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    • 专利摘要:
    9-Amino-1-hydroxyoctahydrobenzo[c]quinoline derivatives offormula and pharmaceutically acceptable acid addition salts thereof wherein R is hydrogen, COR7 or SO2R8 where R7 is hydrogen, alkyl, having from one to five carbon atoms; alkenyl and alkynyl each having from two to six carbon atoms; trifluoromethyl, benzyl, furyl, thienyl, pyridyl or R9C6H4 where R9 is H, NH2, F, Cl, Br, CH3 or OCH3; R8 is alkyl having from one to five carbon atoms or R9C6H4; R1 is hydrogen, benzyl, benzoyl, alkanoyl having from one to five carbon atoms or -CO-(CH2)p-NR2R3 wherein p is 0 or an integer from 1 to 4; each of R2 and R3 when taken individually is hydrogen or alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from piperidino, pyrrolo, pyrrolidino, morpholino or N-alkylpiperazino having from one to four carbon atoms in the alkyl group; R4 is hydrogen, alkyl having from 1 to 6 carbon atoms or -(CH2)7-C6H5 wherein z is an integer from 1 to 4; R5 is hydrogen, methyl or ethyl; R6 is hydrogen, -(CH2)y-carbalkoxy having from one to four carbon atoms in the alkoxy group and wherein y is Q or an integer from 1 to 4, carbobenzyloxy, formyl, alkanoyl having from two to five carbon atoms, alkyl having from one to six carbon atoms; -(CH2)x-C6H5 wherein x is an integer from 1 to 4; or -CO(CH2)x-1C6H5; Z is (a) alkylene having from one to nine carbon atoms; (b) -(alk1)m-X-(alk2)n- wherein each of (alk1) and (alk2) is alkylene having from one to nine carbon atoms, with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not greater than nine; each of m and n is 0 or 1; X is 0, S, SO and SO2; and W is hydrogen, methyl, pyridyl, piperidyl, wherein W1 is selected from the group consisting of hydrogen, fluoro and chloro; and wherein W2 is hydrogen or ; a is an integer from 1 to 5 and b is 0 or an integer from 1 to 5; with the proviso that the sum of a and b is not greater than 5; useful in mammals as analgesics, tranquilizers, antiemetic agents, diuretics, anticonvulsants, antidiarrheals, antitussives, in treatment of glaucoma, and intermediates therefore.
    公开号:SU1217254A3
    申请号:SU813317052
    申请日:1981-07-22
    公开日:1986-03-07
    发明作者:Росс Джонсон Майкл
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    in the presence of alcohol as a solvent.
    3. The method according to the claim 1, characterized in that the hydrogenation is carried out at room temperature and at a pressure of 3.5 kr / cm,
    The invention relates to new benzo (c) quinolines, more specifically to some 9-amino-1-hydroxyoctahydro-benzo (c) quinolines and their derivatives, in particular, to some amide derivatives of the 9-amino group, as well as their pharmaceutically acceptable acid adducts, which can be used as a means of affecting the central nervous system, in particular, as analgesics and antiemetics for use by mammals, including humans.
    The purpose of the invention is the synthesis of new compounds5 possessing valuable pharmacological properties.
    Example 1. DL-1-Acetoxy-5 5 6,6a-p-7-tetrahydro-6-p-methyl-3 (5-phenyl-2-pentyloxy) -benzo (c) quinoline-9 ( 8H) -oxime.
    In a solution of 10.0 g (0.023 mol) of DL-1-acetoxy 5,6,6a-I-7-tetrahydro-6-p-methyl-3- (5-phenyl-2-pentyl-oxy) -benzo (c) quinoline-9 (8H) -one (with a melting point of 136-140 ° C), 25 ml of dry pyridine in a stream of nitrogen in a portion add 2.36 g (0.034 mol of hydroxylaminohydrochloride. The solution thus prepared is stirred S) To room temperature for 18 hours. The reaction mixture is diluted with 500 ml of ethyl acetate and stirred for 5 minutes together with 250 ml of 10% (w / v) hydrochloric acid. The organic phase is separated and washed three more times with 10% hydrochloric acid. An orange solid product precipitates with each flush, so the liquid is filtered before each subsequent wash. The combined mass of the orange solid prop, 1 that, -L, about tl- that the mixture of diastereomers is subjected to separation by fractional crystallization or chromatography.
    The product is stirred for 10 minutes in 75 ml of methylene chloride. The solid is then filtered off and dried under vacuum over phosphorus pentoxide to give 7.8 g
    (75% yield) of the title compound of the example with mp. 182-185 s. Mass Spectrogram (m / e): 448 (M); IR spectrogram (potassium bromide) 2.94 μm (hydroxyl), 6.13 μm
    (carboxyl), 6.4 microns (cyano group), 8.0 microns (-0-).
    Example 2. Pb-9-B-Acetamido-1-acetoxy-5,6, 8,9,10,10-d - o - octahydro-6-p-methyl-3- (5-fennl-2-pentyloxy ) -benzo- (c) quinoling hydrochloride.
    3.2 g of vg-1-acetoxy-5,6,6- / 3-7-tetrahydro-6- / 3-methyl-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline-9 (8H) -oxime (0.007 mol) is combined with 1.5 g of 5% palladium on carbon as a catalyst and hydrogen is introduced into the mixture in 100 ml of methanol in an autoclave under a pressure of 3.5 kg / cm for 3 hours. for hydrogenation. The catalyst is filtered off through diatomaceous earth and then thoroughly washed with methanol. Combined methanol
    the filtrates are evaporated in vacuum to obtain a foam-like material, which is immediately subjected to acetylation by dissolving in 200 ml of methylene chloride and adding 3.03 g (0.03 mol 3 eq) of triethylamine first, and then 3.66 g (0.03 mol ) 4-demethylaminopyridine. After that, the reaction mixture is cooled to O With in a bath of a mixture of ice water,
    and in a stream of nitrogen, 3.06 g (0.03 mol) of acetic anhydride is added dropwise to it. After stirring at 0 ° C for 30 minutes, the reaction
    31
    the mixture is washed with 4 portions of 50 ml each of 10% (w / v) hydrochloric acid Tbij 2 portions of 50 ml each of water and a .50 ml portion of brine and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give a light brown foam-like product (2.7 g), which is chromatographed using 50 parts by weight. Nickel gel, eluted with a mixture of ethyl acetate and toluene in a 1: 1 volume ratio. The analogous fractions were combined and the solvent was removed in vacuo. The residual oil is dissolved in diethyl ether and acidified with dry hydrogen chloride in a nitrogen atmosphere. The resulting solid was filtered and dried in vacuo to give 0.91 g (25% overall yield over two stages) of the title compound of the example. Mp. 188-190 C. Mass spectrogram (t / e): 478 (), IR spectrogram (potassium bromide): 5.6 μm (oxymethyl), 5.9.6 μm (); H-HMP (CDCl5) ppm (8): 2.06 (-MHCOCH3), 2.5 (By repeating the procedure described, but using 6.5 g of palladium-on-carbon catalyst and carrying out hydrogenation under atmospheric pressure, practically same results.
    Example 3. Bb-9- | -Methylsulfonamide-1-acetoxy-5,6,6a-y-7,8, 9,10,1 Oa-N-octahydro-6- / 5-methyl-3- - (5-phenyl-2-pentyloxy a) benzo (c) quinoline.
    0.8 g of DL-1-acetoxy-5,6, SQ-Gi-7-tetrahydro-6-p-methyl-3- (5-phenyl--2-pentyloxy) benzo (c) quinoline-9 (8H a) -oxime (0.0018 mol) is combined with 0.4 g of 5% palladium on carbon as a catalyst in 40 ml of methanol, and the mixture is hydrogenated under an overpressure of 3.5 kg / cm for 2 hours. The catalyst is further was removed by filtration and the solvent was evaporated in vacuo to give 6a, lOq-TpqHC-9-p-amino compounds as a light tan red foam product. The latter is dissolved in 30 ml of methylene chloride, after which 0.21 (0.0021 ml) of triethylamine and 0.256 g (0.0021 mol) of 4-dimers of 1-aminopyridine are added to the solution, and the mixture is cooled to O C and then added drop by drop
    2544:
    for 3 min, 0.24 g (0.0021 mol) of methanesulfonyl chloride. The reaction mixture was stirred at 0 ° C in a stream of nitrogen for 1 h, and poured into a mixture of 50 ml of water and methylene chloride. The aqueous layer is extracted with 20 ml of methylene chloride, and the combined organic layers are washed with 4 portions of 20 ml.
    Q of 10% (by weight) hydrochloric acid, 40 ml of water, 40 ml of sodium bicarbonate, 20 ml of water, and 20 ml of brine. The washed extracts are dried over anhydrous sulphate.
    5 mg, and the solvent is evaporated to give 0.520 g (56.2% yield) of crude product, which is purified by column chromatography using 20 g of silica gel, eluting with a mixture of ethyl acetate and cyclohexane in a volume ratio of 3: 1. The fractions containing the desired product are combined and the solvent is evaporated from them in vacuo to give 300 mg (58% recovery, 32% yield) of a purified, target compound of the example in the form of a foam-like product. Mass spectrogram (m / e): 514 (M). The H-NMR spectrogram (CDCE) showed that the hydrogen atom is in position 9, which corresponds to a peak at 4.78-S (m, 1H), indicating a. is a hydrogen atom. Thus, the 9-methylsulfonylamino group is in the α-position.
    Example 4. By repeating the procedures of Examples 2 and 3, but using instead of acetic anhydride or methanesulfonyl chloride, benzoic anhydride, trifluoroacetic anhydride, valeric anhydride of new acid or AND-toluene sulfonyl chloride, the following compounds are obtained:
    A. Bb-9-p-Benzamido-1-acetoxy- -5,6,6ct- | i-7,8, 9,10,10- |) y-octahydro-6-p-methyl-3 - (5-phenyl-2-pentyl-oxy) benzo (c) quinol hydrochloride.
    0 Mass spectrogram (m / e): 540.518, 497 (M-).
    Found,%: C 71.29; H 7.04; N 4.91.
    C, H4004 "Mr. NCE.
    5Calculated,%: C, 70.75; H, 7.16;
    N 4.85.
    B. VB-9-p-Trifluoroacesh1-amino-1-acetoxy-5,6,6a-p-7,8,9,10, lOa-ttf0
    five
    octahydro-6- | -methyl-3- (5-phenyl-2-pentyloxy) -benzo (c) quinol. H-NMR Spectrogram (CDCP) p.P “ni. (S): 1.02-3.15 (m), 4.3 (s), 4.7 (s), 5.72-6.76 (m), IR spectrogram (potassium bromide): 3, 0, 3.43, 5.65, 85, 8.3-8.67 microns (wide band), 12.5 ,, 13.4-13.8, 14.35 microns.
    Found,%: C 64.20 H 6.67j, 4.82,
    , C2, H ,, 0, N, F ,.
    Calculated,%: C, 65.40; H 6.62; N 5,, 26.
    C.Vb-9-p-Valeroylamino-1-acetox-15 si-5.6, 8,8,10,10,10 s | - “: - octabd-b-methyl-3- (5-phenyl- 2-pentyloxy) benzo (c) quinoline. H-NMR Spectrogram (CDCB-), p.m. (eight);
    : 0.928-3, 12 (m), 4.3 (m ,, 1H), 4.66 20 (m, 9-axial H) 5.94 (t, 2H) ,. 6.83 (s, 2H-aromatic). Mass Spectrogram (m / e): 520 (M),
    D.Bb-9- - (4-Methylphenylsulfonyl) -amino-1-acetoxy-5,6,6a-i -7, 25 8,9,10, IOa-56-octahydro-b-methyl-3- - ( 5-phenyl-2-pentoxy) benzo (c) quinoline, reddish-brown-yellow crystals (20% yield),
    Example 5. A mixture of diastereoiso isomers of 9-amino-1-acetose: Si-5,65,64-, 9, TH., 10a-c-octagidro-6- | -methyl-3- (5-phenyl 2-pentyloxy) -benzo (c) quinoline.
    To 25 ml of methanol, 300 mg of DL-tracky-1-acetoxy-5,6, bd- -B-7,10,10c | - (1-hexahydro-6- / methyl-3- (5- phenyl-2-pentyloxy) benzo (c) -quinoline-9- (8H) -one, 300 mg of 5% palladium on coal and 480 mg of ammonium chloride. This mixture is subjected to hydrogenation at atmospheric pressure and room temperature for 18 h. The catalyst was removed by filtration, the filtrate was evaporated in vacuo to give a colorless crystalline residue, the residue was stirred with 10 ml of methylene chloride, the mixture was filtered to remove ammonium chloride and the filtrate was evaporated to dryness. The residue is triturated in 20 ml of diethyl ether, filtered and the product is dried to dryness at 56 ° C (with a residual pressure of 0.5 mm Hg) for 24 hours. Thus, 262 mg of product is obtained (yield 87, 3%) with a melting point of 194-195.5 C. Mass spectrogram (t / e): 436 (), IR spectrogram35
    45
    50
    55
    ma (bromide ca. pi): 2.80, 2.90, 2.97, 3.43, 5.64, 5.70, 6.13, 6.57, 7.25, 8.20 microns (wide band), 8.87, 9.65, 12.05 microns (wide band).
     Found,%: C 67.93; H 7.87; N 5.97. ,, N, 0, .HCe.
    Calculated,%: C 68.50j H 7.89 N 5.93.
    Example 6, Mixed diastereomers of 9-methylsulfonylamino-1-β-acetoxy-5,6, 6a-p-7,8,9,10,1 Oq-ot-octahydro-6- -methyl-3- (5- phenyl-2- -pentyloxy) benzene (c) quinoline.
    one
    In 1 O ml of methylene chloride, 218 mg (0.5 mol) of the mixed diastereomers of 9-amino-1-acetoxy-5,6,6q -p-7,8,9,10 a-s are added; Octahydro-6- (3-methyl-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline and 0.083 ml (0.6 mol): triethylamine. The solution is cooled to -20 ° C and a solution of 57.3 mg (0.5 mol) of methanesulfonyl chloride in 5 ml of methylene chloride is added dropwise to it over 8 minutes. Then the mixture is heated to 0 ° C for 30 minutes, poured into 20 ml of a mixture of ice-water and 20 ml of methylene chloride, as a result of which the layers are separated. The aqueous layer was extracted with the same solvent, and the combined organic layers were washed with 20 ml of water, saturated sodium bicarbonate solution (20 ml), 10 ml of water, 10 ml of brine and dried over anhydrous magnesium sulfate. As a result, evaporation of the dried extract gives a residue, which is chromatographed on 10 g of silica gel, eluting with a mixture of diethyl ether and cyclohexane in a 1: 3 ratio. The product containing fractions were combined, the solvent was evaporated in vacuo to give a pink foam-like product, which was dissolved in 10 ml of diethyl ether and filtered. Evaporation of the filtrate yields 205 mg (yield 79.8%) of the desired product. Mass spectrogram (m / e): 514 (M), 472 ,, 433, 324, 230, 216, 204, 91, Zh-spectrogram (potassium bromide): 2.95, 3.00, 3.08, 3 , 46, 5.60, 5.75, 6.17, 6.35, 6.88, 7.30, 7.55, 8.25, 8.75, 9.70 microns.
    Found,%: C 65.24; H 7.37, N 5.32.
     .
    Calculated,%: C 65.35 H 7.44, N 5.44.
    Example 7. Mixed diastereomers of 9-acetamido-1-acetoxy-5, 6,6a-p-7,8,9,10, IOa-ui-octahydro-6-B-methyl-3- (5-phenyl 2-pentyloxy) benzo (c) quinoline.
    336 mg of mixed diastereomers of 9-amino-1-acetoxy-5,6,6a-beta-7,8,9,10,10-1-o (.-Octahydro-6- / 3-methyl-3- (5 - phenyl-2-pentyloxy) benzo- (c) quinoline (0.77 mol) is dissolved in 10 ml of methylene chloride and 0.804 ml (10 mol) of pyridine is added. This solution is cooled to -20 ° C and 0.075 ml (0.77 mol) of acetic anhydride in 5 ml of methylene chloride is added over 5 minutes. The mixture is allowed to warm to 5 ° C, poured into ice-water (20 ml of each component), and the product is isolated As in Example 6, 315 mg of amorphous material is obtained (yield 86%).
    Mass Spectrogram (m / e): 478 (I), 433.376, 290, 230, 215, 176, 91; IR spectrogram (potassium bromide): 2.96, 3.43, 3.51, 5.64, 5.72, 6.04, 6.15, 7.28, 8.20 (wide band), 8, 63 microns
    Found,%: C 72.58; H 7.95; N 5.71.
    C2,38,0 ,.
    Calculated,%: C, 72.77; H 8.00, N 5.85.
    Example 8. DL-9-about-Adetami-do-1 -detoxy-5,6, 6a - / U-7,8,9,10,1 Oq-oC-octahydro-6 - /} - methyl-3- (5-phenyl--2-pentyloxy) benzo (c) quinoline and 9-p-acetylamino diastereomer.
    The procedure of Example 7 is repeated on a scale of 3.4 mmol to obtain 1.577 g of mixed diastereomers. The mixture is dissolved in diethyl ether, the solution is filtered, the insoluble material is washed with diethyl ether and dried at room temperature and a residual pressure of 0.05 mm Hg. for 20 hours with the treatment of 964 mg 9-o (, - acetamido isomer with mp. 154-155 C. Mass spectrogram (m / e), 478 (M), 377, 360, 290, 230, 91J IR spectrogram (potassium bromide): 2.94, 3.00, 3.42, 5.72,
    , 6.00, 6.14, 6.24, 6.52, 7.27, 8.08, 8.12, 8.64 microns.
    Found,%: C 72.70; H 7.87; N 5.85.
    С „ll, g N.O,.
    Calculated,%: C, 72.77; H 8.00; N 5.85.
    Evaporation of the uterine solution Q gives a white foam-like product, which is identified as a mixture of 9-01: -acetamido- and 9- / 3-acetamide diastereomers. This mixture was purified by chromatography on a graph B of column j on 75 g of silica gel, eluting with a mixture of diethyl ether and ethyl acetate in a volume ratio of 9: 1. Fractions that contain the less polar 9- / 5-acetylamine isomer, 0 are collected, evaporated and dried to give 58 mg of product which is identified as the free base of the product obtained according to example 2. This is determined by - H-NMR-5 - spectrogram in CDCfj, mass spectrogram and IR spectrogram (potassium bromide).
    Found,%: C 72.35; H 8.15; N 5.88. 0 2,.
    Calculated,%: C, 72.77; H 8.00-, N 5.85.
    Example 9. Bb-9-β-Acetamium-to-1-acetoxy-5,6,6- / 3-7,8, 9,10,10 S- -L-octahydro-5,6- | 3-dimethyl-3 - (5- -phenyl-2-pentyloxy) -benzo (c) quino-LINHydrochloride.
    To a mixture of 475 mg of palladium on carbon and 10 ml of methanol, purged with nitrogen, add a solution of 475 mg (0.99 mmol) of DL-9-acetamido-1-acetoxy-5,6,6a-p-7 , 8, 9,10,1 Oq-ct-6-p-methyl-3- (5-phenyl-2- -pentyloxy) benzo (c) quinoline in d 10 ml of methanol, 7.5 ml of a 37% solution formaldehyde and 0.5 ml of acetic acid. The resulting mixture is hydrogenated at atmospheric pressure and room temperature. The theoretically necessary amount of hydrogen (22 ml) is absorbed within 20 minutes. This mixture is then filtered and the filtrate is separated into a mixture of 10 ml of water with 50 ml of methylene chloride. The aqueous phase is separated, extracted with 50 ml of methylene chloride, the combined organic layers are washed with 50 ml of sodium bicarbonate solution, 50 ml of water,
    0
    five
    and 50 ml of brine and dried over anhydrous magnesium sulphate. Evaporation of the dried extract gives a colorless oil-like product, which is chromatographed on 60 g of silica gel, eluting with a mixture of toluene and diethyl ether in a volume ratio of 1I1. The fractions containing the product are combined and evaporated to give a colorless oil-like product, which is dissolved in 20 ml of diethyl ether, and the solution is filtered. This filtrate is treated with a solution of hydrogen chloride in ethyl acetate until the litmus test shows an acidic reaction. The precipitated product is collected, filtered and dried at 24 ° C and a residual pressure of 0.05 mm Hg. within 2 days of its so-called 115-116 ° C, and the yield of 361 mg (75.7%). Mass spectrogram (m / e); 492 (M), 478, 39L 375, 286, 244, 230, 190 IR spectrogram (potassium bromide): 2.95, 3.45, 4.20 μm (wide band), 5.65, 6.00, 6.14, 6.52, 7.30, 8J35 μm
    Found,%: C 65.97; N. 7.88; N 5.28.
    ,, N, jO ,, hCe.
    Calculated: 5%: C 68, H, 7.81J N 5.30.
    Example 10. Diastereomeric DL-trans-9-p-acetamido-1-acetone si-5,6,6a-I-7,8p 9,10, Yua-c-octahydro-5,6-p- dimethyl-3- (1-p-methyl-4- -phenylbutoxy) benzo (c) quinoline-h-rochloride and its mixture with a 3- (1-o6-methyl-4-phenylbutoxy) diastereomer.
    A mixture of 741 mg DL-trans-9-p-acetam to-1-acetoxy-5,6,6- | 1-7.8, 9, 10, 10a -o, -octagidro-6- | 5-methyl-3- (5-phenes1 2-pentyloxy) benzo (c) quinoline, 25 ml of freshly distilled tetrahydrofuran, 7 , 5 ml of a 37% formaldehyde solution, 550 mg of 5% palladium on carbon and 0.55 ml of acetic acid are hydrogenated under an overpressure of 2.81 kg / cm for 1 hour. The catalyst is removed by filtration and washed ethyl acetate. The filtrate is washed with 4 portions of 150 ml each of sodium bicarbonate solution, 2 portions of 150 ml each of water, 200 ml of brine, and dried over magnesium sulfate.
    and the solvent is evaporated in vacuo to give 800 mg of a colorless foam-like product, which contains a mixture of racemic diastereomers 9- / -acetamido-1-acetoxy-5,6,6- | H-7,8,9,10, Yu-y-octahydro-5,6-p-dimesh-1- 3- (1-methyl-4-phenylbutoxy) benzo (c) quinoline. This
    the mixture is subjected to chromatographic processing on 40 g of silica gel with elution first with a mixture of diethyl ether and toluene in a volume ratio of 1: 1. 15 ml fractions are collected. After collecting 170 fractions, a mixture of ethyl acetate and toluene is used in a volume ratio of 1: 1. A total of 350 fractions are collected.
     - A. Fractions 171-300 are combined
    and concentrate to dryness in vacuo to afford 445 mg of a colorless oil. The addition of diethyl ether to an oil-like product gives 175 mg of the free base of the 3- (methy-1-4-phenylbutoxy) diastereomer with mp. 120-121 ° C. Free
    the base is dissolved in 20 ml of ethyl acetate and saturated with dry hydrogen chloride. Adding diethyl ether causes precipitation of the hydrochloride salt (190 mg) with so pl. 105-120 ° C. By -H-NMR spectro-rpciMMe, it is determined that this 3- (1- - / -methyl-4-phenylbutoxy) diastereomer (racemic).
    Found,%: C 67.52; H 8.01;

    c, H, N, 04 Hce.
    Calculated,%: C 68.11% H 7.81; N 5.30.
    B. The ethereal mother liquor, after completing the described operations, is evaporated to dryness to obtain 300 mg of an oil-like product. The latter was dissolved in 50 ml of diethyl ether, and the solution was pressurized with dry hydrogen chloride to obtain 240 mg of the hydrochloride salt of the mixed 3- (1-pC-methyl- and -methyl-4-phenylbutoxy) diastereomers of the title compound of the example of Tg. 105-120 ° C. H-NMR spectrogram showed that the product was a 50:50 mixture of two racemic diaster "4omers.
    Found,%: C 67.50; H 7.58; N 5.24 s OH about L Nse.
    Calculated,%: C 68.11; H 7.81; N 5.30,
    The structure of both selected pro ;; The evidence was confirmed by mass spectroscopic analysis.
    Example 11. H (1R), 6S, 6aR, 9R, 10o | K1-9-acetamido-1-acetoc Si-5,6,6a, 7,8,9,10, YN-octahydro-6-methyl- H- (1-methyl-4-phenylbutoxy) benzo (c) quinol hydrochloride:
    NHCOCH3
    5 rchosis
    H
    О- СНССННЫ СНз
    A.0.776 g (1.98 mmol) (-)
    , C3 (1K), 6S, 6aK -1-hydroxy-5,6,6a, 7-tetrahydro-6-methyl-3- (1-methyl-4-phenylbutoxy) benzo (c) quinoline-9- - (8H) -one (W-396.37 (C 1, methanol) was dissolved in 3 ml of pyridine, and 0.206 (2.97 mmol) of hydroxylaminohydrochloride was added to the solution. The mixture was stirred at room temperature overnight. and then the resulting solution is washed with 6 portions of 30 ml of 0.5 N. hydrochloric acid, 30 ml of brine and dried over anhydrous magnesium sulfate. The solvent is taken up in vacuo to give the corresponding oxime, which use immediately in the next stage.
    B. The oxime thus obtained is dissolved in 25 ml of methanol, 0.3 g of 5% palladium on carbon is added to the solution, and the mixture is hydrogenated under an overpressure of 3.52 kg / cm overnight. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue is dissolved in 15 ml of methylene chloride, then 0.464 g (4.55 mmol) of triethylamine is added to the solution and the solution is cooled to. After this, 0.555 g (4.55 mmol) of 4-dimethyl-aminopyridine, 0.46 g (4.55 mmol) of acetic anhydride and the prepared mixture are added to the solution.
    stirred at nitrogen flow for 1 hour. This mixture was poured into 50 ml of methylene chloride, washed with 2 portions of 20 ml of 0.5N each. hydrochloric acid, 20 ml of water, 20 ml of brine and dried over anhydrous magnesium sulphate. The dried solution is evaporated in vacuo, the residue is placed on a column with 50 g of silica gel (0.63-0.2 μm), and eluted with a mixture of ethyl acetate and methanol in a volume ratio of 97: 3. The product fractions are combined and evaporated to a small residual volume in vacuo. Hydrogen chloride is passed through this concentrate, resulting in precipitation of 89 mg of solid product with
    0 m.p. 138-142 ° C.
    Found,%: C 68.05, H 7.55 N 5.46.
    .
    Calculated,%: C 67.62 H 7.63, 5 N 5.44.
    Example 12. (+) C (1R, 6S, 6qR, 9R, 10AH-9-Acetamido-1-acetoxy-5,6,6c (, 7.8,9, 10, YA-octahydro-5, 6-dimethyl-3- (1-methyl-4-fensh1- 0 butoxy) benzo (c) quinoline:
    T NSESNz
    1 OOSNz
    five
    V
    0 / (СН) ЗС5Н5
    CHfСНз Нз
    as a result of the hydrogenation of a mixture of 0.71 g (1.48 mmol) H (1R), 6S, 6qR, 9R, 10q R-9-acetamido-1-acetoxy-5.6, 6a, 7.8,9,10, 10a-octahydro-6-methyl- -3- (1-methyl-4-phenylbutoxy) benzo (c) quinoline, 0.71 g of 5% palladium on carbon, 12.0 g of a 37% formaldehyde solution and 0.7 ml of acetic acid in accordance with Example 9, 750 mg of the oily oil are obtained. The latter is purified by chromatography on a column of 35 g of silica gel (0.04-0.063 μm), eluting with diethyl ether containing 2% by volume of methanol. From the fractions containing the product, 0.27 g (37% yield) of the desired N-methyl compound is isolated as a colorless solid with a mp. 120-122 C. Mass spectrogram.
    (m / s): 492 (M-) ,, 304 230, IR-spectrum oam a (bromide potassium): 3.02 ,. 3.4.5.71 / 6.15, 8.17, 13.41, 14.36; k, + 154.88 (c 0.1, methanol).
    Found: C, 72.67; H 8.00 ,, N 5.58,
    SzoN).
    Calculated,%: C 73.14; H, N 5.69.
    Example 13, DL-Throne - 9- Formamide-1-hydroxy-3- (2-heptyloxy) 5 5 6J 6a, 7 oe 8.9.1 O, 1Oq-octahydro-benzo (c) quinoline.
    A, 3.73 g (0.01 mol) DL-1-b. Acetoxy-3- (2-1-epptr {lox) -5, 6, Ь (E- -B-7.10, 10a-a .-hexahydrobenzo (c) - gsinol n-9-- (811) -one with a melting point of 65.5-68 ° C and 1.0 g (0.014 mol) of hydroxylamine hydrochloride is dissolved in 70 ml of ethanol and 10 ml of water. This mixture is stirred by adding 3.8 ml of 5N sodium hydroxide solution in one portion. The resulting mixture is kept at reflux for 30 minutes and then cooled, poured into ice and subjected to extraction treatment with diethyl efnr1om. The extracts are washed with water, dried over a beeBomb som magnesium lithium and parabens to dryness to give DL-trans -1-hydroxy-3- (2-heptyls-5, 6, .6o (5 7 310.1 Oa hexahydrobenzo (c) chinol 1 -9 (8H) -oxime,
    and. A solution of 1.94 g (5 mmol) of DL- - Trans -1-hydroxy 3-- (2-heptyloxy) -5 j6, ba, 7 510.1 Oa-hexa-hydrodibenzo (c) -hi nolin-9 (8H) oxime in 100 ml of ethanol
    and 25 ml of anhydrous ammonia, containing 1 g of nickel: Rene, is subjected to hydrogenation at 100 ° C and an overpressure of 50 atm for 4 hours. The formed / uus mixture is cooled to room temperature, filtered to remove the catalyst and the filter evaporated in vacuo. The residue was dissolved in ethyl formate (75 ml) and the solution was maintained at reflux temperature overnight. The mixture is evaporated to dryness to give the desired product as a mixture of diastereoisomero, which is separated, if necessary, by the chromatogram treatment on silica gel.
    0
    0
    five
    0
    S
    Alternatively, the corresponding dc1I 9-acetamido-1-hydroxybenzo (c) quinhoin is obtained by acetylating the residue obtained during the hydrogenation process with acetic acid;
    In the case of using a molar excess of acetic anhydride, the corresponding 9-acetamido-1-acetobenzo (c) quinoline is obtained.
    The analgesic properties of the proposed compounds are determined by testing using heat pain stimuli causing sharp movements of the mouse tail, or chemical pain stimuli, in particular by measuring the ability of the test compound to suppress painful cramps caused by phenyl benzoquinone used as an irritant.
    Use with thermal pain stimuli.
    Determination of the effect of analgesic on a mouse using a hot plate.
    Adjustable thermal stimuli are applied to the sole of the paw of the mouse with the help of an aluminum plate TOLINOINA 3.175 mm. A reflector of 250 watts power of infrared radiation is placed on the underside of this aluminum plate. Thermostat tor5 connects with thermistors on the plate surface, sets a lamp heater to a program that allows it to maintain a constant temperature of 57 ° C. Each mouse is immersed in a glass cylinder with a diameter of 165.1 mm. which is on a hot plate, and at the beginning of the experiment, the moment 5 is taken, when the sole of the paw myish touches the surface of the plate. After 0.5 and 2 hours after the test compound is injected into the body, nests are carried out by the nests for: determining the initial abrupt: the movements of one or both hind paws of the mouse, or after a 10-second period of time movements. For morphine, the magnitude of MBE jg is 4-5.6 mg / kg (subcutaneously).
    Determination of analgesic action by a sharp dvnzhe {{and m tail of the mouse,
    Each mouse is placed in a metal cylinder fitted with a protrusion, from one end of which a tail protrudes. This cylinder is positioned so that the tail lies on top of the open tube heater. At the beginning of the test, the aluminum curtain located above the lamp is lowered, allowing the light flux to pass through the slit and focus on the tail end of the mouse. At the same time turn on the time controller. The latency of an unexpected sudden tail movement is established. G-1 mouse, in which the analgesic is not injected, usually reacts after 3-4 seconds after exposure to the light of the lamp. To prevent burns on the tail of the mouse, the experiment is automatically terminated after a 10 second exposure. Each mouse was subjected to experiments 0.5–2 h after treatment with morphine and the test compound. For morphine, the value
    MVE
    90
    is 3.2-5.6 mg / kg
    (sc)
    A test with a tail dipped in a bath.
    Male white mice (weight 19-21 g) of Charles River S-1 strain are weighed and tagged for identification. In each group, 5 animals are usually used to test each drug, using each of the animals and as a control. New test agents are initially administered at a dosage of 56 mg / kg, either intraperitoneally or subcutaneously, with the dosage being in a volume of 10 ml / kg. During the administration of the drug into the body and after both 0.5 and 2 hours after the drug is introduced into the mouse, each animal is placed in a cylinder. Each cylinder has holes for the necessary amount of air to enter it and each cylinder is closed round. nylon cork through which the animal's tail is passed. The cylinder is vertical. The tail of the animal is completely immersed in a water bath with a constant temperature of 56 s. The tip of the tail is characterized by energy
    0
    five
    0
    five
    0
    five
    0
    0
    reflex or twitching, which is combined with motor reactions. In some cases, the post-drug final response may be less pronounced. In order to prevent the possibility of tissue damage, the test is completed and the tail is removed from the water bath after 10 s. The latent reaction is fixed in seconds to the nearest 0.5 second.
    Tests to determine the effect of the filler (carrier) and the standard of known strength are conducted in parallel with the screening of candidates. If the activity of the test agent does not return to the main line values after 2 hours, the reaction latency is determined after 4 and 6 hours. The final measurement is made after 24 hours, if activity is still observed at the end of the day of the test.
    Test using chemical pain stimuli.
    Suppression of painful cramps caused by irritation with phenylbenzoquinone.
    The animals are divided into groups of 5 individuals each. Each mouse of the Harworth Pharma CF-1 strain is administered subcutaneously and orally saline, morphine, codeine, or a test compound. After 20 minutes (subcutaneous administration) or 50 minutes (oral administration), animals of each group are treated with intraperitoneal administration of phenylbenzoquinone, a pain irritant, which is known to cause an abdominal contraction. The mouse is observed for 5 minutes to determine the presence or absence of pain writhing 5 minutes after the injection of the pain stimulus. The value for the pretreatment of the drug when blocking the pain writhing is determined.
    Determination of the effect of pain stimuli using pressure.
    Effect on the reaction during the Haffner procedure with tail compression.
    In the course of the experiment, the male white rat (weight 50-60 g) strain of Charles River
    (Spread Dawley) CD. Before the introduction of the drug 8m and after 0 5 5 1,2 1.2 and 3 h after its introduction, a 2.5-inch (63.5 mm) bulldog clip of Johns Hopkins is attached to the base of the rat's tail. Acceptable attacking behavior with the desire to bite, directed against the stimuli, with the latency of the attack, recorded in seconds. In the case of the absence of attacking actions, after 30 seconds the clamp y, r1, are cast and the reaction latency takes 30 seconds. Morphine is active at a dosage of 17J8 Ic / kg (intraperitoneal).
    Tests using electrical pain stimuli.
    A jerk-jump jump.
    During such an experiment, a male white rat (weight 175-200 g) strain of Charles River (Sprit-Dowley) CD is used. Before the introduction of the drug, the paw of each rat is immersed in a glycerin / salt solution. Next, the cbBot is placed in the chamber and exposed to 1-second electric shocks on the solution-treated sole of the foot, and the intensity of these shocks increases at 30-second intervals. The values of this intensity are 05.39, 0.52, 0.78, 1.05, 1.31, 1.58, 1.86, 2.13. 2.42 ,, 2.72 and 3.04 mA. The behavior of the animal fertilizer is assessed by the presence of a shudder of 5 squeaks and a jump, or a fast forward movement when receiving an electric shock. Single seric electric shocks of increasing intensity are used for each rat just before the expiration of 0.5, 2.4 and 24 hours after the animal is treated with the drug,
    The results of the described tests are recorded as the maximum possible percentage efficacy (MVE) The magnitude of the MPE in percent for each group is statistically compared with the percentage of MVE for the standard and prior to the introduction of the drug, the control experiment
    The value of the MPE in percent is calculated by footprint 1, toe |; in the way:
    test start time - control time
    MVE,%
    ) C100
    ten
    test termination time - control time
    0
    five
    0
    five
    In the table, the analgesic activity of typical trans -5,6,6q, 7,8, 9,10,10a-octahydro-1-acetoxy-9-amy-, but-3- (5-phenyl-2-pentyloxy) benzo (c) quinolines with phenylbenzoquinone-induced pain wrists during a test run are indicated as MVE, i.e. at the dosage, when half of the maximum possible analgesic effect is observed.
    The proposed compounds as anti-emetic and anti-nauseous 5 agents when administered to mammals can be used to prevent vomiting and nausea caused by anti-neoplastic drugs.
    The antiemetic properties of the compounds of the formula I are determined on unanesthetized cats, which are not kept in isolated conditions, in accordance with a known method.
    The proposed compounds are active analgesics, vomiting and nausea suppressants, when administered orally and parenterally, they are conveniently used in the form of a composition. Such compositions include a pharmaceutical excipient (carrier), the choice of which is made depending on the route of administration in the body and standard pharmacological practice. For example, they can be ingested in the form of tablets, pills, powders and granules, containing such bases for the preparation of drugs, such as starch, milk sugar, some types of clay, etc. They can also be administered in the form of capsules, in a mixture with the same or equivalent bases for the preparation of drugs. They can also be used in the form of suspensions, solutions, emulsions, syrups and elixirs for oral administration.
    into the body, which may contain flavoring, flavoring and coloring agents. For oral administration in the body, tablets or capsules are used containing / in 0.01-100 mg of active ingredient.
    Suspensions and solutions of these medicinal agents, in particular those in which R ,, is a hydroxyl group, are usually prepared immediately prior to use to ensure the stability of the drug (for example, oxidation), suspensions or solutions (for example, precipitation) during storage . Typically, these are dry solid compositions that are reconstituted for administration in the form of injections.
    The dosage that is most appropriate for the patient is determined by the doctor, and this dosage depends on the age, weight and drug reactions of this particular drug.
    Mhri
     OOSNz
    nViS
    ) ZSbN5 C, Y9

    NHSOgCH, H
    I
    NNSSR „
    NHCO (CH2), CH N
    6f a
    ,
     NHCOCH
    the patient, as well as the route of administration into the body. Typically, the initial analgesic dosage, as well as the initial dosage to prevent and eliminate the feeling of nausea in adults, can vary from 0.01-500 mg per day in a single dose and in a divided dose. In many cases, there is no need for daily intake of the active substance in amounts of 100 mg. The most favorable results are achieved at dosage.
    15 in the range of 0.01-300 mg / day, preferably in the range of 0.10-50 mg / day, when taken by mouth. The best parenteral dosages are found to be in the range of 0,0120 100 mg / day, more preferably in the range of 0.01-20 mg / day.
    Data on the biological activity of the compounds obtained are summarized 25 in the table.
    sn,
    H
    SI, N
    sn
    H
    4.25
    77% with 56 mg / kg
    80% with 56 mg / kg
    .
    H CH,
    H CH,
    CH, H
    CHj N
    35.5 2.67
     racemic mixture of dextro-enantiomer, Gd + 154.88 °,
     q is a 50:50 mixture of diastereomers with a side chain at position 3, L of the A and p configuration;
     - (v -configuration,
     - a mixture of these configurations.
    Editor N. Egorova
    Compiled by G. Zhukov
    Tehred T. Tupik Proofreader I. Myska
    1007/62 Circulation 379 Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Branch PIP Patent, Uzhgorod, st. Project, 4
    Table continuation
    权利要求:
    Claims (4)
    [1]
    METHOD FOR PRODUCING 9-AMINO-1-OXYOKTAGHYDROBENZO (C) QUINOLINE DERIVATIVES OR THEIR PHARMACEUTALLY ACCEPTABLE SALTS.
    (57) 1. A method for producing derivatives of 9-amino-1-hydroxyoctahydrobenzo (c) quinoline of the general formula wherein the dotted line indicates the possible presence of a double bond,
    R - hydrogen or methyl;
    R 2 ~ R ^ and ZW have the indicated meanings, are reacted with hydroxylamine or an acid addition salt thereof to form an intermediate oxime of the general formula
    NOH and ZW have the indicated 'where R ^ -R values, followed by ma of the above formula in the presence of hydrogenation oxySU <,, 1217254 where R ( - COR ^ SO ^, R 5 ~ hydrogen, С ^ -Су - alkyl, trifluoromethyl or phenyl , a R 6 is methyl ylp-tolyl;
    R g is hydrogen, benzyl or lower C, - C - alkanoyl)
    R - methyl;
    R 4 is hydrogen,
    ZW - 2-pentyloxyphenyl, or them; pharmaceutically acceptable salts, characterized in that the compound of the general formula of the palladium catalyst ^ if necessary, the product obtained is acylated, sulfonated or, in the case when R 7 is hydrogen, subjected to Y-methylation, and the product is isolated as a racemate, or as individual isomers, or as a pharmaceutically acceptable salt.
    [2]
    2. The method according to claim 1, characterized in that the palladium catalyst is used in an amount of 0.5-2 hours per weight of the starting eno1217254 in the presence of alcohol as a solvent.
    [3]
    3. The method according to claim 1, characterized in that the hydrogenation is carried out at room temperature and at a pressure of 3.5 to 7 cm 2 .
    [4]
    4. The method according to π. 1, characterized in that the mixture of 9 - Y - and 9-J5 - diastereomers is subjected to separation by fractional crystallization or chromatography.
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    公开号 | 公开日
    EP0045171A3|1982-04-28|
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    HU185133B|1984-12-28|
    ZA815128B|1982-07-28|
    US4309545A|1982-01-05|
    EP0045171A2|1982-02-03|
    AU525944B2|1982-12-09|
    YU185181A|1983-12-31|
    DE3168891D1|1985-03-28|
    JPS57112372A|1982-07-13|
    AU7343481A|1982-05-06|
    PT73440A|1981-08-01|
    PL232331A1|1983-09-26|
    IE811686L|1982-01-28|
    KR850000273B1|1985-03-15|
    IL63423D0|1981-10-30|
    PH17281A|1984-07-06|
    DD202012A5|1983-08-24|
    EP0045171B1|1985-02-13|
    NO854454L|1985-01-29|
    NO812557L|1982-01-29|
    NZ197856A|1984-10-19|
    IE51426B1|1986-12-24|
    FI812338L|1982-01-29|
    AR230988A1|1984-08-31|
    ES504323A0|1982-12-16|
    AT11775T|1985-02-15|
    EG15535A|1986-09-30|
    IN158867B|1987-02-07|
    CA1178274A|1984-11-20|
    CS228515B2|1984-05-14|
    DK334581A|1982-01-29|
    ES8301926A1|1982-12-16|
    KR830006217A|1983-09-20|
    GR75283B|1984-07-13|
    GT198170557A|1983-01-12|
    PT73440B|1983-06-20|
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    法律状态:
    优先权:
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