated by filtration (weight 12.9 g) o The solid is discarded
    The filtrate is adjusted to alkaline reaction by the introduction of a 15N aqueous solution of ammonium hydroxide. The resulting biphasic system ry is extracted several times with equal volumes of 3: 1 chloroform / isopropanol. The organic extracts are combined and the solvent is distilled off in vacuo to give 10.5 g of a viscous red residue. This residue was dissolved in methylene dichloride containing 5% methanol and traces of hydroxide, after which the solution was placed on a chromatographic column using flash chromatography. The column is prepared and the products eluted with the same mixture of solvents. Fractions that according to thin layer chromatography (mixture 9, methylene dichloride / methanol + traces
    ammonium hydroxide) contain the desired product, are combined and the solvent is distilled 5 to obtain 9.4 g of a bright solid, containing trans- (+) -n-prop L 6-phenyl-1-schrazon-7-oxodecahydroquinoline, formed during the described reaction,
    five
    Alternatively, the reaction described is carried out using the reverse administration procedure: the solution is prepared from 5.5 ml of ethyl formate, 3.3 g of trans - (+) - 1-n-propyl-7-oxodecadihydroquinoline and 20 ml of tetrahydrofuran, this the solution is added to a solution of 3, | 8 g of potassium t-butylate in 80 ml of tetrahydrofuran. The reaction mixture is stirred for 2 hours at a temperature of about 0 ° C, after which time the thin layer data
    5 chromatography shows that all the starting ketone has reacted, the pH of the medium is adjusted to about 6 as a result. tata, add 10% hydrochloric acid, then to the reaction mixture
    0 is added a solution of 7.2 g of sodium acetate in 20 ml of water. Then a solution of phenyldiazonium chloride is obtained according to the above described method, starting from 1.6 g of aniline. The trans - (.) - 15N solution of Propyl-6-formyl-7-oxodecahydroquinoline is rapidly introduced through a positive nitrogen pressure under the surface of the phenyldiazonium chloride solution, the temperature of which is maintained around. The reaction mixture is stirred at the indicated temperature for 2 hours, after which it is treated as described above. According to chromatography, the yield of the target
    5 of trans- (±) -1-n-propyl-6-phenyl-hydrazone-7-oxo-dehydroquinoline product is 43.5% compared to 31.4% in the case of the usual order of introduction of reagents.
    7
    This product is subjected to catalytic hydrogenation using as a catalyst 5% palladium on carbon in a mixture of ethanol and hydrochloric acid. The mixture of the ambient hydrirov mixture is filtered and the filtrate is concentrated to a reduced volume, resulting in a crude trans - (+) - 1-n-propyl-6-amino-7-oxodecahydroquinoline in the dihydrochloride form. Output 10.34 g (green foam) „

    2 g of crude trans - (+) - 1-n-propyl-6-amino-7-oxodecahydroquinoline dichlorohydrate, prepared according to the described method, are suspended in a mixture of 50 MP tetrahydrofuran and 10 mp of acetic anhydride. The reaction mixture is cooled to, after which 10 MP of triethylamine are added. The solid fraction is dissolved immediately, and the resulting solution is stirred for
    142
    g of ammonium oxide, and chromatographic the resulting solution on silica gel by the method and Shul chromatography using the same solvent as eluent. The fractions which by the present thin layer chromatography (tetrahydrofuran + traces of ammonium hydroxide) contain the desired product are combined and the solvent is distilled off to give 0.48 g of straw oil at room temperature. Then the reaction mixture is drunk in water and of a yellow color (yield 89.2%). This aqueous reaction mixture is made up to oil, dissolved in a small amount of strongly alkaline reaction and as a result of the introduction of a 15N aqueous solution of ammonium hydroxide. The alkaline aqueous mixture is extracted with several portions of an equal volume of methipandichloride, the organic extracts are combined, the combined organic layer is washed with brine and dried. After distillation
    thirty
    methanol, to which an equivalent amount of p-toluene sulfonic acid is added. The solution is heated to Ki, followed by the addition of ethyl acetate. The solution is boiled until crystallization begins. The solid product resulting from this is filtered off and recrystallized from
    volatile components receive a residue
    dark brown color. Specified 35 methanol / ether solvent mixtures. 06- the residue is dissolved in tetrahydrofuranose during the reaction trans - (+) - not, containing traces of hydroxide of 2-metsh-1-5-n-propyl-4,4a, 5,6,7,8,8a, i ammonium after which the solution of chromate-9-octahydroxazole (4.5q) is quaniline- graphically on silica gel using a flux melting point 198-200 ° C, using tetrahydro-40 as an eluent. 0.38 g.
    furan, to which traces are added. Elemental analysis results: gvdrata ammonia. Fractions that are Calculated,%: C 62.04; H 7.44;
    N 6.89.
    Found,%: C 61.82; H 7.24; N 6,78, PRI me R 3. Obtaining trans- (±) G-5-H-PROPSh1-4, 4a, 5,6,7,8,8. A, 9-oh-hydroxyazolo (4 , 5q) quinoline ,.
    According to thin layer chromatography (tetrahydrophsfane + traces of ammonium hydroxide), they contain the desired product, combine and distill off the solvent, resulting in 0.65 g of a waxy solid product containing trans - (+) - 1-n-proV according to the procedure described in Example 2, the method of 3.0 g of trans - (+) - 1-pil-6-acetypamino-7-oxodecahydroh-50 n-propyl-6-amno-7-oxodecahydroquinonoline, which was formed during the reaction.
    A solution of 0.58 g of acetypamine-I-water in 25 ml of phosphorus oxychloride
    lindichlorohydrate is suspended in 25 MP of dry tetrahydrofuran, the reaction mixture is cooled and 6 ml of mixed anhydride is added to it
    The mixture is heated at boiling with reverse Cc-55 formic acid, after which it is introduced into the boiler for about 4 hours. dropwise 5 mp of triethylamine. Mixture. The reaction mixture is then allowed to acylate for 1 hour at weekends at room temperature and room temperature, followed by heating. The solvent is removed in vacuo and taken in water. Dovo water mixture
    12588
    and the residue thus obtained is dissolved in water. The aqueous solution is brought to alkaline by introducing a 15N aqueous solution of ammonium hydroxide and extracted with an aqueous solution in several portions of equal volume of methylene dichloride. The extracts in methylenchuschid are pooled, and the Q extracts are combined with brine, and then dried. After distilling off the solvent, a dark, viscous residue is obtained, which is dissolved in tetrahydrofuran containing traces of hydroxide.
    g of ammonium oxide, and chromatographic the resulting solution on silica gel by the method and Shul chromatography using the same solvent as eluent. The fractions which by the present thin-layer chromatography (tetrahydrofuran + traces of ammonium hydroxide) contain the desired product are combined and the solvent is distilled off to give 0.48 g of oil of a straw.
     but yellow (yield 89.2%). This oil is dissolved in a small amount of yellow (89.2% yield). This oil is dissolved in a small amount
    thirty
    methanol, to which an equivalent amount of p-toluene sulfonic acid is added. The solution is heated to Ki, followed by the addition of ethyl acetate. The solution is boiled until crystallization begins. The solid product resulting from this is filtered off and recrystallized from
    In accordance with the procedure described in Example 2, 3.0 g of trans - (+) - 1n-propyl-6-amno-7-oxodecahydroquinoline dihydrochloride is converted into suspension in 25 MP of dry tetrahydrofuran, the reaction mixture is cooled and added to 6 ml of mixed anhydride
    9 ,
    d t to acidic reaction as a result of the introduction of 10% hydrochloric acid. The aqueous acidified layer thus obtained is extracted with ether and the resulting EF1-FNI extract is discarded. The acidified layer is brought to alkaline: the reactions result from the introduction of a 15N aqueous solution of ammonium oxide, after which the alkaline layer is extracted with several TORQUE equal volumes of methylene chloride. The extracts in methylendichloride are combined, washed with the combined extract with brine, and then dried. After distilling off the solvent: 1.9 g of a viscous yellow oil are obtained. This oil is dissolved in tetrahydrofuran and the chromatographic solution on silica gel. with use: tetrahydrofuran containing traces of ammonium hydroxide as eluent. The fractions which, according to thin layer chromatography (using the same solvent as the eluent), contain the desired product — trans - (+) - 1-n-propyl-6-forms-1-amino-7 oxodecahydroquinoline; and remove the solvent





    getting IjO g liquid transparent
    viscous residue (yield 83.9%). The residue crystallizes upon standing.
    A solution is obtained by dissolving 0.63 g of trans - (+) - 1-n-propyl-6-formylamino-7-oxyhydroxyquinoline in 8.8 ml of methanesulfonic acid. The reaction mixture is heated to about 100 ° C, after which 1.26 g of phosphorus pentoxide is added. The newly obtained reaction mixture was stirred at 100 ° C for 2.5 hours, then poured onto ice. The acidic solution is brought to alkaline as a result of the addition of a 15% aqueous solution of sodium hydroxide and the alkaline solution is extracted with several portions of equal volume of methylene chloride. The extracts in methylene dichloride are combined and present. After distilling off the solvent, a viscous, transparent brown oil is obtained, which is dissolved in tetrahydrofuran and chromatographed on silica gel. The column was eluted with tetrahydrofuran containing traces of ammonium hydroxide. The second fraction consists of 0.26 g of a viscous transparent brownish oil containing trans - (+) - 5-n-prop-4,4a, 5,6,7,8,8a 9 octahydroxazolo (4,5q) quinoline, formed during the reaction. The compound is converted to salt mapeic acid
    1258
    five
    0
    0
    0
    AND)
    lots in ethanol. The salt is recrystallized from ether / ethanol. Yield 0.26 g of gold-colored crystals having a melting point of 158-160 ° C. Mass spectrum: molecular ion -220. The results of elemental analysis: Calculated,%: C 60,78; H 7.19; N 8.33.
    Found,%: C 60.94 H, 7.26; N 8.20. PRI me R 4. Obtaining trans- (+) - 2-oKco-5-H-nponjm 4,4a, 5,6,7,8, 8a, 9-octahydroxazolo (4,5) quinoline.
    In accordance with the procedure given in Example 2, 5 g of trans - (+) - 1-n-propyl-6-amino-7-oxodecahydroquinoline dichlorohydrate are suspended in 50 ml of tetrahydrofuran. The suspension is cooled to a temperature of about o
    0 ° C and 10 ml of methichlorine formate are added to it, after which 10 ml of trimethylamine are added dropwise. The reaction mixture is stirred at room temperature for 2 hours and after a specified period of time, it is diluted with an excess of
    1N hydrochloric acid. The acidified layer is extracted with one portion of ether and
    discard ethereal layer. Then the acidified layer is cooled, pouring
    ice and the resulting cooled mixture is made alkaline with a 15N aqueous solution of ammonium hydroxide. Then the alkaline mixture is extracted with several portions of equal volume of methylene dichloride, the extracts in methylene dichloride are combined and dried. The solvent is distilled to obtain a dark yellow, viscous residue, which is dissolved in a 1: 1 mixture of tetrahydrofuran and hexane containing traces of ammonium hydroxide. The solution is chromatographed on silica gel using the same solvent as eluent. Fractions that by
    According to thin layer chromatography using the same solvent, the desired product, trans- (+) - 1-n-prop-6-methoxycarbonylamino-7-oxodecahydroquinoline, is combined and the solvent is distilled off to obtain 1.47 g (yield 67%) of a viscous yellow residue, which gives mass ion with mass number 268 in mass spectrum. Of the 0.4 g of carbamate prepared according to the olivine method of the carbamate, a barrier in 10 ml of oleum is prepared. The acidic mixture is stirred at room temperature for 18 hours, then poured onto ice. The acidic aqueous layer is made alkaline.
    reaction by introducing a 15N aqueous solution of ammonium hydroxide. The resulting alkaline layer is extracted with several portions of an equal volume of methylene dichloride, and the extracts are in methylene dichloride. combine, wash the combined extract with brine, and dry. After distilling off the solvent, a dark, viscous residue is obtained. This residue is dissolved in a 1: 2 mixture of tetrahydrofuran and hexane containing traces of ammonium hydroxide, followed by chromatography on the silica gel. The fractions that according to thin layer chromatography (1: 1 tetrahydrofuran / hexane + traces of ammonium hydroxide) contain trans (+) - 2-methoxy-5-n-prop 1-4.4a, 5,6,1, 8,8a, 9-octahydroxazolo (4,5d) quinolNr is combined and the solvent is removed, yielding 0 g of a viscous yellow residue. This residue is dissolved in ether and the ethereal solution is saturated with gaseous hydrogen chloride. The salt formed is crystallized from a mixture of ethanol and diethyl ether, and during this treatment the 2-methoxy group is hydrolyzed to give the corresponding 2-oxazolone. As a result, 0.07 g of trans - (+) - 2-oxo-5-n-prop 1-4.4a, 5,6,7,8,8a, 9-octa-hydroxazolol (4,5q) quinoline in The salt is a hlrr hydrate having a melting point over the mass spectrum that contains a pn-ion molecule with a mass number of 236.
    The results of elemental analysis: Calculated,%: C 57,24; H 7.76; N 10.27,
    Found,%: C 37.28; H 7, 75, N 10.20 Trans - (+) - 2-oxo-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octahydro-1n-rxazolo (4 , 5) quinoline, obtained according to the described method, can be reacted with phosphorus pentachloride or phosphorus oxychloride or PBG to produce the corresponding chloro-bipi-bromo trans - (+) - 2-chloro-5-n-prop1-1-4- 4a, 5,6,7,8, Over, 9-octa-hydroxazolo (4,5 g) quinoline or trans- (+) - 2-bromo-5-n-propyl-4,4a, 5,6,7,8 , 8a, 9-octahydrooxazolo (4,5d) quinoline. These compounds, in turn, can be reacted with primary Hbw or a secondary amine, ammonia or a cyclic amine, for example, piperidine, pyrrolidino or morpholine, to give the corresponding
    g 5 n 5 5
    0
    0
    five
    0
    five
    58I 2
    2-Amino or Substituted Aminooct-G1 Vdroazolo (4,5q) quinoline.
    PRI me R 5, Getting trans- (±) -2-dimethylamino-5-n-propyl-4,4a, 5,6,7,8,8a, 9-octagonal hydroxazole (4,5q) - quinoline.
    0.99 g of trans - (+) - 1-n-propyl-6-methoxycarbonylamino-7-oxo-decahydroquinoline prepared according to Example 4 is dissolved in 20 ml of oleum and the resulting solution is stirred at room temperature for about 20 hours. The acidic reaction mixture was poured into ice and the dilute acid solution thus obtained was stirred at room temperature for half an hour. The solution is then made alkaline by introducing an excess of 14N aqueous ammonium hydroxide solution. The aqueous alkaline mixture is extracted with several portions of an equal volume of 3: 1 chloroform / isopropanol. The organic extracts are combined, and then the combined extract is washed with brine and dried. After distilling off the solvent, an amber-yellow viscous residue is obtained, which is chromatographed on silica gel using tetrahydrofuran as a solvent, containing traces of ammonium hydroxide. The fractions containing the desired 2-methoxy derivatives by thin layer chromatography are combined and the solvent is removed, resulting in 0.42 g of an oily residue containing trans- (±) -2-methoxy-5-n-propyl-4 , 4a, 5,6,7,8,8 a, 9 - octahydrooxazolo (4,5q) quinoline. The NMR spectrum is consistent with the intended structure of the compound. Then, the reaction mixture is obtained by placing 0.15 g of the above product and 10 ml of dimethylamine in a fused tube and heating this fused tube to 100 ° C for 1 hour. Excess dimethylamine is removed by distillation, leaving a viscous brown residue. The residue was chromatographed by flash chromatography on silica gel using a mixture of .1: 1 tetrahydrofuran and hexane, followed by ammonium hydroxide as eluent. The fractions which, according to thin layer chromatography (using the same solvent) are contained, are the desired material, are combined and the solvent is removed to obtain
    50 mg of a light yellow, transparent, glassy product; a narrow singlet with corresponds to an integral intensity of 6 protons) o
    PRI me R. 6 ".An alternative method of trans-(-) - T-n-propyl-7-o1 ssodecahydro quinoline„
    Dissolve 959 g of lithium in 2 liters of anhydrous liquid ammonia 98.7 g of 4- (3-propylamino) pr opilaniz ol dissolve 27.8 ml of anhydrous ethanol and 300 ml of tetrahydrofuran: wound. This solution is slowly added dropwise with stirring to dissolve lithium in liquid ammonia. After the addition is complete, the reaction mixture is stirred for 45 minutes, after which water is slowly added to it until the blue color of the dissolved lithium disappears. A doze of nitrogen is passed over the reaction mixture overnight to distill off ammonia. An additional amount of water is then added to dissolve the resulting salts and extra: an alkaline aqueous solution is added with three portions of equal volume of diethyl ether. The ether extracts are combined and dried. After distilling off the ether, 93 are obtained., 2 g of 1 methoxy - 4- (3-p-PRO) propyl-154-cyclohexadienase yield 9355% „
    0,, 1 g of this compound is stirred at room temperature for 1 hour with 15 ml of O / and hydrochloric acid. The reaction mixture is alkalinized with a 15-bed ammonium hydroxide solution and the resulting alkaline solution is extracted with several portions of equal volume of methylene dichloride. The organic layers are combined and dried. The solvent is removed in vacuo to dryness.
    Thin layer chromatography data
    and NMR of the residue indicates that the residue contains 4- (3-H Gfopilaminopropyl) cyclohex 3-enone and a small amount of cis - (+) 1-n-1-7-oxo-decahydroquinoline as a result of spontaneous cyclization J - isomer formed during the reaction
    5 g of the crude compound obtained as described above was added to a solution of 14.9 mmol of sodium methylate in 10 mp of methanol. The resulting solution is stirred at
    at room temperature for 18 hours, after which they are introduced into water. The alkaline layer is extracted with several portions of equal volume of methylene dichloride, the organic extracts are combined and surat, after which the solvent is removed by distillation in vacuo to obtain 4.5 g of a dark red-orange residue. This residue is dissolved in a mixture of hexane and tetrahydrofuran (2: 1) containing 5 traces of ammonium hydroxide, and the polymerized solution is chromatographed on silica gel using the same solvent as eluent. The first fractions contain mainly 1 - - (+) - 1-n-propyl-7-oxodeca-hydroquinoline and the subsequent fractdies contain trans- (+)-1-n propyl-7-oxo-decahydroquinolineJ yield 2.34 g .
    5 Production Example
    10 g (-) - DI-P-VOLUME WINE KIS POT
    dissolved in 75 MP heated methanol. The solution is added to a solution of g TpaHc - dl-1-H-nponHn-6-OKCo
    Q decahydroquinoline in 15 mp methanol and bring the resulting reactant mixture to a boil, then allow it to cool to room temperature. After pressing the reaction mixture at room temperature overnight, you
     The product crystallizes as a result of the addition of previously obtained seed crystals. The crystalline salt of tartaric acid was filtered, and the filter cake was washed with methanol. Yield 2.813 gH18.7%) of a white crystalline substance, which contains (-) - di-p-toluyl tartrate 4a R, After R-1-n-prop-b-oxodecahydroquinoline; q -107.49 ° (methanol) o After recrystallization of this salt from methanol, 1:; 943 g of optically pure isomer salt, 29 ° (methanol) is obtained. Salt obtained as described
    0 () -d-p-toluic acid is treated with a dilute aqueous solution of sodium hydroxide, and the resulting alkaline solution is extracted with methylene dichloride. The extract in the dichloride is dried and concentrated, after which it is removed from it in vacuo
    solvent. The resulting residue is distilled to give a colorless
    oil containing purified 4a r, 8a
    R-1-n-propyl-b-oxbdecahydroquinoline, U725 ° -88.51 ° (methanol, p. 1).
    The 4a S, 8a S-derivative can be obtained in a similar way as a result of the reaction between (+) - di-p-toluene acid and the racemate.
    As previously noted, the proposed compounds are agents that inhibit the action of dopamine D-2. One of the manifestations of such activity with respect to dopamine. D-2 is the inhibition of prolactin secretion, as illustrated by the following experiments.
    Adult male rats of the Spregyo Dawley species weighing about 200 g are placed in an air-conditioned room with adjustable lighting and give them a standard laboratory ration and enough water to sustain their livelihoods. Each rat was given intraperitoneally 2.0 mg of reserpine as an aqueous suspension 18 hours before the administration of the test drug. The goal of administering reserpine is to maintain prolactin levels in rats at a constantly high level. The test compounds are dissolved in 10% ethanol and administered intraperitoneally at doses of 0.017; 0.03, 0.17; 0.3 µmol / kg. Each dose is administered to a group of 10 rats, and a control group of 10 untreated rats receives an equivalent amount of 10% ethanol. After 1 h after treatment, all rats are decapitated, and 150 μl aliquots of blood serum are examined for prolactin content.
     The difference between the content of prolactin in rats treated and its content in control rats divided by the content of prolactin in control rats gives the value of
    the center of inhibition of secretion of prolac-45 with respect to the binding sites of apomorphintin, corresponding to a given dose. (as illustrated by inhibition
    The proposed compounds affect the binding of N-apomorphine). In the case also of the rotational behavior of rats, trans- (±) -2-methyl-5-n-prop 1-4.4a, 5, which was administered 6-hydroxydopamine according to a test designed to detect 50 compounds suitable
    6,7,8,8 a, 9-octahydroxazolo (4,5) quinoline; the ratio of binding of apomorphine sites and spiperone sites is 40: 1.
    for the treatment of parkinsonism. According to this test, rats infected with nigroneostriatal, prepared according to the procedure, were used; pre-55 ethyl or n-propyl or K is
    Angershtedt and Arbetnot. Compounds, suppressing the action of dopamine, cause rotation in a circle in rats in the direction opposite to R, in relation to sexual activity, illustrated by the results of measuring the latent period of erection, latent period of administration, latent
    five
    Mr. infected side. After a period of latency, which varies from compound to compound, the number of rotations in 15 minutes is calculated.
    The proposed compounds are effective in the treatment of hypertension. This is manifested when standard tests are carried out, in particular, when the active substance is administered to rats with spontaneously increased pressure according to the following procedure.
    Adult male rats with spontaneously increased pressure weighing approximately 5 to 300 g are anesthetized by intraperitoneal administration of sodium pentobarbital (60 mg / kg). Trachea is intubated by a canoe, rats with spontaneously increased0
    five
    0
    0
    They are able to inhale room air by pressure. Pulsating blood pressure was measured on the intubated carotid artery using a Statham transducer (P23 ID). The mean vertical pressure is calculated as the sum of the diastolic pressure plus 1/3 of the pressure pulsations. The rate of contraction of the heart was recorded using a cardiotachometer, which was activated by systolic pressure pulses. Drug solutions were administered intravenously through a catheter placed in the femoral vein. Blood pressure and heart rate were recorded using a multichannel oscilloscope (Beckmann, model R-511A). The process lasted 50 minutes, after which they resorted to surgical intervention to balance the effects.
    Table 1 contains the results of the studies described. Each dose was tested on a group of 4 rats.
    The same three compounds (see Table 1) have selective affinity in
    binding of N-apomorphine). In the case of trans (±) -2-methyl-5-n-prop-1-4.4a, 5,
    6,7,8,8 a, 9-octahydroxazolo (4,5) quinoline; the ratio of binding of apomorphine sites and spiperone sites is 40: 1.
    The activity of the compounds in which R is allyl, methyl.
    ethyl or n-propyl or K is
    in relation to sexual activity is illustrated by the results of measuring the latent period of erection, the latent period of introduction, the latent
    the period of emitting the semen, the time interval after the emitting semen, the erection frequency and the frequency of administration in male rats, which take at least 5 minutes to reach the emitting seed from the moment sexually attractive female is introduced into the male activity zone facilities . A decrease in one or more of the above indicators indicates a positive effect on the sexual behavior of male mammals, including, but not limited to, increasing potency. Male rats without sexual attraction can also be used for such tests.
    Comparative study. All rats subjected to this study were placed in a temperature-controlled room in which the light was turned off in the time interval from 10.00 to 20.00. Male Sprat-Dawley rats and Loug Evans female rats were examined. Acquired at Charlis Rivers Breeding Laboratories (North Wilmington, Mass.) Ovaries were removed from each female during anesthesia, the recovery period was 4 weeks It is susceptible by administering 400 µg of esteron to propylene glycol 48 hours before the test and 2.5 mg of progesterone, to propylene glycol 4 hours before the test.
    one
    The pairing tests were carried out from 12.00 to 17.00 in the dark phase of the lighting cycle. To determine the behavioral response in these tests, plastic drawers of size 24; 24 inches (cm) from the base 12 inches (30 cm) were used which were illuminated with red light. Each test began with the intake of susceptible female rats into the test case and was completed either 30 minutes later or immediately after the first ejection of semen containing spermatozoa. Sexual activity index, assessment Each male before testing 4 niveviya for rats capable of release was in the room. Sexy eu semen was determined
    The daily behavior of each rat was evaluated at two-week intervals, starting at 6 months of age and ending at 12 months of age. Prior to testing with the drug solution, at least 4 consecutive control tests were performed with the administration of the drug carrier. At the same time, male rats were selected with varying degrees of loyalty. Among them were male rats who showed no ability to mate (sexually inactive rats), male rats who were able to mate but unable to release seminal fluid containing spermatozoa during the test period (not discarding seminal fluid). rats) J rat-itself
    as the hidden period of eruption of the semen (the time interval from the moment of intromissia to the eruption of seminal fluid),
    5 Comparative data on the effect of quinopyrol compounds and the compound of Example 1 on the latent period of eruption of semen in male rats are given in Table 2,
    50 Hide the period of eruption of semen is the time required for the eruption of seminal fluid containing spermatozoa after the first intromissia. All presented in the table
    The 55 values are average, N is the number of animals tested in each experiment.
    The proposed compounds have low toxicity.
    15
    20 | Q 21258 tsy,
    25
    thirty
    35
    which are capable of ejecting seminal fluid containing spermatozoa during the test period. Before treatment with the drug solution, each male should be subjected to at least two consecutive trials with a drug carrier with similar sexual activity. After each test with the drug, additional tests were performed with the carrier of the drug. In order to exclude a behavioral response in the treatment of a substance that may be due to spontaneous changes in sexual activity, a criterion for the reversibility of the behavioral reaction followed by the introduction of a drug carrier was used. Thus, the behavioral response to treatment was taken as the norm as arbitrarily determined as a reaction that differed neither from the previous control reaction nor from the subsequent reaction in the control test with the carrier of the substance.
    The pairing tests were carried out from 12.00 to 17.00 in the dark phase of the lighting cycle. To determine the behavioral response in these tests, plastic drawers of size 24; 24 inches (cm) from the base 12 inches (30 cm) were used which were illuminated with red light. Each test began with the intake of susceptible female rats into the test case and was completed either 30 minutes later or immediately after the first ejection of semen containing spermatozoa. Sexual activity index, test for rats capable of ejecting seminal fluid, was determined
    as the hidden period of eruption of the semen (the time interval from the moment of intromissia to the eruption of seminal fluid),
    Comparative data on the effect of quinopyrol compounds and the compound of Example 1 on the latent period of eruption of semen in male rats are given in Table 2,
    Hide the period of eruption of semen is the time required for the eruption of seminal fluid containing spermatozoa after the first intromissia. All presented in the table
    values are average, N is the number of animals studied in each experiment.
    The proposed compounds have low toxicity.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining trans-octahydroxazole (A, 5q) quinoline of a common pho1) mule
    : xf
    where R is C-C-alkyl {
    Rj is an amino group, and the hydrogen atoms in the 4a and 8a positions have a trans configuration relative to each other, or its pharmaceutically acceptable salts, characterized in that the urea is reacted with a 7-bromo-6-keto compound of the general formula
     Xx)
    at
    where R has the indicated meanings
    Table 1
    ConnectionDose, Change Change speed
    mcg / kg of pressure - cardiac contraction,% scientific research institute,%
    trans - () - 2-amino 5-n-propyl-0.1 -18.3 + 5.7 -8.5 + 2.2
    4,4а, 5,6,7,8,8а, 9-octahydroxazole (4,5q) quinoline hydrochloride 1-8.6 + 1.6-4.4 + 0.9
    10 -15.1 + 1.1 -5.6 + 0.7 100 -39.0 + 1.9 -17.5 + 2.3 1000 -51.2 + 1.2 -19.1 + 3, four
    Baseline: mean arterial blood pressure 187 + 10 mmHg, average heart rate 336 ± 13 beats / min.
    trans (±) -2-methyl-5-n-propyl-1 -3.2 + 0.5 -2.4 + 0.8 4.4a, 5,6,7,8,8a, 9-octahydroox - gold (4.5q) quinan-P-tosil 10 -7.0 + 1.0 -2.8 + 0.4
    100 -19.6 + 1.4 -16.117.6 1000 -26.2 + 4.3 -23.6 ± 4.4
    Baseline: mean arterial blood pressure of 212 ± 4 mmHg, frequency of heartbeats, beats / min.
    trans - (+) - 5-n-prop1sh-4.4a, 5.6, 7.8.8a, 9-octahydroxazolo (4.5q) quinoline male
    1-5.0 + 1.2-3.6 + 0.5
    10-10.2 ± 1.0-4.6 + 0.6
    100-27.4 ± 2,, 5 + 2.6
    1000-37.7 + 4, 8 + 3.7
    Baseline: mean arterial blood pressure 194 ± 5 mmHg, average heart rate 371 beats / min.
    Duration 15 min or more
    21
    1247 ± 240
    755t67
    U21258.22
    6lit2
    658 ± 100
    533 + 78
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    同族专利:
    公开号 | 公开日
    CA1292742C|1991-12-03|
    KR880001430B1|1988-08-08|
    EP0172697A2|1986-02-26|
    PT80899A|1985-09-01|
    PH22541A|1988-10-17|
    AR240822A1|1991-02-28|
    IE58695B1|1993-11-03|
    JPS6147487A|1986-03-07|
    IL75991D0|1985-12-31|
    EP0172697A3|1986-03-12|
    AU4573785A|1986-02-06|
    EP0172697B1|1991-09-25|
    PT80899B|1987-12-30|
    IE851921L|1986-02-02|
    ZA855830B|1987-03-25|
    ES545859A0|1987-04-01|
    NZ212946A|1988-07-28|
    HU193338B|1987-09-28|
    HUT38348A|1986-05-28|
    ES8704499A1|1987-04-01|
    GR851895B|1985-12-03|
    DE3584205D1|1991-10-31|
    DK349185A|1986-02-03|
    AR240822A2|1991-02-28|
    KR860001815A|1986-03-22|
    ES551964A0|1987-10-16|
    JPH0670063B2|1994-09-07|
    DK349185D0|1985-08-01|
    AT67766T|1991-10-15|
    AU569406B2|1988-01-28|
    ES8800231A1|1987-10-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4198415A|1979-01-22|1980-04-15|Eli Lilly And Company|Prolactin inhibiting octahydro pyrazolo[3,4-g]quinolines|
    DK349385A|1984-08-03|1986-02-04|Lilly Co Eli|PROCEDURE FOR THE PREPARATION OF TRICYCLIC QUINOLINE DERIVATIVES AND INTERMEDIATE PRODUCTS FOR USING THE PROCEDURE|
    US4826986A|1986-06-16|1989-05-02|Eli Lilly And Company|6-Oxo-trans-octa- and decahydroquinolines|US4826986A|1986-06-16|1989-05-02|Eli Lilly And Company|6-Oxo-trans-octa- and decahydroquinolines|
    US4762843A|1986-09-15|1988-08-09|Warner-Lambert Company|Hetero [f] fused carbocyclic pyridines as dopaminergic agents|
    US4939259A|1989-07-24|1990-07-03|Eli Lilly And Company|2-oxo-pyrido[2,3-g]quinoline derivatives|
    US6395744B1|1994-04-22|2002-05-28|Queen's University At Kingston|Method and compositions for the treatment or amelioration of female sexual dysfunction|
    JP2002518435A|1998-06-22|2002-06-25|クイーンズユニバーシティアットキングストン|Methods and compositions for the treatment or amelioration of female sexual dysfunction|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US63723284A| true| 1984-08-02|1984-08-02|
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