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    • 专利摘要:
    1,9-Dihydroxyoctahydrobenzoc!quinolines (I), 1-hydroxyhaxahydrobenzoc!quinoline-9(??)-ones (II), and 1-hydroxy-tetrahydrobenzoc!quinolines (?V) useful as CNS agents, especially as analgesics and tranquilizers, as hypotensives, as agents for the treatment of glaucoma and as diuratics; intermediates therefor (III) and derivatives thereof having the formulae: , , (I) (II) and (III) (IV) wherein R is hydroxy, alkanoyloxy having from one to five carbon atoms and hydroxymethyl; 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 (piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group); R4 is hydrogen, alkyl having from 1 to 6 carbon atoms and -(CH2)z-C6H5 wherein z is an integer from 1 to 4; R5 is hydrogen, methyl or ethyl; R6 is hydrogen, -(CH2)y-carbalkoxy having from 1 to 4 carbon atoms in the alkoxy group wherein y is 0 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; and -CO(CH2)x-1-C6H5; Ro is oxo, methylene or alkylenedioxy having from two to four carbon atoms; R' is R or Ro; 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 9; each of m and n is 0 or 1; X is O, S, SO or SO2; and W is hydrogen, methyl, wherein W1 is hydrogen, chloro or fluoro; pyridyl, piperidyl, cycloalkyl having from 3 to 7 carbon atoms, or monosubstituted cycloalkyl wherein the substituent is wherein W2 is hydrogen, chloro or fluoro; and pharmaceutically-acceptable acid addition salts of compounds of Formulae I, II and IV and the ketals of compounds of Formulae II, II and IV wherein the ketal moiety has from two to four carbon atoms.
    公开号:SU1098520A3
    申请号:SU813254395
    申请日:1981-03-05
    公开日:1984-06-15
    发明作者:Росс Джонсон Майкл
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of a new benzo derivative (from a quinoline of the general formula 02W where Q is H / OR-X hydrogen, acetyl; hydrogen, acetyl; Rj is hydrogen or C-C-alkyl; R, -C-Cd-alkyl, C2 C SinKaHoii or benzoyl; -C-Cd-alkylene; -hydrogen OR phenyl, or their pharmaceutically acceptable salts, acting on the central nervous system and having analgesic effect. A method of producing alkyl or acylamines by reacting a suitable starting amine with dehydide is known. and subsequently reduced with cyanoborohydride 1 or with alkanoyl or benzoyl chloride and subsequent, if necessary, reduction with lithium aluminum hydride C2 J. The purpose of the invention is to prepare new benzo (c) quinol derivatives or their pharmaceutically acceptable salts of the general formula (II possessing valuable pharmacological properties. This goal is achieved by compounds of the general formula OZW where Q, R, K ", Z and W have the indicated values are subjected to interaction with formaldehyde followed by reduction with cyanborgilride or with the corresponding alkanoi.n-yln with beispghioride 0 if necessary, with further recovery of the resulting product with lithium aluminum hydride with the selection of the target product in free form or in the form of pharmaceutically acceptable salts. Example 1. d, l-TpaHc-5,6,6a / i, 7,10,10ci-Hexahydro-1-acetoxy-3 (2-heptyloxy) -5-benzoyl-6-methylbenzo (c) quinolin-9- (8H) -one. K a, 1-trans-5,6,6s (p, 7,10, Juas hexexyhydro-1-acetoxy-6 / s-methyl-3- {2heptyloxy) benzo (c) quinoline-9 (8H) -one ( 812 mg) in 2.5 ml of pyridine, 421 mg of benzoyl chloride in 3 ml of chloroform are added while transferring. After 2 hours, the reaction mixture is drunk on ice and extracted twice with ether. The combined ether extracts are washed with water, sodium bicarbonate, dried (Mc304) and filtered to give, after concentration and crystallization from ether / petroleum ether d, 1-trans-5,6,6a / b, 7, 10, lOaot-hexahydro-1 -acetoxy-3- (2-heptyloxy) -5benzoyl-6-methylbenzo (c) quinoline-9 (8H) OHJ so pl. 108-110 ° C. ha / e 401 (t). Output 290 mg., 28%. Similarly, using equivalent amounts of acetyl chloride instead of benzoyl chloride and the corresponding benzo (c) quinoline, d, 1-to-5,6 -6, 10,10-Hexahydro-1-acetoxy-3- (2-heptyloxy) -5-acetyl -6p-methylbenzo (s) quinoline-9 (8H) -one, t / e 433 (t), the yield is quantitative. Example 2. d, l-TpaHc-5,6,6a, 7, 10, 10ao1-Hexahydro-1-acetoxy-5methyl-6-methyl-3- (2-heptyloxy) benzo (c) quinoline-9 (8H) -on, To a stirred solution of 387 mg d, l-TpaHc-5,6,6aj8-7,10, IOaot-hexahydro-1-acetoxy-6/3-methyl-3- (2-heptyloxy) benzo (c) quinoline -9 (8N) -one in 3 ml of acetonitrile cooled to 15 ° C, 0.5 ml of 37% formaldehyde was added, followed by 100 mg of cyanoborohydride. Acetic acid is added to maintain the pH until completion of the reaction, which is determined by the disappearance of the starting material on the thin layer chromatogram. The product is listed as follows. Water and ether are added to the reaction mixture, the ether layer is separated, and the aqueous layer is extracted once more with ether. The ether extracts are combined, dried and evaporated to give d, 1-trans-5,6,6a /} 7, 10,10A-hexahydro-1-acetoxy-5methyl 6-motil-3- (2-he-11-thyloxy) benzo (s ) quinolium-9 (8H) -one in the form of oil. Top: one quantitative. H NMR (60 MHz / CDClj) shows a characteristic absorption of 2.85 (ppm) for N-CHj. Similarly, the following compounds are obtained from the corresponding reagents: d, l-TpaHc-5,6,6ap, 7,10, 10aob-hexahydro-1-acetoxy-5-methyl 3- (2-heptyloxy) benzo (c) quinoline-9 ( 8n) it is in the form of oil, yield 46%; d, lTpaHc-5, 6,6a / i, 7,8,9,10,10a. - octphydro-1, 9-diacet6xy-5-methyl-6/1-methyl 3- (2-heptyloxy) benzo (with a) quinoline in the form of oil, t / e 445 (t). The following compounds are prepared in a similar manner (see Table 1). Table 1
    CH-CH - (CHj) 3CbH 5 H94-97449 / CH3 -CH- (CH2) sC4H5- "HMoil 449
    o # V
    - (CH,) CjH
    In the form of HC1 salt.
    Calculated for Cj H j-O N-HCl,%: C 69.19; H 7.47; N 2.88
    Found,%: C 68.72; H 7.18; N 2.74
     Calculated for C28H350 N,%: C, 74.80; H 7.85; N 3.12 Found: C 74.66; Z 8.05; , N 2,66 m. 69-75 ° C in the form of the HC1 salt.
    In the form of HC1 salt.
    Calculated for C, -, H,%: C 74, H 7.64; N 3.22 Found,%: C 73.89; H 7.51; N 3.04
    Example 3. H, 1-trans-5,6,6a / 17, 8,9,10,1 Oao 1-octahydry-1, 9-dihydrorxy-5-ethyl-6 | 3-methyl-3- (2-heptyloxy a) benzo (c) quinoline.
    To a solution of 100 mg of lithium aluminum-50 hydride in 5 ml of dry tetrahydrofuran (cooled in an ice / water bath) is added dropwise a solution of 90 Mr.d, lTpaHC-5, 6.6a | i-7,8,9,10, l Oaoi-octahydro1, 9-dihydroxy-5-acetyl-6p, -methyl-3-55 (2-heptyloxy) benzo (c) quinoline in 3 ml of tetrahydrofuran. After all the product is added, the reaction 102-103 435
    21.3
    The mixture is heated and refluxed with a one-hour cooler for 1 hour and then allowed to cool to room temperature. Equivalent amounts of water are added, followed by the addition of 3% potassium hydroxide, the precipitate is filtered off and the filtrate is concentrated in vacuo to give the desired product as an oil, t / e 375 (t).
    Example 4. d, 1-trans-5,6, L fi, 7,8,9, 10,10ао6-octahilro-1-ace (g: i99 59,9 9-ox-1-meth. 1-3-3 (5-f (M1hil-2-g1-thyloxy) benzo (c) xnolii. Formaldehyde (1.1 ml of a 37% aqueous solution) is added to a solution of d, l-trans-5, 6.6a, 7.10, lOaot-reKcariiapo1- acetoxy-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline-9 (8H) -one in acetonitrile (15 ml) at room temperature followed by the addition of sodium cyanoborohydride (0.262 g). The reaction mixture is stirred during this time, the pH is kept neutral by adding acetic acid as needed. An additional amount is added to the reaction mixture. sodium cyanoborohydride (0.262 g) and methanol (15 ml), then it is acidified to pH 3, stirred for 2 hours, and concentrated under reduced pressure to an oil. The oil is diluted with water (50 ml), the pH is adjusted to 9-1 seconds with aqueous sodium hydroxide, the alkaline mixture is extracted with ether (3 x 200 ml). The combined ether extracts are washed with brine, dried (MgSQ) and concentrated under reduced pressure to obtain a clear oil. The oil is dissolved in a mixture of 50% ether / hexane and introduced into the chromatographic column of silica gel. The column is first washed with a 50% ether / hexane mixture, and then with 60, 70 and 75% ether / hexane respectively. The eluate is examined by thin layer chromatography (ether 10, hexane 1). The first product obtained is d, l-TpaHc-5,6,6a 7,10,10a-hexahydro-1-acetoxy-5methyl-3- (5-phenyl-2-pentyloxy) benz (c) quinoline-9 (8H ) -he (0.125 g), t / e 435 (t +). Calculated for C C, 74.45; H 7.64; N 3.22 Found: C: 74.06; H 7.77; N, 3.31 The second product is a 9 ° C-ox-diastereomer of the indicated (Compound. (25 mg), t / e 437 (t). Calculated for C2 -,} i - ,, sO, C 74.11; H 8 , 06; N 3,20 Found,%: C 73.96; H 8.34; N 3.00 The third product is a 9/5-ox C diastereomer of the indicated compound (0.7 g), t / e 437 (t-). Calculated for С tНjjO.N,%: С 74.11; H 8.06; N 3.20 Found,%: 73.56; H 7.86; N 3.21 Similarly to d, l -trans-5,6, bar, 7, 10.1 OaoC-hexa-hydro-1-acetoxy-3 (2-heptyloxy) benzo (c) quinoline-9 (8H) it is treated with sodium cyanoborohydride, resulting in d , l-TpaHC-5,6,6a, 7,10, IOaoi-hexahydro-1-acetoxy-5-methyl-3- (2-heptyloxy) benzo (c) quinoline-9 (8H) -one in as an oil, t / e 387 (t), yield 46%. IR (CHCl3): 5.80 (ketone); 5.65 (in the ester). Calculated for: C 71.29; H 8.58; N з, 61 Found: C 70.78; H 8.71; N 3.27 d, l-TpaHc-5,6,6a / i, 7,8,9, lO, 10aa | L Octagidro-1- acetoxy-9p-hydroxy-5methyl-3- (2-heptyloxy) benzo (c) quinoline as an oil, m / e - 389 (t), 72% yield. IR (CHClj): 2.80 (0-H) ; 5.70 (, ester) (calculated for C jH350 N,%: C 70.92; H 9.06; N 3.60; Found,%: C 70.56; H 8.95; N, 3.56) and d, l-TpaHc-5,6,6ap, 7,10, Yaoo hexahydro-1-acetoxy-6/1-methyl-3 (5-phenyl-2-pentyloxy) benzo (c) quinoline9 (8H) -one is converted to d, l-TpaHc-5,6, 6a, 7,10, 10ao6-hexahydro-L-acetoxy5-methyl-6-methyl-3- (5-phenyl-2-pentyloxy) benzo ( c) quinoline-9 (8H) -one, yield 23%, d, l-TpaHC-5,6,6a / i, 7,8,9, 10,10ac-octagidro-1-acetoxy-9/1-hydroxy -5-methyl-6-methyl-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline, which is given in the form of hydrochloride, m.p. 163-165 ° C, t / e 451 (t), yield 18%. Example 5. d, l-TpaHc-5,6, 6a / i, 7,10,10ao-Hexahydro-1-acetoxy-6-isobutyryl-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline-9 ( 8H) -one. A solution of isobutyral chloride (114 mg, 1.07 mmol) in chloroform (20 ml) is gradually added with stirring to a solution of d, 1-TpaHC5, 6.6a / i, 7.10, 10ao6-hydroxyhydro-1-a c-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline-9 (8H) -one (450 mg, 1.07 mmol in dry pyridine (1.5 ml) at 0 ° C under nitrogen atmosphere. Reaction mixture stirred for 5 h and then drunk in ice / water (5Q ml). The chloroform layer was separated and the aqueous phase was extracted with chloroform- (2x20 mp). The chloroform extracts were combined and washed with 10% hydrochloric acid (2x10 ml), then brine (1x10 mp) and then dried (MgSO4). A yellow oil is obtained under vacuum, which solidifies upon standing. Rubbing the solid with hexane gives a white crystalline substance, which is filtered and dried (400 mg), mp 128-129 ° C. Concentrating the hexane filtrate gives 121 mg of oil. Example 6. d, l-TpaHC-5,6,6ap, 7,8,9, 10,10ao-octahydro-1 acetoxy-9 hydroxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline. Sodium borohydride (38 mg, 1.0 mmol) is slowly added to a solution of d, l-trans-5, 6.6ar1, 7.10.10 ao-hexahydro-1 acetoxy-5-isobutyryl-3- (5-phenyl-2-pentyloxy) benzo ( c) quinoline-9 (8H) -one (260 mg, 0.529 mmol) in absolute ethanol (20 ml) at 5-10 ° C under nitrogen atmosphere. The reaction mixture is stirred for 1 h and then acidified with 10% hydrochloric acid .. Ethanol is removed by concentration under reduced pressure. 10 ml of water is added to the remaining solution, which is then extracted with ethyl acetate (2 x 50 ml). The extracts are combined, washed with brine and dried (MgSO4). vacuum concentration is obtained in the form of a solid amorphous substance (213 mg), which is used without further purification. P measures 7. d, l-TpaHc-5,6,6a / 3, 7,8,9 10,1 Oaot- Octagidro-1,9 / 3-diacetoxy-5-isobutyl-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline. In a nitrogen atmosphere, the solution is d, l-trans-5, 6, bar, 7,8,9 , 10.1 Oao-octagidro-1-acetoxy-9 / L-hydroxy-5-isobutyr-1- 3- (5-phenyl-2-pentyloxy) benzo (c) quinoline (213 mg, 0.432 mmol) in tetrahydrofuran (5 ml ) lithium aluminum hydride (110 mg, 2.6 mmol) in tetrahydrofuran (5 ml) is added to the suspension at room temperature. The mixture was stirred overnight and then water (0.1 mol), 15% sodium hydroxide solution (0.1 ml) and water (0.3 ml) were added. It is then filtered under nitrogen and the remaining filtrate is washed with tetrahydrofuran (2 x 5 ml). The combined filtrate and washing solution was concentrated to a reddish oil (0.174 g), which was dissolved under nitrogen in pyri-Dyne (1 ml), and the resulting solution was cooled to 0 ° C. Acetic anhydride (1 ml) is added with stirring
    the mixture is stirred for 30 minutes at 0 ° C. Then it is drunk in water (25 ml) and extracted with ethyl acetate (3x25 ml). The extracts were combined, washed with brine, dried (MgSO4). Concentrated to a brown oil (184 mg). The oil is immediately purged with nitrogen and chromatographed on a siccage (49 g), using benzene / ether (9: 1) as an eluting solvent. Collect fractions of 10 ml each. Fractions 2-10 are combined and concentrated to an oil (109 mg), t / e 521 (t +). Calculated for C32H4305N,%: C 73.67; H 8.31; N, 2.68; Found: C, 74.33; H 8.89; N 2.23 H NMR (60 MHz) c1} (y (ppm): 7.22 (s, 5H, aromatics); 6.05 (d, 1H, aromatics); 5.90 (d, 1H aromatics; 4.90 (bs. 1H); 4.30 (bs. 1H); 3.10 (d, 2H, N-CH,); 2.90 (d, 2H, N - CH); 2 , 70 (BS, 2H); 2.40 and 2.15 (s, 6H, 2-CH3-COO-); 1.85 (BS, 2H, Hg); 1.15 (m); 1.05 ( d, 6H,); 1.0-3.0 (trans. other protons). Example 8. (2 R, 6 S, 6a R, 9 R, 10a H) - (-) - 1-Lytotoxy-5, 6a, 7, 8,9,10,10a-octahydro-9-hydroxy-5,6-dimethyl-3- (5-phenyl-2-pentyloxy) benzo (c) chioline. To a stirred solution of 1.0 g (21 mol) (2R, 6S, 6aR, 9R, ... 10aR) - (-) - 1-acetoxy-5,6,6a, 7,8,9, 10,1 Oa-octahydro-9-hydroxy-6-metsh1 -3 (5-phenyl-2-pentyloxy) benzo (c) quinol hydrochloride in 30 ml of CHCl, 30 ml of a saturated solution of Na are added HCO, and the resulting mixture was stirred at room temperature for 5 minutes, the organic and aqueous phases were separated and the aqueous was re-extracted with 20 ml of CHCl 1. The combined chloroform extracts were dried over magnesium sulfate, filtered, and the solvent was distilled off in vacuo .. As a result, free base in a bidet colorless foam. The resulting foam is dissolved in 40 MP of tetrahydrofuran and the solution is mixed with 1.0 g of 5% palladium on carbon, 1.05 ml (0.018, 7 equivalents) of glacial acetic acid and 15.8 ml (0.20 equivalent) 37 % aqueous formaldehyde solution. The mixture is placed in a Parr IH apparatus and hydrogenated at a pressure of 3.5 kg / cm for 50 minutes. The catalyst is filtered through a layer of diatomaceous earth, washed with ethyl acetate. The filtrate was diluted to 130 ml with ethyl acetate, washed successively three times with a saturated solution of NaHCO (100 ml portions), three times with water (75 ml portions) and 75 ml of brine, and then dried over magnesium sulfate. The solution is filtered, after which the solvent is distilled off in vacuo. The result is a yellow-viscous oily liquid, which is subjected to chromatographic separation on a column filled with 50 g of silica gel with a particle size of 0.040, 63 mm, using a mixture of toluene and ether in the ratio of 1: 1 as eluent. Fractions of similar composition are combined, the solvent is distilled off in vacuo, resulting in a colorless oily liquid, which is dissolved in 50 ml of ether. Under stirring, dry HC1 is passed through a solution under nitrogen atmosphere. The precipitated white precipitate is filtered under nitrogen and dried in vacuo (0.1 mm Hg) for 24 hours at room temperature to obtain 0.45 g (44% of the theoretical yield of the target compound. Mp. 90- 95-С (d ЯМ (СОС1з) 2.73 ppm, singlet, ЗН. (N-CH,). IR (КВг) 4.25 ju. -Ш СГ I СН, 5.61 (-0-С-СНз CjgHg O NH.Cl Calculated,%: C 68.90; H 7.85; N 2.87. Found,%: C 68.60; H 7.92; N 2.77 (C, 1.0 , methanol.) Mass spectrometry t / e 451 (ra) The following compounds d, l-1-acetoxy-5,6,6a / J, 7,8,9, 10, 10ac-octahydro-9 can be obtained in a similar way. (3-hydroxy-5,6 / 3-dimethyl-3- (1,1-dimethylheptyl) benzo (c) quinoline hydrochloride. So pl. 129-130 ° С (d); t / e 415 (t 100%). O IR (KVg) 5.67 / U- (- С - СНз). D, 1-1-Acetoxy-5,6,6ar , 7,8,9,10, 10 ao-octahydro-9 / -oxy-5-methyl-6p-nbutyl-3- (5-phenyl-2-pentyloxy) benzo (quinoline hydrochloride, mp 106-108 ° C, t / e 493. Cj H jO N-HCl Calculated,%: C, 70.21; H, 8.37; N, 2.6 Found,%: C, 71.02; H, 8.43; N, 2.6 Example 9. Preparation of d, l-5, 6.6a / j, 7.8.9 °, 10.10ac-octagidro-1 acetoxy-5-benzoyl-9-benzoyloxy-6-methyl-3- (1-methyl-4-phenylbutoxy) benzo (c) quinoline. A stirred suspension of 47.4 g (0.10 mol) d, 1-5,6,6a / j, 7.8,9oi, 10, 10ao-octagvdro-6/1-methyl-3- (1-methyl4-phenylbutoxy ) benzo (c) quinolinohydrochloride in 500 ml of CHCl3 in nitrogen atmosphere is cooled before and treated successively with 250 ml of pyridine and then with a solution of 58 ml (0.50 mol) of benzoyl chloride in 500 ml of chloroform. The resulting homogeneous solution is boiled for an hour on the steam bath under reflux, the reaction mixture is poured onto crushed ice, and extraction is carried out from it with chloroform. The organic extracts are combined, washed successively with water (twice, in 500 ml portions), with a 10% hydrochloric acid solution, with a 500 MP saturated sodium bicarbonate solution and with 500 ml of saturated brine, dried over MgSOq, filtered and concentrated. The result is 119 g of yellowish oily liquid. After chromatography on 2000 g of silica gel using a mixture of ethyl acetate (20%) and cyclohexane as eluent, 50.5 g (78% of the theoretical yield) are obtained: d, l5, 6.6a, 7.8.9ot, 10.10 ° C-octahydro -1 acetoxy-5-benzoyl-9-benzoyloxy-6 methyl-3- (1-methyl-4-phenylbutoxy) benzo (c) quinoline. M.p. 125-130 ° C. C4.H4306N. Calculated,%: C, 76.24; H 6.72; N 2.17 Found,%; C 76.35; H 6.92; N 2, 19 Separation d, l-5,6,6ar, 7,8,9oi, 10, 10ac / .- octahydro-1-acetoxy-5-benzoyl9-benzoyloxy-6p-methyl-3- (1Y-methyl- 4phenylbutoxy) benzo (c) quinoline, and d, 1-5,6,6a, 7,8,9s (, 10, YuoC-octahydro1-acetoxy-5-benzoyl-9-benzoyloxy6) -methyl-3- (1 | b -methyl-4-phenylbutoxy) benzo (c) quinoline .. After recrystallization 50.5 g of d, 1-5.6, 6a / i, 7.8, 9ciC, 10.1 Oaoi-octahydro1-acetoxy-5-benzoyl -9-benzoyloxy6-methyl-3- (1-methyl-4-phenylbutoxy) benzo (c) quinoline from 2 l of 2-propanol, 23.8 g of a white solid material are obtained, mp 136-138 ° C, which is twice recrystallized from 2-propanol, and then from acetonitrile. There is obtained 5.7 g of d, 1-5.6,6a, 7.8, 9oi, 10.10o (-octagidro-1-acetoxy-3benzoyl-9-benzoyloxy-6p-methyl-3- (1 / c) -4-phenylbutoxy) benzo (c) quinoline So pl. UB-lAg C. The filtrate after the first recrystallization d, l-5,6,6a / j, 7,8,9 °, 10, l Oaoi-ok tagidro-1- acetoxy-5-benzoyl-9-benzoyloxy-6 / b-methyl-3- (1-methyl-4-phenylbutoxy) benzo (c) quinoline from 2-propanol is evaporated to form a white pea, which is triturated with 500 ml of ether . The result is 12.9 g of solid white material with so pl. 129-132 ° C, which is still triturated twice with ether, and 3.8 g of d, l-5,6,6a, 7,8.9 S, 10,10ac6-octahydro-1-acetoxy-5-benzo8-1-9- are obtained benzoyloxy-6/5-methyl-3- (1o (-methyl 4-phenylbutoxy) benzo (c) quinoline, mp 139-14Gs. Preparation of hydrochloride d, l5, 6, bar, 7.8,9,10 , 1 Oaoi-octahydro-1 acetoxy-9-hydroxy-6-methyl-3 (1-methyl4-fensh1-butoxy) benzo (c) quinoline. To a stirred solution of lithium aluminum hydride 2.0 g (5.3 mol) in t50 ml of tetrahydrofuran is added dropwise under nitrogen atmosphere over 5 minutes a solution of 5.7 g (8.8 mol) d, 5, 6.6a, 7.8.9ct, 10.10o-octagidro-1 acetoxy-5-benzoyl -9-benzoyloxy-6 methyl-3- (1p-methyl-4 -phenylbutoxy) benzo (c) quinoline in 112 ml of tetrahydrofuran. The resulting solution is boiled for 45 minutes under reflux, cooled and carefully poured onto an ice-cooled mixture of 1125 ml of a 5% aqueous solution of acetic acid, 2250 ml of ether. the mixture is stirred for 10 minutes, after which the phases are separated. From the aqueous layer, additional extraction is carried out with 500 MP ether. The combined ether extracts are washed sequentially with water (three times, 500 ml portions), saturated sodium bicarbonate solution (twice, 500 ml portions), and 500 ml of saturated brine, dried over MgSO4, filtered, and evaporated. The result is 5.4 g d, l-5-benzyl-5,6,6a, 7,8,9c /, 10,10ao octahydro-1, 9-dioxy-6p, -methyl-3- (12 methyl- 4-phenylbutoxy) benzo (c) quinoline in the form of an oily liquid with a violet hue. Received d, 1-5-benzyl-5,6, ba / 3, 7,8,9oi, 10,10ао-octagidro-1,9-dioxy6p-methyl-3- (1 / -methyl-4-phenylbutoxy) benzo (c) The quinoline is immediately dissolved in 450 ml of methanol and hydrogenated at atmospheric pressure for 3 hours in the presence of 4.27 g of palladium on the corner. After completion of the hydrogenation, the catalyst is filtered off and the methanol is distilled off. The result is d, l-5,6,6a / i, 7,8,9 bC, 10, 10aoi-octahydro-1,9-dioxy-6p-methyl 3- (1-methyl-4-phenylbutoxy) benzo (s) quinoline. Received d, l-5,6,6a, 7,8,9 ° (, 10, 10aat-octahydro-1,9-dioxy-6 /} - methyl 3- (1p-methyl-4-phenylbutoxy) benzo (c) quinoline immediately dissolved in 210 ml of methylene chloride, the solution is cooled in a nitrogen atmosphere to OC and 1.35 ml of triethyl1, 19 g (9.7 mmol) of 4-dimethylamine aminopridine and 0.834 ml (8.8 mmol) of acetic anhydride are treated in succession stirring for 30 minutes, the reaction mixture is poured into 250 ml of water and the organic layer is separated. The aqueous phase is extracted with methylene chloride, the combined methylene chloride extracts are washed successively sodium bicarbonate solution (twice in 150 ml portions), once with 150 ml of water and saturated brine, dried over MgSO4, filtered, evaporated and subjected to the residue chromatographically separated on a column filled with 300 g of silica gel, using as eluant mixtures of ether (33%) and toluene. The result is 1.4 g of hydrochloric d, l-5,6,6a / i, 7,8,9oi, 10,10ao (.- octahydro-1-acetoxy-9-hydroxy -6-methy-1-3 (1-methyl-4-phenylbutoxy) benzo (c) quinoline as a free base. After treating it with gaseous HC1, filtration and trituration in acetone, 795 mg of hydrochloric acid d, l-5.6.6a, 7.8.9oi, tO, 10ao-octahydro1-acetoxy-9-hydroxy-6/1-methyl-3 are obtained - (-methyl-4-phenylbutoxy) benzo (c) quinoline. M.p. 213-215С after-filtration and m / e 437 rub in acetone, (t, 100%). N-HC1 Calculated,%: C 68.42; H 7.66; 2.96 N; Found: C, 68.48; H 7.63; 3.05 Similarly, starting from di 1-5,6,6ajB, 7,8, Eo, 10,10aod-octahydro 1-acetoxy-5-benzoyl-9-benzoyloxy6-methyl-3- (1O1-methyl-4-phenylbutoxy ) benzo (c) quinoline (3.8 g), obtain 1.1 g of d, 1-5,6,6a / i, 7,8,90,10,10ao-octagidro-1-acetoxy-9-oxy- 6-methyl 3- (1st (.-Methyl-4-phenylbutoxy) benzo (c) x noline hydrochloride. Mp = 202-205 ° C (d), m / e (100%,). Cj HgjO NHCl C 68 , 42; H 7.66; Calculated, 2.96 C 68.20; H 7.56;. Found: 3.04 10. d, l-TpaHC-5.6, Example, 7.10, 10ао - Hexahydro-1-acetoxy 5-acetyl-6p-methyl-3- (5-phenyl-2-pentioxy) benzo (c) quinoline-9 (8H) -one 3.49 g (0.008 mol) d, l -TpaHc-5,6 6a, 7,8,9,10,10a-octahydro-1-acetoc-6 | 1-methyl-3- (5-phenyl-2-pentyloxy) b nso (c) quinoline-9 (8n) -one is dissolved in 20 ml of chloroform without alcohol impurities, the solution is cooled in an ice-water bath and 14 ml of pyridine (dried over potassium hydroxide granule) are added to it, and 0.95 ml (0.013 mol) of acetic chloride chloride dissolved in 5 ml of chloroform The homogeneous solution is stirred at ambient temperature for 18 hours. After that, the reaction mixture is poured onto a mixture of water and ice and a portion is extracted from it with chloroform. mi to 25 ml. The combined organic extracts are washed successively with 25 ml of a saturated solution of sodium bicarbonate, 25 ml of water, 25 ml of brine, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Purification is carried out using chromatography on silica gel (200 g, Brinxman brand), using a mixture of cyclohexane as solvent. and ether in the ratio of 3: 1. As a result, 2.20 g (83.8% of the theoretical yield) of the target compound are obtained. .jOjN Calculated,%: C 72.90; H 7.39; N, 2.80; Found: C, 72.69; H 7.48; N 2.49 1 0 IR (KBg): 290X); 3.38 /: / (s); 3.48 / i (s); 5.62 / t (s); 5.78 / u (s); 6.00 (s); 6.15 (U (s); 6, (s), m / e 477 (m). NNMR (60 MHz),: 7.20 (y, 5H, aroma); 6.53 (d, 1H, C); 6.39 (d, 1H, 04); 4.71-4.08 (m, 2H ,, methin); 2.29 (s, acetate MiO; 2.02 and 2.04 (2s, 3N , amide Me); 1.25 and 1.23 (2d, 3N, C, Me); 1.12 (d, 3N, side chain. Me); 3.20 - 1.36 (varying residual protons). Similarly, from d, l-cis-5, 6,6a, 7, 10a | B-hexahydro-1-acetoxy6 |% -methyl-3- (5-phenyl-2-pentyloxy) benzo (c) quinoline-9 ( 8H) -one, d, l-cis-5,6,6a / i, 7,10a 5-hexahydro1-acetoxy-5-acetyl-6-methyl-3- (5phenyl-2-pentyloxy) benzo (c) quinoline -9 (8H) -one. 125-128C. Yield 82% .gHgsOjN. 2.%: C 72.90; H 7.39; Calculated, Found, C 72.80; H 7.35; N 2, 70 H NMR (60 MHz), / (: 7.22 (t, 5H, aroma); 6.55 (2d, 2H,. C and C); 5.02 - 4, 62 (t, W, C, methin); 4,524 .12 (t, 1H, side chain, methin); 2.28 (s, 3N, acetate Me); 2.11 and 2.13 (3N, amide Me); 1 , 26 and 1.28 (3N,); 1.22 (d, 3N, side chain MB), 3.42-1.65 (varying residual protons). IR (KBr): 2.95 / i (w ); 3.43 / t (s); 5.65 / ix. (S); 5, (s); 6.02 / u (s); 6.16iU (s); 6.32 (U (s); 6, (s): m / e 477 (). Tests of thermal nociceptive irritation. Test the analgesic effect on mice with a hot plate. Apply 1/8 aluminum plate to the paws of mice (3.1 mm), which is a regulated heat source. An infrared reflector (250 W) is placed on the bottom of the aluminum plate. The thermostat in the form of a thermister located on the surface of the plate controls the heating of the lamp so as to maintain a constant plate temperature. Each mouse is placed in a glass cylinder (61/2/155 mm in-). , diamete), the base of which is an aluminum plate, and the time counting starts from the moment when our legs touch the plate. After 0.5 and 2 hours after treatment with the test compound, the first convulsive movement of one or both back legs is observed or until an interval of 10 s between these movements. Dose of mor finat, 5 mg / kg. (maximum possible effect). Test of aJJHzg-exerting effect on force by fluttering their tails. Each mouse is placed in a conveniently fitted metal cylinder so that its tail protrudes from one end of the cylinder. The cylinder is mounted in such a way that the tail lies flat above the shielded lamp, which is a source of heat. At the beginning of the test, the aluminum screen above the lamp is removed so that a beam of light passes through the slit and focuses on the tail cap. At the same time include a timer. The time of occurrence of the convulsive movement of the tail is determined. Myppies that have not been pretreated usually react 3-4 seconds after the lamp light is exposed. The maximum term for protection is 10 s. Each patient was tested after 0.3 and 2 hours after treatment with morphine and a test compound. Dose of morphine MVE5oZ, 2-5.6 kg / kg. Tests of chemical nociceptive irritation. Suppression of pain caused by phenylbenzoquinone. Groups of 5 mice of 5 Carworth Farms CF-1 are pretreated by subcutaneous or oral administration with a physiological solution of morphine, codeine or a test compound. After 20 minutes (subcutaneously) or 50 minutes (oral administration), each group is injected intraperitoneally with phenylbenzoquinone, which causes abdominal contractions. After 5 min after injection, the pathogens are observed for 5 min and the presence or absence of convulsive contractions is recorded. Determine the effect of pre-entered MVEdr. of the preparation in the dose of convulsive contractions. The text results are expressed in percent of the maximum possible ether (% MVE) and statistically compared for each group with% MVE of control and pretreated animal,% MVE is calculated as follows: test time control time% MVE X 100 cutoff time control
    (d
    Cf
    s c:
    YU
    to
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    (H
    and (
    s
    a w
    f)
    ". s сю «d н
    权利要求:
    Claims (2)
    [1]
    The method of obtaining benzo (c) quinoline derivatives of the general formula
    ABOUT
    I)
    where p - means C h or
    // ° K
    m K - hydrogen, acetyl;
    - hydrogen, acetyl;
    K 2 is hydrogen or C ^ -C ^ alkyl;
    - C., - C 4 -alkyl, C 2 - C 4 -alkanoyl or benzoyl;
    Ζ - C 4 -C9-alkylene;
    And hydrogen or phenyl,
    or their pharmaceutically acceptable salts.
    ΟΣΛν
    where K. 2 , p, Ζ and And have the above values,
    interact with formaldehyde, followed by reduction with cyanoborohydride or with the corresponding alkanoyl chloride or benzoyl chloride and, if necessary, with further reduction of the resulting product with lithium aluminum hydride to isolate the target product in free form or in the form of pharmaceutically acceptable salts.
    Priorities by the signs: 17.05.76:
    about
    with p - means
    n s> - and K, - hydrogen, acetyl, 1C - hydrogen, acetyl - hydrogen, K. 3 - SuC 4 -alkyl,
    C 2 ~ Sualkanoyl or benzoyl; Ζ py C y alkylene, And - hydrogen or phenyl;
    12.22.76 with p - means
    0298601 00 PZ
    iK is hydrogen, acetyl, 1C is hydrogen, acetyl, K 2 - C 4 - Cd-alkyl, - Cy C ^ -alkyl, C 2 ~ Cd-alkanoyl or benzoyl,
    Ζ - Su Cd-alkylene, V - hydrogen or phenyl.
    1.1098520
    [2]
    2
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    同族专利:
    公开号 | 公开日
    LU77341A1|1977-12-13|
    PH16833A|1984-03-06|
    FR2446284A1|1980-08-08|
    YU156882A|1983-02-28|
    PT66550B|1978-10-18|
    AR215896A1|1979-11-15|
    SE7704749L|1977-12-05|
    NO147028C|1983-01-19|
    PT66550A|1977-06-01|
    BG28415A4|1980-04-15|
    IL52087A|1981-11-30|
    FR2362129B1|1983-05-20|
    JPS6016426B2|1985-04-25|
    IL52087D0|1977-07-31|
    JPS52144672A|1977-12-02|
    AU2516277A|1978-06-22|
    CH628034A5|1982-02-15|
    FR2362129A1|1978-03-17|
    CA1095909A|1981-02-17|
    DK212677A|1977-11-18|
    NZ184114A|1982-02-23|
    NO147028B|1982-10-11|
    NL7804461A|1978-08-31|
    CH626881A5|1981-12-15|
    BG28416A4|1980-04-15|
    FI771550A|1977-11-18|
    ES469204A1|1978-11-16|
    NL170141C|1982-10-01|
    RO76839A|1981-05-30|
    FI64141C|1983-10-10|
    FR2446284B1|1983-08-26|
    FI64141B|1983-06-30|
    ES469202A1|1978-11-16|
    DE2722383A1|1977-12-01|
    NL7705433A|1977-11-21|
    DD130855A5|1978-05-10|
    YU156982A|1983-02-28|
    DE2722383C2|1990-06-07|
    ES469203A1|1978-11-16|
    NO771738L|1977-11-18|
    BG27897A3|1980-01-15|
    GR74122B|1984-06-06|
    ES458812A1|1978-08-16|
    BG28414A4|1980-04-15|
    引用文献:
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    US3507885A|1966-03-25|1970-04-21|Hoffmann La Roche|3-alkyl-6h-dibenzopyrans|
    US3636058A|1966-03-25|1972-01-18|Hoffmann La Roche|7 10 - dihydro - 3 - alkyl - 6h - dibenzo pyran-6 9-diones and 5-hydroxy-7-alkyl-4-chromanones|
    US3649650A|1970-02-13|1972-03-14|Little Inc A|Novel derivatives of tetrahydro-cannabinol|
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    US3856821A|1973-07-18|1974-12-24|Smithkline Corp|ALKOXY DIBENZO PYRANS|
    US3968125A|1973-11-05|1976-07-06|Eli Lilly And Company|Dihydroxyhexahydrodibenzo[b,d]pyrans|
    US3928598A|1973-11-05|1975-12-23|Lilly Co Eli|Hexahydro-dibenzo{8 b,d{9 pyran-9-ones as an anti-anxiety drug|
    US3944673A|1973-11-05|1976-03-16|Eli Lilly And Company|Hexahydro-dibenzo[b,d]pyran-9-ones as analgesic drugs|
    GB1522057A|1975-11-03|1978-08-23|Pfizer|9-hydroxydibenzopyrans and intermediates therefor|DE2802211A1|1978-01-19|1979-07-26|Basf Ag|N-SUBSTITUTED 2,6-DIALKYLANILINES AND METHOD FOR PREPARING N-SUBSTITUTED 2,6-DIALKYLANILINES|
    US4206225A|1978-09-22|1980-06-03|Pfizer Inc.|2,10-Disubstituted dibenzo[b,d]pyrans and benzo[c]quinolines|
    US4228169A|1979-06-26|1980-10-14|Pfizer Inc.|1,9-Dihydroxyoctahydrobenzo[c]quinolines and 1-hydroxyhexahydrobenzo[c]quinoline-9-ones as antiemetic agents|
    US4309545A|1980-07-28|1982-01-05|Pfizer Inc.|Oximino-1-hydroxyoctahydrobenzo[c]quinolines and derivatives thereof|
    US4406888A|1981-01-09|1983-09-27|Pfizer Inc.|Aqueous micellar solutions of levonantradol and N-methyllevonantradol and lyophilic forms thereof for reconstitution|
    HU194858B|1982-12-03|1988-03-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing dibenzo/b,d/pirane derivatives and pharmaceutical compositions containing them|
    RU2015144653A|2009-03-25|2018-12-29|Эббви Инк.|ANTIVIRAL COMPOUNDS AND THEIR APPLICATIONS|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US68733276A| true| 1976-05-17|1976-05-17|
    US75361976A| true| 1976-12-22|1976-12-22|
    US77792877A| true| 1977-03-15|1977-03-15|
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