Tetrahydroprotoberberine compound, preparation method therefor and uses thereof, and pharmaceutical composition

Abstract

The present invention provides a tetrahydroprotoberberine compound represented by the formula (I), enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof. The invention also provides a method for preparing the compound and the use thereof in the preparation of a medicament for preventing and/or treating central nervous system diseases. ##STR00001##

Claims

1. A tetrahydroprotoberberine compound of formula (I-A-1), enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, crystalline hydrates or solvates thereof, ##STR00087## wherein, R2 is selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, amino, C1-C6 alkyl substituted amino, C1-C6 alkanoyl substituted amino, C1-C6 alkyl sulfonyl substituted amino, cyano, carboxy, aldehyde group, amino-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkanoyl, halo-C1-C6 alkanoyl, sulfoamido, C1-C6 alkyl substituted sulfoamido, carbamoyl, C1-C6 alkyl substituted carbamoyl, carboxy-C1-C6 alkyl, C1-C6 alkyl sulfonyl, halo-C1-C6 alkyl sulfonyl, C1-C6 alkyl substituted amino-C1-C6 alkyl, C1-C6 alkanoyl substituted amino-C1-C6 alkyl, C1-C6 alkoxycarbonyl, carbamoyl-C1-C6 alkyl, or C1-C6 alkyl substituted carbamoyl-C1-C6 alkyl; or R2 is selected from halogen, mercapto, halo-C1-C4 alkoxy, hydroxy-C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl, C3-C5 cycloalkyl, C3-C5 cycloalkoxy, C2-C4 alkenyl, C2-C4 alkenyloxy, C2-C4 alkynyl, C2-C4 alkynyloxy, halo-C1-C4 alkyl, amino, C1-C4 alkyl substituted amino, C1-C4 alkanoyl substituted amino, C1-C4 alkyl sulfonyl substituted amino, cyano, carboxy, aldehyde group, amino-C1-C4 alkyl group, hydroxy-C1-C4 alkyl, cyano-C1-C4 alkyl group, C1-C4 alkanoyl, halo-C1-C4 alkanoyl, sulfoamido, C1-C4 alkyl substituted sulfoamido, carbamoyl, C1-C4 alkyl substituted carbamoyl, carboxy-C1-C4 alkyl, C1-C4 alkansulfonyl, halo-C1-C4 alkansulfonyl, C1-C4 alkyl substituted amino-C1-C4 alkyl, C1-C4 alkanoyl substituted amino-C1-C4 alkyl, C1-C4 alkoxycarbonyl, carbamoyl-C1-C4 alkyl, or C1-C4 alkyl substituted carbamoyl-C1-C4 alkyl; or R2 is selected from fluorine, chlorine, bromine, mercapto, trifluoromethoxy, —SCH.sub.3, —SCH.sub.2CH.sub.3, methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, bromomethyl, chloromethyl, vinyl, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, cyano, carboxyl, aldehyde group, —CH.sub.2NH.sub.2, —CH.sub.2CH.sub.2NH.sub.2, —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CH.sub.2CN, —CH.sub.2CH.sub.2CN, formyl, acetyl, propionyl, trifluoroacetyl, sulfo amido, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N,N-diethylcarbamoyl, —CH.sub.2CO.sub.2H, —CH.sub.2CH.sub.2CO.sub.2H, —SO.sub.2CH.sub.3, —SO.sub.2CF.sub.3, —CH.sub.2NHMe, —CH.sub.2NMe.sub.2, —CH.sub.2CONH.sub.2, —CH.sub.2CONHMe or —CH.sub.2CONMe.sub.2.

2. The tetrahydroprotoberberine compound, enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, crystalline hydrates or solvates thereof, wherein the compound is selected from: (1) (S)-2-methyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (2) (S)-2-n-propyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (3) (S)-2-isobutyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (4) (S)-2-cyano-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (5) (S)-2-carbamoyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (6) (S)-2-formyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (7) (S)-2-hydroxymethy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (8) (S)-2-carboxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (9) (S)-2-ethoxycarbonyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (10) (S)-2-aminomethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (11) (S)-2-acetaminomethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (12) (S)-2-acetyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (13) (S)-2-amino-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (14) (S)-2-acetylamino-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (15) (S)-2-bromo-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (16) (S)-2-chloro-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (17) (S)-2-vinyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g]quinolizine; (18) (S)-2-hydroxyethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (19) (S)-2,3,10-trimethoxy-9-cyano-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (20) (S)-2,3,10-trimethoxy-9-carbamoyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (21) (S)-2,3,10-trimethoxy-9-acetyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (22) (S)-2,3,10-trimethoxy-9-aminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (23) (S)-2,3,10-trimethoxy-9-acetylaminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (24) (S)-2,3,10-trimethoxy-9-formyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (25) (S)-2,3,10-trimethoxy-9-hydroxymethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (26) (S)-2,3,9-trimethoxy-10-methyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (27) (S)-2,3,9-trimethoxy-10-cyano-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (28) (S)-2,3,9-trimethoxy-10-carbamoyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (29) (S)-2,3,9-trimethoxy-10-formyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (30) (S)-2,3,9-trimethoxy-10-hydroxymethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (31) (S)-2,3 ,9-trimethoxy-10-aminomethyl-6, 8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (32) (S)-2,3,9-trimethoxy-10-acetaminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (33) (S)-2,10-diamino-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (34) (S)-2,10-diacetylamido-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (35) 2,3-dicyano-9,10-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (36) 9,10-dimethoxy-5,6,13,13a-tetrahydroisoquinolino[3,2-a]pyrrolo[3,4-g]isoquinoline-1,3(2H,8H)-dione; (37) (S)-2,10-dicyano-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (38) (S)-2,10-dicarbamoyl-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (39) 2,3-dicarbamoyl-9,10-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (40) (S)-4,10,11-trimethoxy-3,6,7,9,14,14a-hexahydroimidazo[4,5-h]isoquinolino [3,2-a]isoquinolin-2(1H)-one; (41) (S)-4,10,11-trimethoxy-3,6,7,9,14,14a-Hexahydroimidazo[4,5-h] isoquinolino [3,2-a]isoquinoline-2(1H)-thione; (42) (S)-4,10,11-trimethoxy-1,6,7,9,14,14a-hexahydroimidazo[4,5-h] isoquinolino [3,2 a]isoquinoline; (43) (S)-4,10,11-trimethoxy-1,6,7,9,14,14a-hexahydroisoquinolino[3,2-a][1,2,3] triazolo [4,5-h]isoquinoline; (44) 9,10-dimethoxy-1,5,6,8,13,13a-hexahydroimidazo[4,5-g]isoquinolino[3,2-a] isoquinoline; (45) 9,10-dimethoxy-6,8,13,13a-tetrahydro-5H-isoquino[3,2-a]oxazolo[4,5-g] isoquinolin; (46) 9,10-dimethoxy-3,5,6,8,13,13a-hexahydro-2H-isoquino[3,2-a]oxazolo[4,5-g] isoquinolin-2-one; (47) 10,11-dimethoxy-4,6,7,9,14,14a-hexahydroisoquinolino[3,2-a][1,4]oxazino[3,2-g] isoquinolin-3(2H)-one; (48) 10,11-dimethoxy-7,9,14,14a-tetrahydro-6H-isoquino[3,2-a]oxazolo[5,4-h] isoquinoline; (49) 10,11-dimethoxy-6,7,14,14a-tetrahydro-1H-isoquino[3,2-a]oxazolo[5,4-h] isoquinolin-2(9H)-one; (50) 11,12-dimethoxy-3,7,8,10,15,15a-hexahydroisoquinolino[3,2-a][1,4]oxazino [2,3-h] isoquinolin-2(1H)-one; (51) (S)-2-(difluoromethoxy)-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (52) (S)-2-allyloxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (53) (S)-2-cyclopropoxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (54) (S)-2-cyclopentyloxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (55) (S)-2,10-di(hydroxyethoxy)-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (56) (S)-2,3,10-trimethoxy-9-hydroxyethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (57) (S)-2,3,10-trimethoxy-9-cyclopropyloxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (58) (S)-2,3,10-trimethoxy-9-cyclopentyloxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine; (59) (S)-2,3,9-trimethoxy-10-cyclopropyloxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine; and (60) (S)-2-methanesulphonylamino-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine.

3. A pharmaceutical composition, comprising a therapeutically effective amount of the tetrahydroprotoberberine compound, enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, crystalline hydrates or solvates thereof of claim 1, and optionally a pharmaceutically acceptable carrier.

4. A pharmaceutical composition, comprising a therapeutically effective amount of the tetrahydroprotoberberine compound, enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, crystalline hydrates or solvates thereof of claim 2, and optionally a pharmaceutically acceptable carrier.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a bar graph of the effect of a single-dose administration of Example 60 on the sleep latency of PCPA-induced insomnia model in rats treated with sodium pentobarbital (*P<0.05 vs model group); and

(2) FIG. 2 is a bar graph of the effect of a single-dose administration of Example 60 on the sleep time of PCPA-induced insomnia model in rats treated with sodium pentobarbital.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

EXAMPLE 1

(S)-2-methyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-A)

(3) ##STR00026##
The preparation of compound 1-a can be referred to the previous patent CN102399166B of the same applicant. Step 1:

(4) The 1-a (300 mg, 0.72 mmol) was dissolved in DMF (4 mL). Thereto, dimethyl sulfate (0.07 mL, 0.72 mmol), sodium hydride (69 mg, 2.88 mmol) were added. The reaction was performed for 6 h while stirring. The resultant was extracted with dichloromethane, and washed with a saturated ammonium chloride solution. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain 1-b (60 mg, yield: 19%), .sup.1H-NMR (300 Hz, CDCl.sub.3) δ 2.53-2.79 (m, 3H), 3.03-3.23 (m, 3H), 3.42-3.56 (m, 2H), 3.84 (s, 6H), 3.87 (s, 3H), 4.22 (d, 1H), 5.14 (s, 2H), 6.64 (s, 1H), 6.74 (s, 1H), 6.81 (m, 2H), 7.29-7.49 (m, 5H). ESI-MS m/z 432.3 (M+H).sup.+. Step 2:

(5) The 1-b (60 mg, 0.14 mmol) was dissolved in ethyl acetate (2 mL). Thereto, the palladium on carbon (10 mg) was added. The hydrogenation reaction was carried out for 10 h. The mixture was filtered, and the mother liquor was concentrated. The resultant was slurried in petroleum ether, filtered to obtain 1-c (12 mg, yield: 25%). .sup.1H-NMR (300 Hz, CDCl.sub.3) δ 2.57-2.71 (m, 2H), 2.80 (dd, 1H), 3.07-3.29 (m, 3H), 3.47-3.57 (d, 2H), 3.84 (s, 6H), 3.87 (s, 3H), 4.24 (d, 1H), 6.59 (s, 1H), 6.78 (d, 1H), 6.81 (s, 1H), 6.87 (d, 1H). ESI-MS m/z 342.33 (M+H).sup.+. Step 3:

(6) Dichloromethane (5 ml) and triethylamine (0.82 ml, 5.8 mmol) were added into 1-c (1 g, 2.9 mmol) and then Tf.sub.2O (0.58 ml, 3.48 mmol) was slowly added dropwise under an ice bath. After completion of addition, the mixture was stirred for 3 h at room temperature. The resultant was extracted with dichloromethane-water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 1-d (0.8 g, yield: 57%). Step 4:

(7) 1-d (150 mg, 0.317 mmol) was placed in a three-necked flask, and methylboronic acid (76 mg, 1.27 mmol), potassium carbonate (175 mg, 1.27 mmol), and tetrakis (triphenylphosphonium) palladium (79 mg, 0.063 mmol) and 1,4-dioxane (3 mL) were added thereto. The mixture was refluxed at 100° C. overnight under a nitrogen atmosphere. The resulting reaction solution was filtered, and the filtrate was concentrated and subjected to column chromatography to obtain the title compound (10 mg, yield: 9%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.20 (s, 3H), 2.57-2.86 (m, 3H), 3.11-3.34 (n, 3H), 3.48-3.58 (m, 2H), 3.81 (s, 3H), 3.84 (s, 6H), 4.24 (d, 1H), 6.56 (s, 1H), 6.78 (d, 1H), 6.87 (d, 1H), 7.01 (s, 1H). ESI-MS m/z 340.1 (M+H).sup.+.

EXAMPLE 2

(S)-2-n-propyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-A)

(8) ##STR00027##

(9) The title compound was prepared from 1-d and propylboronic acid, with reference to the method for synthesizing the product of Example 1. That is, methylboronic acid (76 mg, 1.27 mmol) was replaced with propylboronic acid (111.6 mg, 1.27 mmol). The yield was 25%. .sup.1 H NMR (300 MHz, CDCl.sub.3) δ 0.96 (t, 3H), 1.54-1.65 (m, 2H), 2.52-2.90 (m, 5H), 3.11-3.35 (m, 3H), 3.49-3.63 (m, 2H), 3.80 (s, 3H), 3.85 (s, 6H), 4.27 (d, 1H), 6.58 (s, 1H), 6.79 (d, 1H), 6.88 (d, 1H), 7.00 (s, 1H). ESI-MS m/z 368.2 (M+H).sup.+.

EXAMPLE 3

(S)-2-isobutyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-A)

(10) ##STR00028##

(11) The title compound was prepared from 1-d and isobutylboronic acid, with reference to the method for synthesizing the product of Example 1. That is, methylboronic acid (76 mg, 1.27 mmol) was replaced with isobutylboronic acid (129.5 mg, 1.27 mmol). The yield was 28%. ESI-MS m/z 382.29 (M+H).sup.+.

EXAMPLE 4

(S)-2-cyano-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-A)

(12) ##STR00029##

(13) DMAc (15 ml), zinc cyanide (328 mg, 2.78 mmol), zinc powder (28 mg, 0.41 mmol), DPPF (155 mg, 0.27 mmol) and Pd.sub.2(dba).sub.3 (80 mg, 0.13 mmol) were added into 1-d (660 mg, 1.39 mmol). The mixture was heated at 160° C. overnight. DMAc was concentrated, and the resultant was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain the title compound. (450 mg. yield: 92%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.42-2.62(m, 2H), 2.81(d, 1H), 2.97-3.20(m, 2H), 3.35-3.50(m, 3H), 3.72(s, 3H), 3.77(s, 3H), 3.88(s, 3H), 4.07(d, 1.H), 6.87(two d peaks), 7.01 (s, 1H) , 7.74(s, 1H). ESI-MS m/z 350.7 (M+H).sup.+.

EXAMPLE 5

(S)-2-carbamoyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-A)

(14) ##STR00030##

(15) DMSO (3 ml), hydrogen peroxide (3 ml) and sodium hydroxide (75 mg, 1.82 mmol) were added into the product of Example 4 (320 mg, 0.91 mmol). The mixture was heated at 70° C. for 2 h. The saturated ammonium chloride solution was used to adjust the pH of the mixture to alkalescency. The resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain the title compound (130 mg, yield: 38%). .sup.1H NMR (300 MHz, CD.sub.3OD) δ 2.59-2.95(m, 3H), 3.11-3.29(m, 2H), 3.40-3.61(m, 3H), 3.81(s, 3H), 3.82(s, 3H), 3.95(s, 3H), 4.21(d, 1H), 6.91(m, 3H), 7.97(s, 1H). ESI-MS m/z 369.1 (M+H).sup.+.

EXAMPLE 6

(S)-2-formyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-A)

(16) ##STR00031##

(17) Dichloromethane (2 ml) was added into the product of Example 4 (500 mg, 1.42 mmol), and then DIBAL (2.8 ml) was added under an ice bath. The reaction was kept under an ice bath for 3 h. 1M hydrochloric acid was used to adjust the pH of the mixture to around 5. The resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain the title compound (390 mg, yield: 77%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.59-2.87 (m, 3H), 3.17-3.28 (m, 2H), 3.39 (dd, 1H), 3.48-3.61 (m, 2H), 3.85 (s, 6H), 3.92 (s, 3H), 6.73 (s, 1H), 6.79 (d, 1H), 6.88 (d, 1H), 7.75 (s, 1H), 10.42 (s, 1H).

EXAMPLE 7

(S)-2-hydroxymethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-A)

(18) ##STR00032##

(19) Methanol (3 ml) and sodium borohydride (84 mg) were added into the product of Example 6 (390 mg, 1.10 mmol). The mixture was stirred at room temperature for 30 min. Methanol was concentrated, and the resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain the title compound (210 mg, yield: 53%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.41-2.75 (m, 3H), 2.91-3.17 (m, 2H), 3.24-3.47 (m, 3H), 3.72 (s, 3H), 3.74 (s, 3H), 3.77 (s, 3H), 4.07 (d, 1H), 4.45 (d, 1H), 4.94 (t, 1H), 6.67 (s, 1H), 6.88 (s, 2H), 7.28 (s,1H), ESI-MS m/z 355.6 (M+H).sup.+.

EXAMPLE 8

(S)-2-carboxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (class I-A)

(20) ##STR00033##

(21) 30% hydrogen peroxide solution (10 ml), 10M sodium hydroxide solution (5 ml) and ethanol (5 ml) were added into the product of Example 4 (400 mg, 1.14 mmol). The mixture was heated to reflux for 72 h. Most parts of the solvent were distilled off, and the concentrated hydrochloric acid was used to adjust the pH of the mixture to subacidity. The resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain the title compound (150 mg, yield: 35%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.59-2.89 (m, 3H), 3.17-3.32 (m, 2H), 3.42 (dd, 1H), 3.50-3.63 (m, 2H), 3.85 (s, 6H), 4.07 (s, 3H), 4.26 (d, 1H), 6.77-6.83 (m, 2H), 6.88 (d, 1H), 8.10 (s, 1H). ESI-MS m/z 369.5 (M+H).sup.+, 367.8 (M−H).sup.−.

EXAMPLE 9

(S)-2-ethoxycarbonyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-A)

(22) ##STR00034##

(23) Ethanol (3 ml) was added into the product of Example 8 (137 mg, 0.37 mmol), and sulfoxide chloride (0.08 ml, 1.11 mmol) was added at room temperature. The mixture was heated to reflux for 2 h. The solvents were distilled off. The resulting mixture was extracted with dichloromethane-saturated sodium bicarbonate solution, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain the title compound (50 mg, yield: 34%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 1.39 (t, 3H), 2.57-2.87 (m, 3H), 3.14-3.27 (m, 2H), 3.33 (dd, 1H), 3.48-3.60 (m, 2H), 3.85 (s, 6H), 3.88 (s, 3H), 4.24 (d, 1H), 4.36 (q, 2H), 6.71 (s, 1H), 6.78 (d, 1H), 6.89 (d, 1H), 7.71 (s, 1H). ESI-MS m/z 398.1 (M+H).sup.+.

EXAMPLE 10

(S)-2-aminomethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-A)

(24) ##STR00035##

(25) THF (2 ml) and borane-tetrahydrofuran solution (1.2 ml) were added into the product of Example 4 (150 mg, 0.42 mmol). The mixture was heated to reflux overnight, 1M hydrochloric acid was added thereto to adjust pH to around 2. The mixture was heated at 100° C. for 1 h. The sodium bicarbonate solution was used to adjust the pH of the mixture to alkalescency. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain the title compound (50 mg, yield: 33%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.98 (d, 1H), 3.26 (t, 1H), 3.69-4.04 (m, 13H), 4.24-4.79 (m, 3H), 6.96 (s, 1H), 6.97 (d, 1H), 7.08 (d, 1H), 7.63 (s, 1H), 8.42 (brs, 2H), 12.08 (s, 1H). ESI-MS m/z 355.0 (M+H).sup.+.

EXAMPLE 11

(S)-2-acetaminomethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (type IA)

(26) ##STR00036##

(27) Dichloromethane (1.5 ml), triethylamine (0.09 ml, 0.63 mmol) and acetic anhydride (0.04 ml, 0.42 mmol) were added into the product of Example 10 (75 mg, 0.21 mmol). The mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain the title compound (20 mg, yield: 24%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 1.97 (s, 3H), 2.56-2.85 (m, 3H), 3.12-3.37 (m, 3H), 3.47-3.59 (m, 2H), 3.85 (s, 9H), 4.24 (d, 1H), 4.41 (d, 2H), 6.01 (brs, 1H), 6.62. (s, 1H), 6.79 (d, 1H), 6.88 (d, 1H), 7.17 (s, 1H), ESI-MS m/z 397.0 (M+H).sup.+.

EXAMPLE 12

(S)-2-acetyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-A)

(28) ##STR00037##

(29) 1M methyl magnesium bromide (5 ml) was added into the product of Example 4 (250 mg, 0.71 mmol). The mixture was heated to reflux overnight. The resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain the title compound (20 mg, yield: 7%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.57-2.86 (m, 3H), 2.62 (s, 3H), 3.15-3.31 (m, 3H), 3.39 (dd, 1H), 3.48-3.62 (m, 2H), 3.85 (s, 6H), 3.90 (s, 3H), 4.26 (d, 1H), 6.71 (s, 1H), 6.79 (d, 1H), 6.88 (d, 1H), 7.70 (s, 1H). ESI-MS m/z 368.2 (M+H).sup.+.

EXAMPLE 13

(S)-2-amino-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine hydrochloride (Class I-A)

(30) ##STR00038## Step 1:

(31) 1-d (2 g, 4.22 mmol) was place in a double-necked flask. Thereto, cesium carbonate (3.4 g. 10.5 mmol), palladium acetate (189 mg, 0.84 mmol), BINAP (789 mg, 1.26 mmol), and toluene (15 ml) were added. After completion of nitrogen replacement for 15 min, benzylamine (0.92 ml, 8.44 mmol) was added thereto. The reaction was performed at 110° C. overnight. Toluene was concentrated. Dichloromethane was added to dissolve the product. The insoluble matter was removed by filtration. The filtrate was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain 13-a (400 mg, yield: 22%). ESI-MS m/z 430.8 (M+H).sup.+. Step 2:

(32) Methanol (5 ml), palladium on carbon (40 mg) and ammonium formate (293 mg, 4.65 mmol) were added into 13-a (400 mg, 0.93 mmol). The mixture was heated to reflux for 2 h. The palladium on carbon was filtered off, and the methanol was distilled off. The resulting mixture was extracted with dichloromethane-water, washed. with saturated brine, dried, concentrated, and subjected to column chromatography to obtain oily product. HCl-EtOH was added thereto to form a salt so as to obtain the title compound as a yellow solid (225 mg, yield: 64%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.98 (d, 1H), 3.17 (t, 1H), 3.48 (m, 2H), 3.69-3.96 (m, 11H), 4.38 (d, 1H), 4.62 (d, 1H), 4.75 (d, 1H), 6.94-7.15 (m, 3H), 7.45 (s, 1H), 9.75 (brs, 2H), 11.99 (s, 1H). ESI-MS m/z 341.3 (M+H).sup.+.

EXAMPLE 14

(S)-2-acetamido-3,9,10-trimethoxy-6,8,13,13a4tetrahydro-5H-dibenzo[a,g] quinolizine hydrochloride (Class I-A)

(33) ##STR00039##

(34) The title compound was prepared from the product of Example 13 and acetic anhydride, with reference to the method for synthesizing the product of Example 11. That is, the product of Example 10 (75 mg, 0.21 mmol) was replaced with the product of Example 13 (72 mg, 0.21 mmol). The yield was 38%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.19 (s, 3H), 2.61-2.93 (m, 3H), 3.15-3.31 (m, 2H), 3.39 (dd, 1H), 3.51-3.69 (m, 2H), 3.83 (s, 6H), 3.86 (s, 3H), 6.60 (s, 1H), 6.78 (d, 1H), 6.87 (d, 1H), 7.72 (brs, 1H), 8.32 (s, ESI-MS m/z 383.1 (M+H).sup.+.

EXAMPLE 15

(S)-2-bromo-3,9,10-tritmethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-A)

(35) ##STR00040## Step 1:

(36) Lithium chloride (135 mg, 3.15 mmol), tetrakis(triphenylphosphine)palladium (80 mg, 0.063 mmol), hexabutylditin (0.65 ml, 1.26 mmol) and 1,4-dioxane (2 ml) were added into 1-d (300 mg, 0.63 mmol). The mixture was heated to reflux overnight after nitrogen replacement. The solvent was distilled off. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain 15-a (132 mg, yield: 33%). ESI-MS m/z 615.4. (M+H).sup.+. Step 2:

(37) Dichloromethane (3 ml) was added into 15-a (110 mg, 0.17 mmol), and then NBS (40 mg, 0.22 mmol) was added under an ice bath. The mixture was stirred for 5 min. Dichloromethane and water were added for extraction, and the mixture was washed with saturated brine, dried, and concentrated and subjected to column chromatography to obtain the title compound (56 mg, yield: 77%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.56-2.87 (m, 3H), 3.09-3.31 (m, 3H), 3.48-3.58 (m, 2H), 3.85 (s, 6H), 3.88 (s, 3H), 4.24 (d, 1H), 6.65 (s, 1H) (d, 1H), 6.88 (d, 1H), 7.42 (s, 1H). ESI-MS m/z 403.6 (M+H).sup.+.

EXAMPLE 16

(S)-2-chloro-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-A)

(38) ##STR00041##

(39) The title compound was prepared by reacting 15-a with NCS, with reference to the method for synthesizing the product of Example 15. That is, NBS (40 mg, 0.22 mmol) was replaced with NCS (29 mg, 0.22 mmol). The yield was 35%. ESI-MS m/z 360.7 (M+H).sup.+.

EXAMPLE 17

(S)-2-vinyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (class I-A)

(40) ##STR00042##

(41) Dry DMF (15 ml), lithium chloride (270 mg, 5.07 mmol), bis(triphenylphosphine)palladium dichloride (25 mg, 0.03 mmol) and tributylvinyltin (0.6 ml, 2.02 mmol) were added into 1-d (800 mg, 1.69 mmol). The mixture was heated to reflux overnight after nitrogen replacement. DMF was distilled off. The resultant was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain the title compound (275 mg, yield: 46%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.62-2.92 (m, 3H), 3.15-3.29 (m, 2H), 3.35 (dd, 1H), 3.51-3.65 (m, 2H), 3.84 (s, 3H), 3.86 (s, 6H). 4.27 (d, 1H), 5.25 (d, 1H), 5.73 (d, 1H), 6.62 (s, 1H), 6.80 (d, 1H), 6.90 (d, 1H), 7.02 (dd, 1H), 7.34 (s,1H). ESI-MS m/z 352.0 (M+H).sup.+.

EXAMPLE 18

(S)-2-hydroxyethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-A)

(42) ##STR00043##

(43) THF (1 ml) and a 1M borane-tetrahydrofuran solution (1.7 ml, 1.68 mmol) were added into the product of Example 17 (200 mg, 0.56 mmol). The mixture was stirred at room temperature overnight Water (2 ml), 1M sodium hydroxide solution (6 ml) and 30% hydrogen peroxide (1.2 ml) were added thereto. The mixture was heated at 65° C. for 2 h. The saturated ammonium chloride solution was used to adjust the pH of the mixture to alkalescency. The resulting mixture was extracted with dichloromethane-water, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the title compound (60 mg, yield: 28%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.58-2.93 (m, 5H), 3.12-3.36 (m, 3H), 3.49-3.60 (m, 2H), 3.83 (s, 3H), 3.86 (s, 6H), 3.80-3.88 (m, 2H), 4.25 (d, 1H), 6.62 (s, 1H), 6.80 (d, 1H), 6.89 (d, 1H), 7.05 (s, 1H). ESI-MS m/z 370.1 (M+H).sup.+.

EXAMPLE 19

(S)-2,3,10-trimethoxy-9-cyano-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-C)

(44) ##STR00044## Step 1:

(45) D-Tetrahydropalmatine 19-a (10 g, 28.1 mol) was dissolved in methanesulfonic acid (12 mL). Thereto, methionine (5 g, 30.9 mmol) was added. The reaction was performed at 30° C. for 3 h. The reaction solution was slowly added to the NaOH solution under an ice bath, and the pH of the mixture was adjusted to 13. The raw materials were filtered off with suction. The filtrate was extracted with dichloromethane several times. The organic phase was combined, and washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to recrystallization in methanol to give 19-b as a white solid (1.59 g, 16% yield). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.58-2.72 (m, 2H), 2.83 (dd, 1H), 3.07-3.30 (m, 3H), 3.47-3.62 (m, 2H), 3.87 (s, 6H), 3.89 (s, 3H), 4.24 (d, 1H), 5.68 (s, 1H), 6.62 (s, 1H), 6.68 (d, 1H), 6.74 (m, 2H). ESI-MS m/z 342.3 (M+H).sup.+. Step 2:

(46) Dichloromethane (5 ml) and triethylamine (0.82 ml, 5.8 mmol) were added into 19-b (1 g, 2.9 mmol), and then Tf.sub.2O (0.58 ml, 3.48 mmol) was slowly added dropwise under an ice bath. After completion of addition, the mixture was stirred for 3 h at room temperature. The resultant was extracted with dichloromethane-water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 19-c (0.8 g, yield: 57%). Step 3:

(47) The title compound was prepared from the 19-c via cyanation reaction, with reference to the method for synthesizing the product of Example 4. That is, 1-d (660 mg, 1.39 mmol) was replaced with 19-c (660 mg, 1.39 mmol). The yield was 50%, .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.60-2.73 (m, 2H), 2.82 (dd, 1H), 3.05-3.32 (m, 3H), 3.60 (dd, 1H), 3.73 (d, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 6.63 (s, 1H), 6.70 (s, 1H), 6.81 (d, 1H), 7.33 (d, 1H). ESI-MS m/z 351.0 (M+H).sup.+.

EXAMPLE 20

(S)-2,3,10-trimethoxy-9-carbamoyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-C)

(48) ##STR00045##

(49) The title compound was prepared from the product of Example 19, with reference to the method for synthesizing the product of Example 5. That is, the product of Example 4 (320 mg, 0.91 mmol) was replaced with the product of Example 19 (320 mg, 0.91 mmol). The yield was 40%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.63 (m, 2H), 2.83 (dd, 1H), 3.10 (m, 2H), 3.30 (dd, 1H), 3.58 (dd, 1H), 3.85 (m, 10H), 4.13 (d, 1H), 5.86 (s, 1H), 6.08 (s, 1H), 6.60 (s, 1H), 6.72 (s, 1H), 6.80 (d, 1H), 7.17 (d, 1H). ESI-MS m/z 369.2 (M+H).sup.+.

EXAMPLE 21

(S)-2,3,10-trimethoxy-9-acetyl-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (class I-C)

(50) ##STR00046##

(51) The title compound was prepared from the product of Example 19, with reference to the method for synthesizing the product of Example 12. That is, the product of Example 4 (250 mg, 0.71 mmol) was replaced with the product of Example 19 (250 mg, 0.71 mmol). The yield was 33%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.51 (s, 3H), 2.63 (m, 2H), 2.84 (dd, 1H), 3.11 (m, 2H), 3.30 (dd, 1H), 3.57 (dd, 1H), 3.68 (d, 1H), 3.85 (m, 10H), 6.60 (s, 1H), 6.72 (s, 1H), 6.80 (d, 1H), 7.16 (d, 1H). ESI-MS m/z 368.1 (M+H).sup.+.

EXAMPLE 22

(S)-2,3,10-trimethoxy-9-aminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-C)

(52) ##STR00047##

(53) The title compound was prepared from the product of Example 19 via cyanation reduction, with reference to the method for synthesizing the product of Example 10. That is, the product of Example 4 (150 mg, 0.42 mmol) was replaced with the product of Example 19 (150 mg, 0.42 mmol). The yield was 50%

EXAMPLE 23

(S)-2,3,10-trimethoxy-9-acetylaminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-C)

(54) ##STR00048##

(55) The title compound was prepared from the product of Example 22 via acetylation, with reference to the method for synthesizing the product of Example 11. That is, the product of Example 10 (75 mg, 0.21 mmol) was replaced with the product of Example 22 (75 mg, 0.21) mmol). The yield was 80%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 1.93 (s, 3H), 2.64 (m, 2H), 2.84 (dd, 1H), 3.04-3.32 (m, 3H), 3.54 (d, 1H), 3.66 (d, H), 3.84 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 4.32 (d, 1H), 4.44 (m, 2H), 5.77 (t, 1H), 6.61 (s, 1H), 6.71 (s, 1H), 6.77 (d, H), 7.10 (d, 1H). ESI-MS m/z 397.1 (M+H).sup.+.

EXAMPLE 24

(S)-2,3,10-trimethoxy-9-formyl-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-C)

(56) ##STR00049##

(57) The title compound was prepared from the product of Example 19, with reference to the method for synthesizing the product of Example 6. That is, the product of Example 4 (500 mg, 1.42 mmol) was replaced with the product of Example 19 (500 mg, 1.42 mmol). The yield was 49%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.58-2.75 (m, 2H), 2.87 (t, 1H), 3.02-3.33 (m, 4H), 3.57 (d, 1H), 3.86 (s, 3H), 3.87 (5, 3H), 3.90 (s, 3H), 4.61 (d, 1H), 6.61 (s, 1H), 6.71 (s, 1H), 6.87 (d, 1H), 7.35 (d, 1H), 10.63 (s, 1H). ESI-MS m/z 354.3 (M+H).sup.+.

EXAMPLE 25

(S)-2,3,10-trimethoxy-9-hydroxymethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-C)

(58) ##STR00050##

(59) The title compound was prepared from the product of Example 24, with reference to the method for synthesizing the product of Example 7. That is, the product of Example 6 (390 mg, 1.10 mmol) was replaced with the product of Example 24 (390 mg, 1.10 mmol). The yield was 69%, .sup.1H NMR (300 MHz, CD.sub.3OD) δ 3.10 (t, 2H), 3.27 (m, 2H), 3.58 (td, 1H), 3.78-3.97 (m, 11H), 4.67 (m, 2H), 4.74-4.84 (m, 2H), 6.84 (s, 1H), 6.98 (s, 1H), 7.06 (d, H), 7.30 (d, 1H). ESL-MS m/z 356.1 (M+H).sup.+.

EXAMPLE 26

(S)-2,3,9-trimethoxy-10-methyl-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-D)

(60) ##STR00051## Step 1:

(61) Dichloromethane (5 ml) and triethylamine (0.67 ml, 4.8 mmol) were added into 1-a (1 g, 2.4 mmol), and then Tf.sub.2O (0.48 ml, 2.88 mmol) was slowly added dropwise under an ice bath. After completion of addition, the mixture was stirred for 3 h at room temperature. The resultant was extracted with dichloromethane-water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 26-a (0.74 g, yield: 56%). Step 2:

(62) 26-a (500 mg, 0.91 mmol) was placed in a three-necked flask. Thereto, methylboronic acid (218 mg, 3.64 mmol), potassium carbonate (502 mg, 3.64 mmol), and tetrakis(triphenylphosphonium)palladium (210 mg , 0.182 mmol) and 1,4-dioxane (5 mL) were added. The mixture was refluxed at 100° C. overnight after nitrogen. replacement. The reaction solution was filtered, and the filtrate was concentrated and subjected to column chromatography to obtain 26-b (75 mg, yield: 20%). Step 3:

(63) 26-b (75 mg, 0.180 mmol) was dissolved in ethyl acetate (2 mL). Thereto, palladium on carbon (10 mg) was added. The hydrogenation reaction was performed for 10 h. The resulting mixture was filtered and the mother liquor was concentrated to give 26-c (53 mg, yield: 90%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.27 (s, 3H), 2.59-2.71 (m, 2H), 2.85 (dd, 1H), 3.08-3.23 (m, 2H), 3.27 (dd, 1H), 3.55 (d, 2H), 3.75 (s, 3H), 3.88 (s, 3H), 4.23 (d, 1H), 6.60 (s, 1H), 6.82 (s, 1H), 6.84 (d, 1H), 7.00 (d, 1H). ESI-MS m/z 326.2 (M-HH).sup.+. Step 4:

(64) The title compound was prepared from the 26-c and dimethyl sulfate via methylation reaction, with reference to the method for synthesizing the compound 1-b. That is, 1-a was replaced with 26-c. The yield was 40%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.27 (s, 3H), 2.61-2.72 (m, 2H), 2.87 (dd, 1H), 3.11-3.25 (m, 2H), 3.29 (dd, 1H), 3.58 (d, 2H), 3.76 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 4.24 (d, 1H), 6.62 (s, 1H), 6.74 (s, 1H), 6.86 (d, 7.01 (d, ESI-MS m/z 340.3 (M+H).sup.+.

EXAMPLE 27

(S)-2,3,9-trimethoxy-10-cyano-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-D)

(65) ##STR00052## Step 1:

(66) DMAc (15 ml), zinc cyanide (214 mg, 1.82 mmol), zinc powder (18 mg, 0.27 mmol), DPPF (101 mg, 0.18 mmol) and Pd.sub.2(dba).sub.3 (83 mg, 0.09 mmol) were added into 26-a (500 mg, 0.91 mmol). The mixture was heated at 160° C. overnight. DMAc was distilled off, and the resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated and subjected to column chromatography to give 27-a (348 mg, yield: 92%). Step 2:

(67) 27-a (300 mg, 0.70 mmol) was dissolved in ethanol (4 mL). Thereto, 2 ml of concentrated hydrochloric acid was added, and the reaction was performed at 100° C. for 1 h. The solvent was directly distilled off to obtain compound 27-b (236 mg, yield: 90%). Step 3:

(68) 27-b (250 mg, 0.67 mmol) was dissolved in acetone (4 mL). Thereto, dimethyl sulfate (0.095 mL, 1.01 mmol) and sodium hydroxide (107 mg, 2.68 mmol) were added. The reaction was performed at room temperature for 6 hours while stirring. The resultant was extracted with dichloromethane, washed with a saturated ammonium chloride solution. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain the title compound (200 mg, yield: 85%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.60-2.73 (m, 2H), 2.91 (dd, 1H), 3.05-3.24 (m, 2H), 3.34 (dd, 1H), 3.49 (d, HI), 3.59 (dd, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 4.08 (s, 3H), 4.19 (d, 1H), 6.62 (s, 1H), 6.69 (s, 1H), 6.96 (d, 1H), 7.38 (d, 1H), ESI-MS m/z 351.0 (M+H).sup.+.

EXAMPLE 28

(S)-2,3,9-trimethoxy-10-carbamoyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-D)

(69) ##STR00053##

(70) The title compound was prepared from the product of Example 27 via oxidative hydrolysis, in reference to the method for synthesizing the product of Example 5. That is, the product of Example 4 (320 mg, 0.91 mmol) was replaced with the product of Example 27 (320 mg, 0.91 mmol). The yield was 54%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.69 (m, 2H), 2.94 (m, 1H), 3.06-3.28 (m, 2H), 3.38 (dd, 1H), 3.60 (m, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 4.26 (d, 1H), 5.87 (s, 1H), 6.63 (s, 1H), 6.72 (s, 1H), 7.08 (d, 1H), 7.57 (s, 1H), 7.90 (d, 1H). ESI-MS m/z 369.0 (M+H).sup.+.

EXAMPLE 29

(S)-2,3,9-trimethoxy-10-formyl-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-D)

(71) ##STR00054##

(72) The title compound was prepared from the product of Example 27 via reduction reaction, in reference to the method for synthesizing the product of Example 6. That is, the product of Example 4 (500 mg, 1.42 mmol) was replaced with the product of Example 27 (500 mg, 1.42 mmol). The yield was 64%. .sup.1H NMR (300 MHz, CD.sub.3OD) δ 2.62-2.78 (m, 2H), 2.85 (dd, H), 3.02-3.27 (m, 2H), 3.54-3.72 (m, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 3.93 (s, 3H), 4.27 (d, 1H), 6.71 (s, 1H), 6.89 (s, 1H), 7.16 (d, 1H), 7.67 (d, 1H), 10.27 (s. 1H). ESI-MS m/z 354.0 (M+H).sup.+.

EXAMPLE 30

(S)-2,3,9-trimethoxy-10-hydroxymethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (I-D)

(73) ##STR00055##

(74) The title compound was prepared from the product of Example 29 via reduction reaction, in reference to the method for synthesizing the product of Example 7. That is, the product of Example 6 (390 mg, 1.10 mmol) was replaced with the product of Example 29 (390 mg, 1.10 mmol). The yield was 80%. .sup.1H NMR (300 MHz, CD.sub.3OD) δ 2.60-2.87 (m, 3H), 3.02-3.28 (m, 2H), 3.46-3.66 (m, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 4.22 (d, 1H), 4.64 (s, 2H), 6.71 (s, 1H), 6.88 (s, 1H), 7.01 (d, 1H), 7.28 (d, 1H). ESI-MS m/z 356.0 (M+H).sup.+.

EXAMPLE 31

(S)-2,3,9-trimethoxy-10-aminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-D)

(75) ##STR00056##

(76) The title compound was prepared from the product of Example 27 via reduction reaction, in reference to the method for synthesizing the product of Example 10. That is, the product of Example 4 (150 mg, 0.42 mmol) was replaced with the product of Example 27 (150 mg, 0.42 mmol). The yield was 60%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.67˜2.88 (m, 3H), 3.10˜3.30 (m, 3H), 3.60 (d, 2H), 3.74 (d, 1H), 3.82 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 4.31-4.51 (m, 3H), 6.61 (s, 1H), 6.72 (s, 1H), 6.77 (d, 1H), 7.11 (d, 1H). m/z 355.0 (M+H).sup.+.

EXAMPLE 32

(S)-2,3,9-trimethoxy-10-acetaminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-D)

(77) ##STR00057##

(78) The title compound was prepared by reacting the product of Example 31 with acetic anhydride, in reference to the method for synthesizing the product of Example 11. That is, the product of Example 10 (75 mg, 0.21 mmol) was replaced with the product of Example 31 (75 mg, 0.21 mmol). The yield was 67%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 1.99 (s, 3H), 2.68 (m, 2H), 2.88 (dd, 1H), 3.14-3.37 (m, 3H), 3.59 (m, 2H), 3.79 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 4.23 (d, 1H), 4.45 (m, 2H), 5.86 (t, 1H), 6.62. (s, 1H), 6.72 (s, 1H), 6.93 (d, 1H), 7.12 (d, 1H). ESI-MS m/z 397.0 (M+H).sup.+.

EXAMPLE 33

(S)-2,10-diamino-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-B)

(79) ##STR00058## Step 1:

(80) Dichloromethane (5 ml) and pyridine (1.25 ml, 15 mmol) were added into l-SPD (1 g, 3.0 mmol), and then Tf.sub.2O (1.5 ml, 9.0 mmol) was slowly added dropwise under an ice bath. After completion of addition, the mixture was stirred for 1 h at room temperature. Pyridine was washed off with 1M hydrochloric acid. The resultant was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain 33-a (1 g, yield: 60%). .sup.1H-NMR (300 Hz, CDCl.sub.3) δ 2.59-2.94 (m, 3H), 3.10-3.31 (m, 3H), 3.58 (m, 2H), 3.90 (s, 6H), 4.23 (d, 1H), 6.78 (s, 1H), 6.98 (d, 1H), 7.06 (s, 1H), 7.09 (d, 1H). ESI-MS m/z 592.0 (M+H).sup.+. Step 2:

(81) DMF (10 ml), cesium carbonate (1.32 g), palladium acetate (184 mg) and X-phos (132 mg) were added into 33-a (800 mg, 1.35 mmol), After completion of nitrogen replacement for 15 min, benzylamine (0.372 ml) was added thereto. The reaction was performed at 150° C. for 3 h while heating, DMF was distilled off. The resultant was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain 33-b (180 mg, yield: 26%). ESI-MS m/z 506.4 (M+H).sup.+. Step 3:

(82) Palladium on carbon (40 mg), methanol (3 ml) and ammonium formate (436 mg, 6.8 mmol) were added into 33-b (175 mg, 0.34 mmol). The mixture was heated to reflux overnight. The palladium on carbon was filtered off, and methanol was distilled off. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain the title compound (53 mg, yield: 47%). .sup.1H-NMR (300 Hz, CD.sub.3OD) δ 2.72-2.95 (m, 3H), 3.06-3.28 (m, 3H), 3.42 (m, 2H). 3.77 (s, 3H), 3.85 (s, 3H), 4.35 (d, 1H), 6.64 (s, 1H), 6.75 (m, 2H), 6.81 (d, 1H). ESI-MS m/z 326.2 (M+H).sup.+.

EXAMPLE 34

(S)-2,10-di(acetamino)-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-B)

(83) ##STR00059##

(84) The title compound was prepared from he product of Example 33 and acetic anhydride, in reference to the method for synthesizing the product of Example 11. That is, the product of Example 10 (75 mg, 0.21 mmol) was replaced with the product of Example 33 (69 mg, 0.21 mmol). The yield was 34%. .sup.1H-NMR (300 Hz, CDCl.sub.3) δ 2.20 (s, 6H), 2.57-2.89 (m, 3H), 3.09-3.26 (m, 2H), 3.41 (d, 1H), 3.51-3.65 (m, 2H), 3.78 (s, 3H), 3.87 (s, 3H), 4.20 (d, 1H), 6.61 (s, 1H), 6.94 (d, 1H), 7.58 (s, 1H), 7.73 (s, 1H), 8.09 (d, 1H), 8.32 (s, 1H). ESI-MS m/z 409.9 (M+H).sup.+.

EXAMPLE 35

2,3-dicyano-9,10-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-F)

(85) ##STR00060## Step 1:

(86) 35-a (10 g, 29.4 mmol) was dissolved in dichloromethane (300 ml). Thereto, a solution of BCl.sub.3 in dichloromethane (59 ml, 58.8 mmol) was added dropwise under an ice bath. The mixture was stirred at room temperature overnight. The next day, methanol (100 ml) was added dropwise to quench the excessive BCl.sub.3. The solvent was evaporated and the resultant was directly subjected to the next reaction. Step 2:

(87) 35-b (9 g, 27.5 mmol) was suspended in dichloromethane (100 ml). Thereto, pyridine (20 ml) was added, and then trifluoromethanesulfonic anhydride (10 ml) was added dropwise under an ice bath, and the mixture was stirred at room temperature for 5 h. Dichloromethane was added for dilution. The mixture was washed with a 1M HCl solution and saturated brine. The organic layer was dried and concentrated, and subjected to column chromatography to obtain 35-c (3 g, 17% of yield in two steps). Step 3:

(88) Zinc cyanide (1.6 g, 13.6 mmol), 1,1-bisdiphenylphosphine ferrocene (383 mg, 0.69 mmol), zinc powder (110 mg, 1.69 mmol). Pd.sub.2(dba).sub.3 (273 mg, 0.47 mmol) and DMAc (10 ml) were added into 35-c (2.7 g, 4.5 mmol). The mixture was refluxed at 160° C. for 2 h after nitrogen replacement, and cooled to room temperature. Thereto, water and ethyl acetate were added for extraction. The organic layer was combined, washed with saturated brine, dried, concentrated and subjected to column chromatography to obtain the title compound (1 g, yield: 63%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.59-2.71 (m, 1H), 2.77-2.94 (m, 2H), 3.17-3.33 (m, 3H), 3.58 (d, 1H), 3.67 (dd, 1H), 3.85 (s, 6H), 4.26 (d, 1H), 6.81 (d, 1H), 6.89 (d, 1H), 7.59 (s, 1H), 7.71 (s, 1H) ESI-MS m/z 346.3 (M+H).sup.+.

EXAMPLE 36

9,10-dimethoxy-5,6,13,13a-tetrahydroisoquinolino[3,2-a]pyrrolo [3,4-g]isoquinoline-1,3(2H,8H)-dione (Class I-F)

(89) ##STR00061##

(90) The sodium metal (170 mg, 7.3 mmol) was added to absolute ethanol (10 ml). After completely dissolved, the product of Example 35 (200 mg, 0.57 mmol) was added. The mixture was heated at 50° C. for 2 h. The reaction solution was poured into a 10% HNO.sub.3 solution (10 ml), and stirred for 30 minutes. The solid was gradually precipitated therefrom. The mixture was filtered to obtain the product. The mother liquor was concentrated, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried, concentrated, subjected to column chromatographyto give the title compound (110 mg when combined with the filter cake, yield: 52%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.16-2.39 (m, 2H), 2.65 (t, 1H), 2.75-2.95 (m, 2H), 3.17 (t, 2H), 3.35 (d, 1H), 3.44 (s, 3H), 3.49 (s, 3H),3.82 (d, 1H), 6.60 (s, 2H), 7.30 (s, 1H), 7.51 (s, 1H), 10.93 (s, 1H). ESI-MS m/z 365.2 (M+H).sup.+.

EXAMPLE 37

(S)-2,10-dicyano-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (class I-B)

(91) ##STR00062##

(92) The title compound was prepared from 33-a, in reference to the method for synthesizing the product of Example 35. That is, 35-c was replaced with 33-a. The yield was 74%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.58-2.94 (m, 3H), 3.13-3.38 (m, 3H), 3.48 (d, 1H), 3.58 (d, 1H), 3.91 (s, 3H), 4.09 (s, 3H), 4.19 (d, 1H), 6.71 (s, 1H). 6.96 (d, 1H), 7.41 (m, 2H). ESI-MS m/z 346.5 (M+H).sup.+.

EXAMPLE 38

(S)-2,10-dicarbamoyl-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-B)

(93) ##STR00063##

(94) The title compound was prepared from the product of Example 37 via oxidation hydrolysis reaction, in reference to the method for synthesizing the product of Example 5. That is, the product of Example 4 (0.91 mmol) was replaced with the product of Example 37 (0.91 mmol). The yield was 40%. .sup.1H NMR (300 MHz, CD.sub.3OD) δ 2.64-2.97 (m, 3H), 3.12-3.38 (m, 2H), 3.50-3.74 (m, 3H), 3.84 (s, 3H), 3.97 (s, 3H), 4.28 (d, 1H), 6.95 (s, 1H), 7.11 (d, 1H), 7.65 (d, 1H), 7.99 (s, 1H). ESI-MS m/z 382.1 (M+H).sup.+.

EXAMPLE 39

2,3-Dicarbamoyl-9,10-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-F)

(95) ##STR00064##

(96) The title compound was prepared from the product of Example 35 via oxidation hydrolysis reaction, in reference to the method for synthesizing the product of Example 5. That is, the product of Example 4 (0.91 mmol) was replaced with the product of Example 35 (0.91 mmol). The yield was 42%. .sup.1H NMR (300 MHz, CD.sub.3OD) δ 2.61-2.92 (m, 3H), 3.18 (m, 2H), 3.47 (dd, 1H), 3.55 (d, 1H), 3.68 (dd, 1H), 3.82 (s, 3H), 3.83 (s, 3H), 4.23 (d, 1H),6.88 (d, 1H), 6.93 (d, 1H), 7.39 (s, 1H), 7.58 (s, 1H). ESI-MS m/z 382.1 (M+H).sup.+.

EXAMPLE 40

(S)-4,10,11-trimethoxy-3,6,7,9,14,14a-hexahydroimidazo[4,5-h] isoquinolino[3,2-a]isoquinoline-2(1H)-one (Class I-A)

(97) ##STR00065## Step 1:

(98) Dichloromethane (20 ml) and acetic acid (10 ml) were added into 1-c (4 g, 11.7 mmol), and then 30% nitric acid (4.6 ml) was added dropwise under an ice bath. The mixture was stirred at room temperature for 5 h. Dichloromethane-water was added for extraction. The organic phase was combined, washed three times with saturated brine, dried, and concentrated to obtain crude product 40-a (5 g), which was directly used in the next step. Step 2:

(99) Dichloromethane (40 ml) and triethylamine (2.86 ml, 20.6 mmol) were added into 40-a (4 g, 10.3 mmol), and then Tf.sub.2O (1.7 ml, 10.3 mmol) was added dropwise under an ice bath. After completion of addition, the mixture was stirred at room temperature for 3 h. Dichloromethane-water was added for extraction, and the mixture was washed with saturated brine, dried, concentrated, and subjected to column chromatography to give 40-b (2.4 g, 49% of yield in two steps). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.69-2.83 (m, 3H), 2.91-3.20 (m, 3H), 3.84 (d, 6H), 3.91 (d, 1H), 3.97 (s, 3H), 4.10 (t, 1H), 4.20 (d, 1H), 6.77 (s, 2H), 6.97 (s, 1H). Step 3:

(100) Dry toluene (20 ml), cesium carbonate (2.26 g, 6.9 mmol), palladium acetate (104 mg, 0.46 mmol), BINAP (289 mg, 0.46 mmol) were added into 40-b (2.4 g, 4.6 mmol). After completion of nitrogen replacement, benzylamine (1 ml, 9.2 mmol) was added thereto. The mixture was heated to reflux for 3 h. Toluene was distilled off. The resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain 40-c (1.4 g, yield: 63%). Step 4:

(101) Methanol (15 ml), palladium on carbon (140 mg) and ammonium formate (1.85 g, 29 mmol) were added into 40-c (1.4 g, 2.9 mmol). The mixture was heated to reflux for 2 h. The palladium on carbon was filtered, and methanol was distilled off. The resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and formed into a salt by addition of HCl-MeOH to give 40-d as pale yellow solid (1 g, yield: 87%). Step 5:

(102) Dichloromethane (2.5 ml) and triethylamine (0.3 ml, 2.1 mmol) were added into 40-d (164 mg, 0.42 mmol). Triphosgene (50 mg, 0.16 mmol) was dissolved in toluene (2.5 ml), and the mixture was slowly added into the above reaction solution by using a constant pressure dropping funnel. The mixture was stirred at room temperature for 2 h. An appropriate amount of a saturated sodium bicarbonate solution was added thereto. Then the resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain the title compound (75 mg, yield: 46%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.31-2.74 (m, 3H), 2.90-3.12 (m, 2H), 3.28-3.42 (m, 1H), 3.63 (t, 2H), 3.73 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 4.05 (d, 1H), 6.43 (s, 1H), 6.84 (d, 1H), 6.89 (d, 1H), 10.51 (s, 1H), 10.63 (s, 1H). ESI-MS m/z 382.2 (M+H).sup.+, 380.2 (M−H).sup.−.

EXAMPLE 41

(S)-4,10,11-trimethoxy-3,6,7,9,14,14a-Hexahydroimidazo[4,5-h] isoquinolino [3,2-a]isoquinoline-2(1H)-thione (Class I-A)

(103) ##STR00066##

(104) Water (2 ml), sodium hydroxide (51 mg, 1.26 mmol) and carbon disulfide (0.051 ml 0.84 mmol) were added into 40-d (150 mg, 0.42 mmol). The mixture was heated at 80° C. for 1 h. Dichloromethane-water was added for extraction, and the mixture was washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain the title compound (100 mg, yield: 59%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.61-2.85 (m, 3H), 3.10-3.30 (m, 3H), 3.76 (m, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 4.20 (d, 1H), 6.46 (s, 1H), 6.77 (m, 2H). ESI-MS m/z 398.3 (M+H).sup.+.

EXAMPLE 42

(S)-4,10,11-trimethoxy-1,6,7,9,14,14a-hexahydroimidazo[4,5-h] isoquinolino[3,2-a]isoquinoline (Class I-A)

(105) ##STR00067##

(106) Formic acid (3 ml) was added into 40-d (200 mg, 0.56 mmol). The mixture was heated to reflux for 1 h. The solvent was distilled off. The mixture was adjusted to be alkalescency by adding saturated sodium bicarbonate. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain the title compound (90 mg, yield: 43%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.68-2.88 (m, 3H), 3.19-3.39(m, 2H), 3.72(d, 1H), 3.84(s, 3H), 3.85(s, 3H), 3.95(s, 3H), 4.07(d, 2H), 4.29(d, 1H), 6.49(s, 1H), 6.76(d, 1H), 6.87(d, 1H), 7.93(s, 1H). ESI-MS m/z 366.1 (M+H).sup.+.

EXAMPLE 43

(S)-4,10,11-trimethoxy-1,6,7,9,14,14a-hexahydroisoquinolino[3,2-a] [1,2,3]triazolo[4,5-h]isoquinoline (Class I-A)

(107) ##STR00068##

(108) Water (2 ml) and acetic acid (0.42 ml, 7.28 mmol) were added into 40-d (200 mg, 0.56 mmol). The mixture was cooled to 0° C. under an ice bath. Sodium nitrite aqueous solution (containing 50 mg sodium nitrite) was added dropwise thereto. After reacting for 1 h under an ice bath, the mixture was heated to 85° C. for 1 h. The mixture was adjusted to be alkalescency by adding saturated sodium bicarbonate. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain the title compound (80 mg, yield: 38%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.70-2.87 (m, 3H), 3.22-3.39 (m, 2H), 3.69 (d, 1H), 3.85 (d, 6H), 3.99 (s, 3H), 4.05 (d, 1H), 4.14 (d, H), 4.30 (d, 1H), 6.53 (s, 1H), 6.77 (d, 1H), 6.88 (d, 1H). ESI-MS m/z 367.2 (M+H).sup.+.

EXAMPLE 44

9,10-Dimethoxy-1,5,6,8,13,13a-hexahydroimidazo[4,5-g]isoquinolino [3,2-a]isoquinoline (Class I-F)

(109) ##STR00069## ##STR00070##

(110) The raw material 44-h can be prepared from p-hydroxyphenylacetonitrile via multi-step reaction, with reference to the patent document CN102399166B or non-patent documents such as J. Org. Chem, 2009, 74, 9225-8228; Bioorg. Med. Chem. 2013, 21, 856-868. The title compound was prepared from the compound 44-h via method 5 (reaction formula 11). The specific operations are as follows: Step 1:

(111) Acetone (30 ml), potassium carbonate (6.2 g, 45 mmol) and benzyl bromide (3.2 ml) were added into p-hydroxyphenylacetonitrile 44-a (3 g, 22 mmol). The mixture was heated to reflux for 2 h. Acetone was distilled off. The resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and slurried in methanol, filtered to obtain 44-b as a white solid (3.8 g, yield: 76%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 3.68 (s, 2H), 5.07 (s, 2H), 6.97 (d, 2H), 7.23 (d, 2H), 7.29-7.47 (m, 5H). Step 2:

(112) The sodium borohydride (1.3 g) was suspended in THF (5 ml), 2.66 ml of trifluoroacetic acid (diluted with 5 ml of THF) was slowly added dropwise to the sodium borohydride solution under an ice bath. After completion of addition, the mixture was increased to room temperature. 44-b (2 g) was dissolved in THF (5 ml), which was then slowly injected into the reaction system. Reaction was performed at room temperature for 4 h. The reaction solution was slowly added dropwise into ice water and stirred. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, formed into a salt by adding HCl-MeOH, concentrated, and slurried in acetone, filtered to obtain 44-c as a white solid (1 g, yield: 42%). Step 3:

(113) Ethanol (20 ml) and triethylamine (2.4 ml) were added into 44-e (1.15 g, 4.4 mmol) and 44-d (0.92 g). The mixture was heated to reflux for 12 h. Ethanol was distilled off. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and slurried in petroleum ether/ethyl acetate, filtered to obtain 44-e (1,3 g, yield: 68%). ESI-MS m/z 436.3 (M-H).sup.+. Step 4:

(114) Toluene (30 ml) and phosphorus oxychloride (26 ml) were added into 44-e (10 g, 23.0 mmol). The mixture was heated to reflux for 4 h. The phosphorus oxychloride and toluene were distilled off. The residue was poured into ice water. Sodium carbonate solution was added to adjust pH=7. The resulting mixture was extracted with ethyl acetate, dried, and concentrated. Thereto, methanol was added, and then sodium borohydride (3 g) was added under an ice bath condition. After completion of addition, the mixture was stirred overnight at room temperature. Methanol was distilled off. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain 44-g (0.7 g, two-step yield: 7%), .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.56-2.93 (m, 3H), 3.05-3.32 (m,3H), 3.56 (m, 2H), 3.86 (s, 6H), 4.26 (d, 1H), 5.06 (s, 2H), 6.74-6.92 (m, 4H), 7.06 (d, 1H), 7.29-7.50 (m, 5H). ESI-MS m/z 402.7 (M+H).sup.+. Step 5:

(115) Ethanol (5 ml) and palladium on carbon (70 mg) were added into 44-g (1.4 g). The hydrogenation reaction was performed at room temperature for 12 h. The resultant was filtered and the filtrate was concentrated to dryness to give 44-h (1.2 g, 100% yield), Step 6:

(116) Dichloromethane (5 ml) was added into 44-h (0.9 g, 2.8 mmol), and then 65% concentrated nitric acid (0.33 ml) was added under an ice bath. After completion of addition, the mixture was stirred at room temperature for 2 h. Saturated sodium bicarbonate solution was added to adjust pH>7. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain 44-i (0.3 g). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.56-2.95 (m, 3H), 3.06-3.33 (m, 3H), 3.50-3.66 (m, 2H), 3.86 (s, 6H), 4.26 (d, 1H), 6.81 (d, 1H), 6.88 (d, 1H), 7.06 (s, 1H), 7.90 (s, 1H), 10.38 (brs, 1H). ESI-MS m/z 357.3 (M+1H).sup.+. Step 7:

(117) Dichloromethane (5 ml), pyridine (0.34 ml, 4.2 mmol) and trifluoromethanesulfonic anhydride (0.28 ml, 1.68 mmol) were added into 44-i (300 mg, 0.84 mmol). The mixture was stirred overnight at room temperature. 1M hydrochloric acid (4 ml) was added, and the mixture was extracted with saturated brine, dried, concentrated, and subjected to column chromatography to obtain 44-j (330 mg, yield: 80%). ESI-MS m/z 489.1 (M+H).sup.+. Step 8:

(118) Toluene (3 ml), palladium acetate (15 mg, 0.067 mmol.), BINAP (42 mg, 0.067 mmol), cesium carbonate (330 mg, 1.00 mmol) and benzylamine (0.15 ml, 1.34 mmol) were added into 44-j (330 mg, 0.67 mmol). The mixture was heated to reflux for 2 h. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain 44-k (250 mg, yield: 83%), ESI-MS m/z 446.3 (M+H).sup.+. Step 9:

(119) Methanol (5 ml), palladium hydroxide (25 mg) and ammonium formate (360 mg) were added into 44-k (250 mg, 0.56 mmol). The mixture was heated to reflux for 2 h. Methanol was concentrated, and the mixture was extracted with dichloromethane-water, dried, and concentrated. Thereto, ethanol was added, and then HCl-MeOH was added dropwise to form a salt to obtain 44-1 as a pale yellow solid (180 mg, yield: 88%). Step 10:

(120) Formic acid (2.5 ml) was added into 44-1 (108 mg, 0.30 mmol). The mixture was heated to reflux for 1 h. Formic acid was distilled off, and a saturated sodium bicarbonate solution was added. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to obtain the title compound (50 mg, yield: 50%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.64-2.78 (m, 1H), 2.86-2.98 (m, 2H), 3.21-3.46 (m, 3H), 3.59 (d, 1H), 3.79 (d, 1H), 3.85 (s, 6H), 4.28 (d, 1H), 5.34 (brs, 1H), 6.80 (d, 1H), 6.90 (d, 1H), 7.38 (s, 1H), 7.59 (s, 1H), 7.99 (s, 1H). ESI-MS m/z 336.2 (M+H).sup.+.

EXAMPLE 45

9,10-Dimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[3,2-a] oxazolo[4,5-g]isoquinoline (Class I-F)

(121) ##STR00071## Step 1:

(122) Methanol (20 ml) and palladium on carbon (40 mg) were added into 44-i (520 mg, 1.46 mmol). The hydrogenation reaction was performed at room temperature for 3 h, After filtration, the filtrate was added into HCl-MeOH to form a salt, and a pale yellow solid was precipitated. The mixture was filtered, and dried to obtain 45-a (480 mg, yield: 91%). Step 2:

(123) Trimethyl orthoformate (1.5 ml) was added into 45-a (85 mg, 0.23 mmol). The mixture was heated to reflux for 2 h. Trimethyl orthoformate was distilled off. The resulting mixture was subjected to silica gel column chromatography to obtain the title compound (60 mg, yield: 76%).

(124) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.63-2.74 (m, 1H), 2.86-2.99 (m, 2H), 3.21-3.41 (m, 3H), 3.58 (d, 1H), 3.76 (dd, 1H), 3.86 (d, 6H), 6.80 (d, 1H), 6.89 (d, 1H), 7.49 (s, 1H), 7.54 (s, 1H), 8.04 (s, 1H). ESI-MS m/z 337.2 (M+H).sup.+.

EXAMPLE 46

9,10-Dimethoxy-3,5,6,8,13,13a-Hexahydro-2H-isoquinolino[3,2-a] oxazolo[4,5-g]isoquinolin-2-one (Class I-F)

(125) ##STR00072##

(126) Tetrahydrofuran (2 ml) and CDI (90 mg, 0.54 mmol) were added into 45-a (90 mg, 0.27 mmol). The reaction was performed at room temperature for 5 h. The resultant was extracted with dichloromethane-water, dried, concentrated and subjected to column chromatography to give the title compound as a white solid (62 mg, yield: 63%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.41-2.64 (m, 2H), 2.73 (d, 1H), 2.92-3.17 (m, 2H), 3.26-3.44 (m, 2H), 3.49 (d, 1H), 3.72 (s, 3H), 3.77 (s, 3H), 4.07 (d, 1H), 6.82 (s, 1H), 6.87 (dd, 1H), 7.29 (s, 1H), 11.50 (s, 1H). ESI-MS m/z 353.3 (M+H).sup.+.

EXAMPLE 47

10,11-Dimethoxy-4,6,7,9,14,14a-Hexahydroisoquinolino[3,2-a][1,4] oxazino[3,2-g]isoquinoline-3(2H)-one (Class I-F)

(127) ##STR00073## Step 1:

(128) Dichloromethane (5 ml), triethylamine (0.18 ml) and chloroacetyl chloride (0.038 ml) were added into 45-a (150 mg, 0.46 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to obtain 47-a (100 mg, yield: 54%). ESI-MS m/z 403.2 (M+H).sup.+. Step 2:

(129) Acetone (3 ml) and potassium carbonate (53 mg) were added into 47-a (100 mg, 0.24 mmol). The mixture was heated to reflux for 5 h. Acetone was distilled off, and the mixture was extracted with dichloromethane-water, washed with saturated brine, dried, concentrated, and subjected to column chromatography to give the title compound as a pure white solid (60 mg, yield: 66%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.37-2.68 (m, 3H), 2.89 (t, 1H), 3.09 (d, 1H), 3.24-3.45 (m, 3H), 3.71 (s, 3H), 3.76 (s, 3H), 4.05 (d, 1H), 4.52 (s, 2H), 6.61 (s, 1H), 6.80-6.98 (m, 3H), 10.66 (s, 1H). ESI-MS m/z 367.2 (M+H).sup.+, 365.2 (M−H).sup.−.

EXAMPLE 48

10,11-Dimethoxy-7,9,14,14a-tetrahydro-6H-isoquinolino[3,2-a] oxazolo[5,4-h]isoquinoline (Class I-E)

(130) ##STR00074## Step 1:

(131) Dichloromethane (5 ml) was added into 44-h (0.9 g, 2.8 mmol), and then 65% concentrated nitric acid (0.33 ml) was added under an ice bath. After completion of addition, the mixture was stirred at room temperature for 2 h. Saturated sodium bicarbonate solution was added to adjust pH>7. The resulting mixture was extracted with dichloromethane-water, dried, concentrated, and subjected to column chromatography to give 48-a (0.5 g). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.66-2.94 (m, 4H), 2.98-3.18 (m, 2H), 3.85 (s, 6H), 3.93 (d, 1H), 4.22 (d, 1H), 4.63 (dd, 6.76 (d, 2H), 7.01 (d, 1H), 7.29 (d, 1H). EST-MS m/z 357.3 (M+H).sup.+. Step 2.

(132) Methanol (20 ml) and palladium on carbon (40 mg) were added into 48-a (400 mu, 1.12 mmol). The hydrogenation reaction was performed at room temperature for 3 h. After filtration, the filtrate was added into HCl-MeOH to form a salt, and a pale yellow solid was precipitated. The resultant was filtered, and dried to obtain 48-b (410 mg, yield: 100%). Step 3:
Trimethyl orthoformate (1.5 ml) was added into 48-b (85 mg, 0.23 mmol). The mixture was heated to reflux for 2 h. Trimethyl orthoformate was distilled off, and the resultant was subjected to silica gel column chromatography to give the title compound (42 mg, yield: 53%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.66-3.00 (m, 3H), 3.17 (t, 1H), 3.42 (d, 1H), 3.75 (s, 3H), 3.78 (s, 3H), 3.88 (dd, 1H), 4.16 (d, 1H), 4.34 (d, 2H), 6.93 (m, 2H). 7.26 (d, 1H), 7.64 (d, 1H), 8.75 (s, 1H). ESI-MS m/z 337.2 (M+H).sup.+.

EXAMPLE 49

10,11-Dimethoxy-6,7,14,14a-tetrahydro-1H-isoquinolino[3,2-a] oxazolo[5,4-h] isoquinoline-2 (9H)-one (Class I-E)

(133) ##STR00075##

(134) The title compound was prepared from 48-b, in reference with the method for synthesizing the product of Example 46. That is, 45-a was replaced with 48-b. The yield was 75%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.60-2.87 (m, 3H), 3.09-3.25 (m, 3H), 3.68 (t, 2H), 3.85 (s, 6H), 4.17 (d, 1H), 6.73-6.81 (dd, 2H), 6.90 (d, 1H), 7.03 (d, 1H), 9.41 (s, 1H). ESI-MS m/z 353.2 (M+H).sup.+.

EXAMPLE 50

11,12-Dimethoxy-3,7,8,10,15,15a-hexahydroisoquinolino[3,2-a][1,4] oxazino [2,3-h]isoquinoline-2(1H)-one (Class I-E)

(135) ##STR00076##

(136) The title compound was prepared from 48-b, in reference with the method for synthesizing the product of Example 47. That is, 45-a was replaced with 48-b. The yield: 59%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.61-2.90 (m, 3H), 2.93-3.19 (m, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 3.91 (m, 2H), 4.20 (d, 1H), 4.31 (d, 1H), 4,48 (d, 1H), 6.69-6.89 (m, 4H), 8.14 (brs, 1H). ESI-MS m/z 367.2 (M+H).sup.+, 365.2 (M−H).sup.−.

EXAMPLE 51

(S)-2-(difluoromethoxy)-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-A)

(137) ##STR00077##

(138) 1-c (200 mg, 0.58 mmol) was dissolved in DMF (5 ml). Thereto, cesium carbonate (378 mg, 1.16 mmol) was added. The mixture was heated to 100° C. Monochlorodifluoromethane was passed into the reaction system for 5 to 6 hours until TLC shows the reaction of the starting materials was completed. The reaction was stopped, and DMF was distilled off The resultant was extracted with dichloromethane-water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the title compound (69 mg, yield: 30%). .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2,58-2.88 (m, 3H), 3.12-3.29 (m, 3H), 3.54 (d, 2H), 3.85 (s, 6H), 3.86 (s, 3H), 4.25 (d, 1H), 654 (t, 1H), 6.70 (s, 1H), 6.79 (d, 1.H), 6.88 (d, 1H), 7.05 (s, 1H). ESI-MS m/z 392.3 (M+H).sup.+.

EXAMPLE 52

(S)-2-allyloxy-3,9,10-trimethoxy-6,8,13,13a-tetahydro-5H-dibenzo [a,g] quinolizine (Class I-A)

(139) ##STR00078##

(140) 1-c (200 mg, 0.58 mmol) was dissolved in DMF (5 ml). Thereto, cesium carbonate (378 mg, 1.16 mmol) and 3-bromopropene (0.073 ml, 0.87 mmol) were added. The mixture was stirred at room temperature for 3 h. DMF was distilled off. The resultant was extracted with dichloromethane-water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the title compound (112 mg, yield: 50%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.96 (m, 2H), 3.38 (m, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 3.84 (m, 2H), 4.33-4.72 (m, 5H), 5.27 (dd, 1H), 5.42 (dd, 1H), 6.05 (m, 1H), 6.84 (s, 1H), 7.03 (d, 1H), 7.05 (s, 1H), 7.09 (d, 1H), 11.06 (brs, 1H). ESI-MS m/z 382.2 (M+H).sup.+.

EXAMPLE 53

(S)-2-cyclopropoxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine hydrochloride (Class I-A)

(141) ##STR00079##

(142) 1-c (200 mg, 0.58 mmol) was dissolved in DMF (5 ml). Thereto, cesium carbonate (378 mg, 1.16 mmol) and bromocyclopropane (0.070 ml, 0.87 mmol) were added. The mixture was stirred at 150° C. for 3 h. DMF was distilled off, and the resultant was extracted with dichloromethane-water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the title compound (141 mg, yield: 63%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 0.56-0.87 (m, 4H), 2.89 (d, 1H), 3.06 (t, 1H), 3.37 (m, 2H), 3.74 (s, 3H), 3.80 (s, 3H), 3.82 (s, 3H), 3.84 (m, 3H), 4.39 (dd, 1H), 4.66 (m, 2H), 6.83 (s, H), 7.04 (d, 1H), 7.09 (d, 1H), 7.26 (s, 1H), 11.27 (brs, 1H). ESI-MS m/z 382.2 (M+H).sup.+.

EXAMPLE 54

(S)-2-cyclopentyloxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine hydrochloride (Class I-A)

(143) ##STR00080##

(144) The title compound was prepared from 1-c and bromocyclopentane, with reference to the method for synthesizing the product of Example 52. That is, 3-bromopropene was replaced with bromocyclopentane. The yield: 42%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 1.89 (m, 8H), 2.56-2.72 (m, 2H), 2.82 (dd, 1H), 3.05-3.28 (m, 3H), 3.54 (d, 2H), 3.83 (s, 3H), 3.85 (s, 6H), 4.24 (d, 1H), 4.76 (m, 1H), 6.61(s, 1H), 6.74 (s, 1H), 6.79 (d, 1H), 6.88 (d, 1H).

EXAMPLE 55

(S)-2,10-di(hydroxyethoxy)-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo [a,g] quinolizine (Class I-B)

(145) ##STR00081##

(146) DMF (3 ml), potassium carbonate (1.26 g, 9.1 mmol), bromoethanol (0.13 ml, 1.82 mmol), potassium iodide (75 mg, 0.45 mmol) were added into l-SPD (300 mg, 0.91 mmol). The reaction was performed at 120° C. for 3 h. The resultant was extracted with dichloromethane, and washed three times with water. DMF was washed off, and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected. to column chromatography to obtain the title compound (10 mg, yield: 2%). .sup.1H NMR (300 Hz, DMSO-d.sub.6) δ 2.85 (d, 1H), 3.01 (t, 1H), 3.35 (m, 2H), 3.64-3.88 (m, 12H), 4.00 (m, 4H), 4.36 (dd, 4.60 (m, 2H), 4.92 (brs, 2H), 6.81 (s, 1H), 6.97 (d, 1H), 7.02 (s, 1H), 7.06 (d, 1H). ESI-MS m/z 416.0 (M+H).sup.+.

EXAMPLE 56

(S)-2,3,10-trimethoxy-9-hydroxyethoxy-6.8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-C)

(147) ##STR00082##

(148) The title compound was prepared from 19-b and bromoethanol, with reference to the method for synthesizing the product of Example 55. That is, l-SPD was replaced with 19-b. The yield: 44%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 2.56-2.74 (m, 2H), 2.83 (dd, 1H), 3.06-3.33 (m, 3H), 3.56 (d, 2H), 3.80-3.95 (m, 11H), 3.99-4.20 (m, 2H), 4.27 (d, 1H), 6.61 (s, 1H), 6.72 (s, 1H), 6.79 (d, 1H), 6.91 (d, 1H), ESI-MS m/z 386.0 (M+H).sup.+.

EXAMPLE 57

(S)-2,3,10-trimethoxy-9-cyclopropoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine hydrochloride (Class I-C)

(149) ##STR00083##

(150) The title compound was prepared from 19-b and bromocyclopropane, with reference to the method for synthesizing the product of Example 53. That is, 1-c was replaced with 19-b. The yield: 65%. .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 0.53 (m, 2H), 0.77 (m, 2H), 2.86 (d, 1H), 3.04 (dd, 1H), 3.37 (m, 2H), 3.76 (s, 3H), 3.78 (s, 3H), 3.80-3.90 (m, 5H), 4.25 (dd, 1H), 4.34 (m, 1H), 4.41 (d, 1H), 4.66 (t, 1H), 6.82 (s, 1H), 7.02 (s, 1H), 7.03 (d, 1H), 7.10 (d, 1H), 11.59 (brs, 1H). ESI-MS m/z 382.1 (M+H).sup.+.

EXAMPLE 58

(S)-2,3,10-trimethoxy-9-cyclopentyloxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-C)

(151) ##STR00084##

(152) The title compound was prepared from 19-b and bromocyclopropane, with reference to the method for synthesizing the product of Example 54. That is, 1-c was replaced with 19-b. The yield: 33%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ 1.85 (m, 8H), 2.55-2.73 (m, 2H), 2.84 (dd, 1H), 2.06-3.30 (m, 3H), 3.51 (m, 2H), 3.82 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 4.20 (d, 1H), 4,95 (m, 1H), 6.61 (s, 1H), 6.73 (s, 1H), 6.77 (d, 1H), 6.84 (d, 1H). ESI-MS m/z 410.3 (M+H).sup.+.

EXAMPLE 59

(S)-2,3,9-trimethoxy-10-cyclopropoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-D)

(153) ##STR00085## Step 1:

(154) 1-a (500 mg, 1.20 mmol) was dissolved in DMF (8 ml). Thereto, cesium carbonate (782 mg, 2.40 mmol) and bromocyclopropane (0.12 ml, 1.80 mmol) were added. The mixture was stirred at 150° C. for 3 h. DMF was distilled off, and the resultant was extracted with dichloromethane-water, washed with saturated saline solution, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give 59-a (356 mg, yield: 65%). Step 2:

(155) 59-a (300 mg, 0.65 mmol) was dissolved in ethanol (4 mL). Thereto, 2 ml of concentrated hydrochloric acid was added. The reaction was performed at 100° C. for 1 h. The solvent was directly distilled off to obtain compound 59-b (233 mg, yield: 88%). Step 3:

(156) 59-b (200 mg, 0.49 mmol) was dissolved in acetone (4 mL). Thereto, dimethyl sulfate (0.070 mL, 0.74 mmol) and sodium hydroxide (80 mg, 1.98 mmol) were added. The reaction was performed at room temperature for 6 h while stirring. The resultant was extracted with dichloromethane, and washed with a saturated ammonium chloride solution. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to obtain the title compound (155 mg, yield: 82%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 0.55-0.81 (m, 4H), 2.35-2.69 (m, 3H), 2.83-3.16 (m, 3H), 3.34 (m, 2H), 3.68 (s, 3H), 3.73 (d, 6H), 3.85 (m, 1H), 4.04 (d, 1H), 6.67 (s, 1H). 6.86 (s, 1H), 6.89 (d, 1H), 7.13 (d, 1H). ESI-MS m/z 382.3 (M+H).sup.+.

EXAMPLE 60

(S)-2-methanesulfonylamino-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine (Class I-A)

(157) ##STR00086##

(158) The product of Example 13 (40 mg) was added to 2 ml of dichloromethane, and one drop of pyridine (about 1.5 eq) was added thereto. One drop of methanesulfonyl chloride (about 1.5 eq) was added dropwise under an ice bath. The mixture was kept in an ice bath for 10 minutes while stirring, and moved to room temperature for reaction for 3 hours. The system was extracted with dichloromethane and water, washed with saturated brine, dried and concentrated to obtain 40 mg of a crude product. The residue was subjected to column chromatography (eluent: DCM/MeOH=100:1) to obtain the title compound (20 mg). ESI-MS m/z 419.24 (M+H).sup.+.

(159) Pharmacological Experiments

(160) 1) D.sub.1 antagonistic activity test

(161) LANCE™ cAMP 384 Kit (PerkinElmer, USA) was used to test the antagonism of the compound against the D.sub.1 receptor using the HEK293 cells expressing human recombinant D.sub.1 receptor. The D.sub.1 antagonism of the compound was evaluated by testing the antagonistic action of the compounds against dopamine on the induction of cAMP production in HEK293 cells. The cAMP concentration test was performed according to the method described in the kit instructions. The test concentration of the compound was 0.1 nM to 10000 nM. SCH23390 was used as a positive control. The IC.sub.50 was calculated by Excelfit software. The test results of some compounds were shown in Table 1. 2) D.sub.2 antagonistic activity test

(162) LANCE™ cAMP 384 Kit (PerkinElmer, USA) was used to test the antagonism of the compound against the D.sub.2 receptor using the HEK293 cells expressing human recombinant D.sub.2 receptor. The D.sub.2 antagonism of the compound was evaluated by testing the antagonistic action of the compounds against dopamine on the inhibition of cAMP production in HEK293 cells. The cAMP concentration test was performed according to the method described in the kit instructions. The test concentration of the compound was 0.1 nM to 10000 nM. Risperidone was used as a positive control. The IC.sub.50 was calculated by Excelfit software. The test results of some compounds were shown in Table 1 (ND means the test was not performed).

(163) TABLE-US-00001 TABLE 1 D.sub.1 Antagonistic D.sub.2 Antagonistic Activity Activity Test Compound (IC.sub.50, nmol/L) (IC.sub.50, nmol/L) Compound of Example 1 34.9 620 Compound of Example 2 ND 280 Compound of Example 4 310 950 Compound of Example 5 170 35 Compound of Example 6 49 210 Compound of Example 7 61 770 Compound of Example 11 500 750 Compound of Example 12 240 500 Compound of Example 13 140 280 Compound of Example 15 120 550 Compound of Example 17 240 150 Compound of Example 18 390 610 Compound of Example 19 1300 ND Compound of Example 21 1500 ND Compound of Example 24 1300 ND Compound of Example 25 1700 2300 Compound of Example 26 ND 940 Compound of Example 27 311 1000 Compound of Example 28 2160 ND Compound of Example 29 ND 2500 Compound of Example 30 1080 510 Compound of Example 32 ND 663 Compound of Example 33 270 440 Compound of Example 36 26.2 427 Compound of Example 37 211 19 Compound of Example 38 3400 620 Compound of Example 40 4.0 27 Compound of Example 41 ND 20 Compound of Example 42 31.1 291 Compound of Example 43 ND 54 Compound of Example 44 672 139 Compound of Example 45 116 ND Compound of Example 46 378 184 Compound of Example 47 19.9 146 Compound of Example 49 219 ND Compound of Example 50 855 ND Compound of Example 51 ND 390 Compound of Example 52 220 450 Compound of Example 53 960 1300 Compound of Example 55 443 ND Compound of Example 56 1050 2800 Compound of Example 60 525 6.2 l-SPD 7.7 37 Positive Control 0.92 2.8 3) 5-HT.sub.1A agonistic activity test

(164) LANCE™ cAMP 384 Kit (PerkinElmer, USA) was used to test the agonistic effect of the compound on 5-HT.sub.1A receptor using the HEK293 cells expressing human recombinant 5-HT.sub.1A receptor. The 5-HT.sub.1A agonistic effect of the compound was evaluated by testing the the inhibitory effect of the compound on cAMP production in HEK293 cells. The cAMP concentration test was performed according to the method described in the kit instructions. The test concentration of the compound was 0.1 nM to 10000 nM. 8-OH-DPAT was used as a positive control. The EC.sub.50 was calculated by Excelfit software. The results were shown in Table 2.

(165) TABLE-US-00002 TABLE 2 5-HT.sub.1A Agonistic Activity Test Compound (EC.sub.50, nmol/L) Compound of Example 5 450 Compound of Example 11 1700 Compound of Example 12 2300 Compound of Example 14 514 Compound of Example 21 238 Compound of Example 23 1900 Compound of Example 27 1200 Compound of Example 35 5900 Compound of Example 37 3030 Compound of Example 38 4580 Compound of Example 56 150 Compound of Example 57 110 Positive Control 12.0

(166) It can be seen from the above that the tested compounds have good antagonistic activity on the dopamine D.sub.1 and D.sub.2 receptors, and have an agonistic effect on the 5-HT.sub.1A receptor. They can be used to prepare a medicament for treating the central nervous system disease, especially D.sub.1, D.sub.2, 5-HT.sub.1A receptor-related diseases.

(167) Efficacy Tests

(168) 1) Sedative and Hypnotic Effects

(169) The sedative and hypnotic effects of Example 60 were evaluated using a model of insomnia induced by injection with 4-Chlorophenylalanine (PCPA) in rats. The results were shown in FIGS. 1 to 2.

(170) Dosage and method of administration: PCPA was administered at a dose of 150 mg/kg. PCP was administered by a single intraperitoneal injection at 72 hours before the experiment in all Wistar rats. The diazepam group (DI) was administered at a dose of 2 mg/kg and 4 mg/kg, a single intraperitoneal injection; the test drug group was administered at a dose of 1 mg/kg and 3 mg/kg, a single intragastric administration; sodium pentobarbital was administered at a dose of 25 mg/kg, a single intraperitoneal injection. The administration volume was 10 ml/kg. On the day of the test, the model group was given sodium pentobarbital 30 minutes after the same volume of physiological saline was given; the DI group was given sodium pentobarbital 30 minutes after DI was administered; the test drug group was given sodium pentobarbital 60 minutes after the drug was administered.lndex observation: After the administration of sodium pentobarbital, the rats' response was closely observed. The time from the administration to 1 minute after the righting reflex disappeared is the sleep latency. The time from 1 minute after the righting reflex disappeared to the point that the righting reflex returned is sleep time. It can be seen from FIGS. 1-2 that Example 60 can significantly prolong the sleep time of model rats at a dose of 1 mg/kg, and can significantly reduce the sleep latency and prolong the sleep time of insomnia rats induced by PCPA at a dose of 3 mg/kg. Example 60 had a good hypnotic effect. 2) PCP-induced high spontaneous activity test in mice

(171) PCP (phencylidine) was dissolved in physiological saline to prepare a 7 mg/kg solution. The test compound was formulated with a 0.5% CMC-Na solution to a solution with suitable concentration, ready-to-use. Male ICR mice were 18-22 g. Mice were randomly divided into a solvent control group, a model control group, a positive control group, and each test drug group during the test. There were 8 mice in each group. Mice in each group were given each test drug by gavage. 45 minutes after the test drug was administered, mice were injected with a PCP (7 mg/kg) solution intraperitoneally. The spontaneous, open field video analysis system was used to record the mouse movement trajectory within 45 min after administration of test drug or saline, and then the mouse movement trajectory within 75 min after PCP administration. Spontaneous, open field video analysis system was used to analyze the mouse's movement trajectory, and the total distance of the movement of the mice in each group was counted. The result was expressed as mean±SD. Results were analyzed by one-way analysis of variance.

(172) After administration of PCP, the spontaneous activity of mice increased significantly compared with the physiological saline group. The test compounds at the following doses (Table 3) can significantly reduce the high spontaneous activity of mice induced by PCP, which is significantly different from the model group. The compound of the present invention is orally effective, its effective dose is lower than that of l-stepholidine, and its efficacy is maintained for a long time. However, l-stepholidine has a high effective dose, fast metabolism, and short duration of effect.

(173) TABLE-US-00003 TABLE 3 Test Compound Effective Dose (mg/kg) Compound of Example 1 20 Compound of Example 2 20 Compound of Example 5 10 Compound of Example 7 10 Compound of Example 11 10 Compound of Example 13 10 Compound of Example 14 10 Compound of Example 17 20 Compound of Example 18 20 Compound of Example 19 20 Compound of Example 21 20 Compound of Example 25 20 Compound of Example 33 20 Compound of Example 34 20 Compound of Example 36 10 Compound of Example 40 20 Compound of Example 41 3 Compound of Example 42 10 Compound of Example 46 10 Compound of Example 47 10 Compound of Example 49 10 Compound of Example 50 10 Compound of Example 52 20 Compound of Example 53 20 Compound of Example 56 20 Compound of Example 57 20 l-stepholidine >100