Diaryl[A, G]quinolizidine compound, preparation method therefor, pharmaceutical composition, and uses thereof

Abstract

The present invention relates to a diarylo[a,g]quinolizidine compound of formula (I), enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof; the preparation method thereof, and uses thereof in preparing an experimental model drugs related to dopamine receptors and 5-HT receptors or a medicament for treating or preventing a disease related to dopamine receptors and 5-HT receptors. ##STR00001##

Claims

1. A diarylo[a,g]quinolizine compound of formula (I), an enantiomer, a diastereoisomer, a racemate, a mixture, a pharmaceutically acceptable salt, a crystalline hydrate or a solvate thereof: ##STR00166## wherein ring A is one selected from the group consisting of benzene ring, pyrrole ring, furan ring, thiophene ring, pyridine ring, benzoxazole ring, benzofuran ring and indole ring; ring D is one selected from the group consisting of benzene ring, pyrrole ring, furan ring, thiophene ring, pyridine ring, benzoxazole ring and benzofuran ring; the rings A and D are not simultaneously benzene ring, and ring A is not an indole ring when ring D is a benzene ring; R.sup.5 and R.sup.10 each independently represent 1 to 4 substituents selected from the group consisting of halogen, C1-C6 straight or branched alkyl unsubstituted or substituted with 1-3 halogens, C3-C6 cycloalkyl unsubstituted or substituted with 1-3 halogens, C1-C6 straight or branched alkyl substituted with a C 1-C6 alkoxy, C1-C6 straight or branched alkyl substituted with a C3-C6 cycloalkyl, OR.sup.6, NR.sup.6R.sup.7, OR.sup.9OR.sup.6, OR.sup.9NR.sup.6R.sup.7, R.sup.9COOR.sup.6, R.sup.9CONR.sup.6R.sup.7, R.sup.9OR.sup.6, R.sup.9NR.sup.6R.sup.7, and N(R.sup.6)SO.sub.2R.sup.7, alternatively, any two adjacent R.sup.5s or adjacent R.sup.10s, together with the carbon atom or the heteroatom to which they are adjacent, may form a 5-7 membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; R.sup.1, R.sup.2and R.sup.3 are each independently hydrogen, halogen, hydroxy, oxo (O), or C1-C6 straight or branched alkyl unsubstituted or substituted with 1-3 halogens, R.sup.4 is hydrogen, halogen, hydroxy, or C1-C6 straight or branched alkyl unsubstituted or substituted with 1-3 halogens, R.sup.6 and R.sup.7 are each independently hydrogen, or C1-C6 straight or branched alkyl unsubstituted or substituted with 1-3 halogens or hydroxys, R.sup.9 is C1-C6 straight or branched alkylene; the halogen is F, Cl or Br; and the chiral carbon atom in the compound of formula (I) may be on R- or S- configuration.

2. A diarylo[a,g]quinolizine compound, enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof, wherein the diarylo[a,g]quinolizine compound is ##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182## ##STR00183## ##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193##

3. A process of preparing the diarylo[a,g]quinolizine compound, enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof according to claim 1, wherein the process is carried out as any one of the following methods: ##STR00194## ##STR00195## the method A comprises: a) reacting a1 with a2 through an amino-ester exchange reaction in a polar protic solvent to give a3, b) reacting a3 with an acylating agent through an acylation reaction in the presence of a base to give a4; c) dehydrlating and cyclizing a4 in the presence of a condensing agent to give a5; d) asymmetrically reducing a5 in the presence of a hydrogenation reagent and a chiral catalyst to give a6; e) hydrolyzing a6 in the presence of a base to give a7; f) halogenating a7 with a halogenating reagent, and then directly cyclizing it in the presence of a base to give a8; g) optionally, when a8 has a protective group to be removed, a8 is deprotected to remove the protective group; ##STR00196## the method B comprises: 1) reacting a1 with b2 by a condensation reaction in the presence of a condensing agent to give b3; 2) dehydrlating and cyclizing b3 in the presence of a condensing agent to give b4; 3) asymmetrically reducing b4 in the presence of a chiral catalyst and a hydrogenation reagent to give b5; and 4) reacting b5 with a substituted aldehyde R.sup.4CHO through a Pictet-Spengler reactionunder an acidic condition to give b6; In the above methods A and B, rings A and D as well as the substituents are defined the same as those in claim 1.

4. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the diarylo[a,g]quinolizine compound, enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof according to claim 1, and one or more pharmaceutically acceptable carriers.

5. A method for treating a disease related to dopamine receptors and 5-HT receptors in a subject, wherein the disease related to dopamine receptors and 5-HT receptors is schizophrenia, Parkinson's disease, mania, depression, drug addiction or migraine, comprising: administering to the subject an effective amount of the diarylo[a,g]quinolizine compound, enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof according to claim 1.

Description

BEST MODE FOR CARRYING OUT THE INVENTION

(1) The present invention will be further illustrated in the following examples. However, the following examples are merely provided for illustration, and the present invention is not limited to the following examples in any manner. Unless otherwise stated, all of the parameters and other description in the following examples are based on mass.

EXAMPLE 1

(S)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS001)

1.1 Preparation of 2-(2-nitrovinyl)thiophene

(2) 1.5 g of 2-thienal was dissolved in 10 mL of glacial acetic acid, added with 2 equivalent of ammonium acetate, and then with 5 equivalent of nitromethane at room temperature. The mixture was placed in an oil bath at 80 C. and kept for 10 hours. TLC monitoring showed that the starting material disappeared. The reaction mixture was cooled to room temperature, distilled off most of the solvent, adjusted with saturated NaHCO.sub.3 to be neutral, and extracted triply with dichloromethane. The organic phase was combined and distilled off the organic solvent. 1.89 g of yellow solid product was obtained by column chromatography. Yield, 91%.

(3) .sup.1H NMR (CDCl.sub.3, 300 MHz): 8.15 (d, J=13.2 Hz, 1H), 7.84 (d, J=13.2 Hz, 1H,) 7.65 (d, J=4.2 Hz, 1H), 7.15 (dd, J=4.2 Hz, 3.8 Hz, 1H), 7.01 (d, J=4.2 Hz, J=3.8 Hz, 1H). ESI-MS m/z: 156.0 [M+H].sup.+.

1.2 Preparation of thiophene-2-ethylamine

(4) 1.89 g of 2-(2-nitrovinyl)thiophene was dissolved in anhydrous tetrahydrofuran, added with 4 equivalent of Lithium aluminum hydride in four batches under ice bath, and refluxed over night. The solvent was evaporated, and a small amount of water was added to extinct the reaction. The solid was removed by filtration, and washed with dichloromethane. The filtrate was dried over anhydrous sodium sulphate, and the solvent was evaporated to obtain 1.42 g of oily product. Yield, 92%.

(5) .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.24 (dd, 1H, J=5.1 and 1.3 Hz), 6.96 (dd, J=5.1 and 1.3 Hz, 1H), 6.89 (d, 1H, J=3.3 Hz), 3.09-3.23 (m, 4H). ESI-MS m/z: 128.2 [M+H].sup.+.

1.3 Preparation of methyl 3-bromo-4-hydroxyphenylacetate

(6) 4.88 g of methyl p-hydroxyphenylacetate was dissolved in acetic acid, and liquid bromine (1.1 eq) in acetic acid was dropwisely added in to the above solution. The reaction was preformed at room temperature and monitored by TLC. After the reaction was completed, saturated aqueous solution of Na.sub.2S.sub.2O.sub.3 was added to remove excess Br.sub.2, and then part of acetic acid was evaporated, and the solution was extracted several times until there was no product in aqueous phase. The organic phase was washed with saturated brine, dried over anhydrous sodium sulphate, and distilled off the solvent to give 6.3 g of white solid product. Yield, 88%.

(7) .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.39 (d, J=1.5 Hz, 1H), 7.11 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 3.70 (s, 3H), 3.54 (s, 2H). ESI-MS m/z: 246.0 [M+H].sup.+.

1.4 Preparation of methyl 3-bromo-4-benzyloxyphenylacetate

(8) Methyl 3-bromo-4-hydroxyphenylacetate and K.sub.2CO.sub.3(1.5 eq) were dissolved in acetone, and BnBr (1.05 eq) was added thereto. The reaction was performed under refluxing and monitored by TLC. After the reaction was completed, the solid in the reaction solution was removed by filtration, and the solvent was evaporated off to give methyl 3-bromo-4-benzyloxyphenylacetate without further purification.

(9) .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.51-733 (m, 6H), 7.15 (dd, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 5.15 (s, 2H), 3.70 (s, 3H), 3.55 (s, 2H). ESI-MS m/z: 336.1 [M+H]+.

1.5 Preparation of 3-hydroxy-4-benzyloxy phenylacetic acid

(10) Methyl 3-bromo-4-benzyloxyphenylacetate (1.5 g), KOH (1.5 g), copper powder (0.15 g), and CuO powder (0.15 g) were dispersed in 8 mL of water, agitated at room temperature for 10 min, and degassed ultrasonically. The reaction was performed at 140 C. under microwave for 45 min. After the reaction was completed, Cu and CuO were removed by filtration, and pH was adjusted with concentrated HCl to be acidic to precipitate a white solid, which was filtered to give crude 3-hydroxy-4-benzyloxyphenylacetic acid. The solid was dissolved in methanol, added with an appropriate amount of active carbon, refluxed for 30 minutes and decolored. Purification by column chromatography gave a white solid. Yield, 56%.

(11) .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.43-7.38 (m, 5H), 6.90 (s, 11-1), 6.89 (dd, J=8.1 Hz, J=2.1 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 5.10 (s, 2H), 3.56 (s, 2H). ESI-MS m/z: 273.2 [M+H].sup.+.

1.6 Preparation of 7-benzyloxy-8-hydroxy-3-isochromanone

(12) 3-hydroxy-4-benzyloxyphenylacetic acid (3.0 g) and phenylboronic acid (3.0 g) were dissolved in redistilled toluene (60 mL), and refluxed at 110 C. for 1 hour. The produced water was removed by an oil-water separation device. Paraformaldehyde (3 g) and an appropriate amount of molecular sieve (4 ) were added into a pressure bottle, and the hot reaction mixture was poured into the pressure bottle. The reaction was performed at 100 C. for 46 hours. After the reaction was completed, the hot reaction mixture was filtered to remove the molecular sieve, and filtrate was evaporated to dryness to obtain a yellowish solid. 75 mL water was added thereto, and the reaction was performed under refluxing at 100 C. for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and extracted with dichloromethane several times. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulphate, and distilled off the solvent to give a crude 7-benzyloxy-8-hydroxy-3-isochromanone. The crude was added with 35 mL of anhydrous ethyl ether, agitated at room temperature for 3 hours and filtered to give the target product as a white solid.

(13) .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.45-7.34 (m, 5H), 6.93 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 5.40 (s, 1H), 5.12 (s, 1H), 3.91 (s, 3H), 3.62 (s, 2H). ESI-MS m/z: 271.1 [M1-1].sup.+.

1.7 Preparation of 7-benzyloxy-8-methoxy-3-isochromanone

(14) 7-methoxy-8-hydroxy-3-isochromanone (1.5 g) and K.sub.2CO.sub.3(3 eq) were dissolved in acetone in a flask, added with CH.sub.3I (3 eq), and heated under refluxing for 2 hours. TLC was used to monitor the reaction. After the reaction was completed, the solid in reaction mixture was removed by filtration, the filtrate was evaporated to dryness, and the residue was passed through a silica column to give 7-benzyloxy-8-methoxy-3-isochromanone.

(15) .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.45-7.34 (m, 5H), 6.92 (d, J=8.2 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 5.40 (s, 2H), 5.12 (s, 2H), 3.91 (s, 3H), 3.62 (s, 2H). ESI-MS m/z: 285.1 [M+H].sup.+.

1.8 Preparation of N-(thiophene-2-ethyl)-2-hydroxy-3-methoxy-4-benzyloxyphenylace tamide

(16) 7-benzyloxy-8-methoxy-3-isochromanone and thiophene-2-ethylamine were dissolved in an appropriate amount of ethanol, and the mixture was agitated under refluxing overnight. The reaction was monitored by TLC. After the reaction was completed, the mixture was cooled, and evaporated to dryness, and the residue was passed through a silica column to give a white solid product. Yield, 84%.

(17) .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.45-7.25 (m, 6H), 6.82-6.85 (m, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.4, 1H), 5.12 (s, 2H), 4.65 (s, 2H), 3.79 (s, 3H), 3.60 (s, 2H), 3.39 (t, J=6.8 Hz, 2H), 2.65 (t, J=6.8 Hz, 2H). ESI-MS m/z: 412.1 [M+H].sup.+.

1.9 Preparation of N-(thiopheneethyl)-2-acetoxy-3-methoxy-4-benzyloxyphenylacetamide

(18) N-(thiopheneethyl)-2-hydroxy-3-methoxy-4-benzyloxyphenylacetamide was dissolved in a small amount of anhydrous dichloromethane, added with pyridine (3 eq) and a catalytic amount of DMAP, followed by dropwise addition of acetyl chloride in ice bath. After the addition, the ice bath was removed and the reaction was preformed at room temperature. After the reaction was completed, the reaction mixture was washed with 1 N HCl, and extracted. The organic phase was dried, evaporated to dryness. And the reissue was purified by column chromatography to give a white solid. Yield, 92%.

(19) .sup.1H NMR (CDCl.sub.3, 300 MHz): 7.45-7.25 (m, 6H), 6.82-6.85 (m, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.64 (d, J=8.4, 1H), 5.12 (s, 2H), 5.10 (s, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.42 (t, J=7.0 Hz, 2H), 2.65 (t, J=7.0 Hz, 2H), 2.00 (s, 3H). ESI-MS m/z: 454.1 [M+H].sup.+.

1.10 Preparation of 2-methoxy-3-benzyloxy-6-((6,7-dihydro-thieno[3,2-c]pyridin-4-yl)-methyl)-benzyl acetate

(20) N-(thiopheneethyl)-2-acetoxy-3-methoxy-4-benzyloxyphenylacetamide (1.19 g) was dissolved in an appropriate amount of anhydrous acetonitrile and refluxed, followed by addition of POCl.sub.3 (3 eq). The reaction was preformed under nitrogen for 0.5 hour and monitored by TLC. The reaction mixture was evaporated to dryness, and the residue was dissovled in a small amount of dichloromethane, added with saturated NaHCO.sub.3 aqueous solution to be adjusted to be alkaline, and extracted triply with dichloromethane. The organic phase was washed with saturated brine, dried over sodium sulphate, and evaporated to dryness to give yellow oily crude without further purification.

(21) ESI-MS m/z: 436.1 [M+H].sup.+.

1.11 Preparation of (S)-2-methoxy-3-benzyloxy-6-((4,5,6,7-tetrahydro-thieno(3,2-c)pyridin-4-yl)-methyl)-benzyl acetate

(22) The product (1.07 g) of last step was dissolved in a small amount of DMF (5 ml), added with a catalyst (R,R)-Noyori (0.02 eq), and then with a mixture of formic acid/triethanolamine (0.5 ml/0.2 ml/1 mmol raw material). The reaction was preformed at room temperature for about 8 hours. After the reaction was completed, the reaction mixture was added with saturated NaHCO.sub.3 aqueous solution to be adjusted to be alkaline, added with a large amount of water, and extracted triply with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulphate and evaporated to dryness to give a dark green solid. In the case that (S,S)-Noyori was used to catalyze the reaction, a product in R-configuration was obtained.

(23) ESI-MS m/z: 438.1 [M+H].sup.+.

1.12 Preparation of (S)-2-methoxy-3-benzyloxy-6-((4,5,6,7-tetrahydro-thieno(3,2-c)pyridin-4-yl)-methyl)-benzyl alcohol

(24) The product (1.21 g) of last step was dissolved in a mixture of ethanol (6 mL) and water (2 mL) and stirred at room temperature, followed by addition of NaOH (170 mg, 2 eq). The reaction was preformed for about 2 hours. After that, the reaction mixture was evaporated to remove part of the solvent, and extracted triply with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulphate and evaporated to dryness to give a light green solid.

(25) ESI-MS m/z: 396.1 [M+H].sup.+.

1.13 Preparation of (S)-4-(2-chloromethyl-3-methoxy-4-benzyloxy)-4,5,6,7-tetrahydro-thieno(3,2-c)pyridine

(26) The product (1.03 g) of last step was dissolved in redistilled dichloromethane (10 mL) an agitated at room temperature, followed by slow and dropwise addition of thionylchloride (4 eq). After addition, the reaction was preformed for 2 hours at room temperature.

(27) ESI-MS m/z: 324.9 [M+H].sup.+.

1.14 Preparation of (S)-8-methoxy-9-benzyloxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine

(28) The reaction mixture of last step was added with saturated NaHCO.sub.3 solution to adjust its pH to be alkaline, and stirred at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction mixture was extracted triply with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by column chromatography to give the target product.

(29) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.5-7.28 (m, 5H), 7.21 (d, J=5.4 Hz, 1H), 6.88 (d, J=5.4 Hz, 1H), 6.64 (d, J=8.1, 1H), 6.58 (d, J=8.1, 1H), 5.00 (s, 2H), 4.16 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.56-3.45 (m, 2H), 3.25-3.10 (m, 3H), 2.88-2.80 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 378.1 [M+H].sup.+.

1.15 Preparation of (S)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS001)

(30) To (S)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine, were added ethanol (5 mL) and concentrated HCl (10 mL), and the mixture was refluxed at 90 C. for 2 hours. After the reaction was completed, the reaction mixture was evaporated to remove most of the HCl aqueous solution, neutralized with saturated NaHCO.sub.3 aqeuous solution to be alkaline, and extracted several times with dichloromethane until there was no product in the aqueous phase. Purification by column chromatography gave the product AS001.

(31) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.24 (d, J=5.4 Hz, 1H), 6.86 (d, J=5.4 Hz, 1H), 6.62 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 3.91 (d, J=14.8 Hz, 1H), 3.81 (s, 3H), 3.66 (dd, J=10.8 Hz, J=3.9 Hz, 1H), 3.53 (d, J=14.5 Hz, 1H), 3.27-3.21 (m, 1H), 3.14-3.04 (m, 2H), 2.82-2.70 (m, 3H). ESI-MS m/z: 288.0 [M+H].sup.+.

EXAMPLE 2

(R)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS002)

(32) The titled product was prepared by the same procedure as that in example 1, except that (S,S)-Noyori catalyst was used to replace (R,R)-Noyori.

(33) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.21 (d, J=5.4 Hz, 1H), 6.85 (d, J=5.4 Hz, 1H), 6.62 (d, J=8.1, 1H), 6.55 (d, J=8.1, 1H), 3.92 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.55 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 288.0 [M+H].sup.+.

EXAMPLE 3

(S)-2-methyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS003)

(34) The titled product was prepared by the same procedure as that in example 1, except that 5-methylthiophene-2-aldehyde was used to replace thiophene-2-aldehyde.

(35) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.14 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.37 (s, 3H). ESI-MS m/z: 302.0 [M+H].sup.+.

EXAMPLE 4

(R)-2-methyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS004)

(36) The titled product was prepared by the same procedure as that in example 2, except that 5-methylthiophene-2-aldehyde was used to replace thiophene-2-aldehyde.

(37) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.0, 1H), 6.55 (d, J=8.0, 1H), 6.14 (s, 1H), 3.92 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.66 (dd, J=10.8 Hz, J=3.9 Hz, 1H), 3.56 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.23-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.37 (s, 3H). ESI-MS m/z: 288.0 [M+H].sup.+.

EXAMPLE 5

(S)-2-ethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS005)

(38) The titled product was prepared by the same procedure as that in example 1, except that 5-ethylthiophene-2-aldehyde was used to replace thiophene-2-aldehyde.

(39) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.14 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.26 (t, J=7.2 Hz, 3H). ESI-MS m/z: 316.0 [M+H].sup.+.

EXAMPLE 6

(S)-2-n-propyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS006)

6.1 Preparation of 2-propionyl thiophene

(40) 1 g of thiophene was dissolved in 10 mL of anhydrous dichloromethane, added with 1.2 eq of propionylchloride at 0 C. under nitrogen, and then with 1.5 eq of anhydrous AlCl.sub.3 in batches. The reaction was preformed at 0 C. for 1.5 hours, and monitored by TLC. The reaction mixture was treated with an icy 1N HCl under stirring and extracted with dichloromethane. The organic phase was evaporated to dryness to give oily 2-propionylthiophene (1.65 g). Yield, about 100%.

(41) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.70 (d, J=4.0 Hz, 1H), 7.64 (d, J=5.0 Hz, 1H), 7.13 (dd, J=4.0, J=5.0 Hz, 1H), 2.94 (q, J=7.2 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H). ESI-MS m/z: 142.2 [M+H].sup.+.

6.2 Preparation of 2-n-propylthiophene

(42) 2-propionylthiophene (1.5 g) was dissolved in trifluoroacetic acid (10 mL) at 0 C., added with 4 eq of triethyl silane, and stirred at room temperature overnight. Purification by column chromatography gave 2-n-propylthiophene. Yield, 92%.

(43) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.10 (d, J=4.0 Hz, 1H), 6.91 (dd, J=4.0, J=5.0 Hz, 1H), 6.78 (d, J=5.0 Hz, 1H), 2.79 (t, J=7.4 Hz, 2H), 1.69 (m, 2H), 0.90 (t, J=7.4 Hz, 3H). ESI-MS m/z: 127.0 [M+H].sup.+.

6.3 Preparation of 5-n-propylthiophene-2-aldehyde

(44) 2-n-propylthiophene was dissolved in anhydrous dichloromethane at 0 C., and slowly added with titanium tetrachloride and dichloromethylether. The reaction was preformed at 0 C. to room temperature for about 1 hour. TLC showed that the reaction was completed. The reaction mixture was treated with ice water under agitating, and extracted with dichloromethane. The organic phase was evaporated to dryness to give 5-n-propyl thiophene-2-aldehyde.

(45) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.70 (d, J=5.0 Hz, 1H), 6.91 (d, J=5.0 Hz, 1H), 2.66 (t, J=7.4 Hz, 2H), 1.60 (m, 2H), 0.91 (t, J=7.4 Hz, 3H). ESI-MS m/z: 155.1 [M+H].sup.+.

(46) The following procedure was conducted the same as that in example 1 to give the title product, except that 5-n-propylthiophene-2-aldehyde was used to replace thiophene-2-aldehyde.

(47) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.14 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.60 (m, 2H), 0.91 (t, J=7.2 Hz, 3H). ESI-MS m/z: 330.0 [M+H].sup.+.

EXAMPLE 7

(S)-2-n-butyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS007)

(48) The titled product was prepared by the same procedure as that in example 6, except that n-butyrylchloride was used to replace propionylchloride.

(49) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.0, 1H), 6.51 (d, J=8.0, 1H), 6.14 (s, 1H), 3.95 (d, J=14.4 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.58 (m, 2H), 1.33 (m, 2H), 0.86 (t, J=7.2 Hz, 3H). ESI-MS m/z: 344.0 [M+H].sup.+.

EXAMPLE 8

(S)-2-n-amyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS008)

(50) The titled product was prepared by the same procedure as that in example 6, except that valerylchloride was used to replace propionylchloride.

(51) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.0, 1H), 6.50 (d, J=8.0, 1H), 6.14 (s, 1H), 3.95 (d, J=14.4 Hz, 1H), 3.83 (s, 3H), 3.71 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.55 (d, J=14.4 Hz, 1H), 3.30-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.58 (m, 2H), 1.33-1.28 (m, 4H), 0.86 (t, J=7.2 Hz, 3H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 9

(S)-2-(2-methylpropyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS009)

(52) The titled product was prepared by the same procedure as that in example 6, except that 2-methylpropionylchloride was used to replace propionylchloride.

(53) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.0, 1H), 6.51 (d, J=8.0, 1H), 6.14 (s, 1H), 3.95 (d, J=14.4 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.63 (m, 1H), 0.86 (t, J=7.2 Hz, 6H). ESI-MS m/z: 344.0 [M+H].sup.+.

EXAMPLE 10

(S)-2-(3-methylbutyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS010)

(54) The titled product was prepared by the same procedure as that in example 6, except that 3-methylbutyrylchloride was used to replace propionylchloride.

(55) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.0, 1H), 6.51 (d, J=8.0, 1H), 6.14 (s, 1H), 3.95 (d, J=14.4 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.65-1.60 (m, 3H), 0.86 (t, J=7.2 Hz, 6H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 11

(S)-2-cyclopropylmethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS011)

(56) The titled product was prepared by the same procedure as that in example 6, except that 2-cyclopropylformylchloride was used to replace propionylchloride.

(57) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.14 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 3H), 2.55 (m, 2H), 0.94-1.27 (m, 1H), 0.51-0.55 (m, 2H), 0.19-0.47 (m, 2H). ESI-MS m/z: 342.0 [M+H].sup.+.

EXAMPLE 12

(S)-2-cyclobutylmethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS012)

(58) The titled product was prepared by the same procedure as that in example 6, except that 2-cyclobutylformylchloride was used to replace propionylchloride.

(59) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 3H), 2.62 (m, 2H), 2.34 (m, 1H), 2.05-1.78 (m, 6H). ESI-MS m/z: 356.1 [M+H].sup.+.

EXAMPLE 13

(S)-2-(2,2-dimethylpropyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS013)

(60) The titled product was prepared by the same procedure as that in example 6, except that 2,2-dimethylpropionylchloride was used to replace propionylchloride.

(61) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 3H), 2.45 (s, 2H), 0.98 (s, 9H). ESI-MS m/z: 358.1 [M+H].sup..

EXAMPLE 14

(S)-2-(2,2-dimethylbutyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS014)

(62) The titled product was prepared by the same procedure as that in example 6, except that 2,2-dimethylbutyrylchloride was used to replace propionylchloride.

(63) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H), 1.55 (d, J=7.0 Hz, 2H), 0.94 (s, 9H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 15

(S)-2-(2-methylbutyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS015)

(64) The titled product was prepared by the same procedure as that in example 6, except that 2-methylbutyrylchloride was used to replace propionylchloride.

(65) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H), 2.60-2.42 (m, 2H), 2.04 (m, 1H), 1.55 (m, 2H), 0.98-0.90 (m, 6H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 16

(S)-2-(2-chloroethyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS016)

(66) The titled product was prepared by the same procedure as that in example 6, except that 2-chloroacetylchloride was used to replace propionylchloride.

(67) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.70-3.58 (m, 3H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H). ESI-MS m/z: 350.0 [M+H].sup.+.

EXAMPLE 17

(S)-2-(3-chloro propyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS017)

(68) The titled product was prepared by the same procedure as that in example 6, except that 3-chloropropionylchloride was used to replace propionylchloride.

(69) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.70-3.58 (m, 3H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H), 1.86 (m, 2H). ESI-MS m/z: 364.0 [M+H].sup.+.

EXAMPLE 18

(S)-2-(2-chloro propyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS018)

(70) The titled product was prepared by the same procedure as that in example 6, except that 2-chloropropionylchloride was used to replace propionylchloride.

(71) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.99 (d, J=7.2 Hz, 1H), 3.92 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H), 1.60 (d, J=7.2 Hz, 3H). ESI-MS m/z: 364.1 [M+H].sup.+.

EXAMPLE 19

(S)-2-(4-chloro butyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS019)

(72) The titled product was prepared by the same procedure as that in example 6, except that 4-chlorobutyrylchloride was used to replace propionylchloride.

(73) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.70-3.58 (m, 3H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H), 1.77-1.61 (m, 4H). ESI-MS m/z: 378.1 [M+H].sup.+.

EXAMPLE 20

(S)-2-(3-bromo propyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS020)

(74) The titled product was prepared by the same procedure as that in example 6, except that 3-bromopropionylchloride was used to replace propionylchloride.

(75) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.62-3.50 (m, 3H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H), 2.07 (m, 2H). ESI-MS m/z: 408.0 [M+H].sup.+

EXAMPLE 21

(S)-2-(2,2,2-trifluoroethyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS021)

(76) The titled product was prepared by the same procedure as that in example 6, except that 2,2,2-trifluoroacetylchloride was used to replace propionylchloride.

(77) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 3.02 (s, 3H), 2.85-2.70 (m, 3H). ESI-MS m/z: 370.1 [M+H].sup.+.

EXAMPLE 22

(S)-8,9-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS022)

(78) The titled product was prepared by the same procedure as that in example 1, except that 7,8-dimethoxy-3-isochromanone was used to replace thiophene-2-aldehyde.

(79) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.64 (d, J=8.0, 1H), 6.58 (d, J=8.0, 1H), 6.12 (s, 1H), 3.91 (d, J=14.8 Hz, 1H), 3.81 (s, 6H), 3.66 (dd, J=10.8 Hz, J=3.9 Hz, 1H), 3.53 (d, J=14.5 Hz, 1H), 3.27-3.21 (m, 1H), 3.14-3.04 (m, 2H), 2.82-2.70 (m, 3H). ESI-MS m/z: 302.0 [M+H].sup.+.

EXAMPLE 23

(S)-2-methyl-8,9-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS023)

(80) The titled product was prepared by the same procedure as that in example 22, except that 5-methyl-thiophene-2-aldehyde was used to replace thiophene-2-aldehyde.

(81) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.68 (d, J=8.1, 1H), 6.60 (d, J=8.1, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.37 (s, 3H). ESI-MS m/z: 316.0 [M+H].sup.+.

EXAMPLE 24

(S)-2-ethyl-8,9-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS024)

(82) The titled product was prepared by the same procedure as that in example 22, except that 5-ethyl-2-thienal was used to replace 2-thienal.

(83) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.67 (d, J=8.1, 1H), 6.59 (d, J=8.1, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.26 (t, J=7.2 Hz, 3H). ESI-MS m/z: 330.0 [M+H].sup.+.

EXAMPLE 25

(S)-2-n-propyl-8,9-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS025)

(84) The titled product was prepared by the same procedure as that in example 22, except that 5-n-propyl-2-thienal was used to replace 2-thienal.

(85) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.68 (d, J=8.1, 1H), 6.61 (d, J=8.1, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.60 (m, 2H), 0.91 (t, J=7.2 Hz, 3H). ESI-MS m/z: 344.0 [M+H].sup.+.

EXAMPLE 26

(S)-2-(2-methyl propyl)-8,9-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS026)

(86) The titled product was prepared by the same procedure as that in example 22, except that 2-methylpropionylchloride was used to replace propionylchloride.

(87) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.66 (d, J=8.0, 1H), 6.60 (d, J=8.0, 1H), 6.14 (s, 1H), 3.95 (d, J=14.4 Hz, 1H), 3.83 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.63 (m, 1H), 0.86 (t, J=7.2 Hz, 6H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 27

(S)-2-cyclopropylmethyl-8,9-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS027)

(88) The titled product was prepared by the same procedure as that in example 22, except that 2-cyclopropylformylchloride was used to replace propionylchloride.

(89) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.64 (d, J=8.0, 1H), 6.55 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 3H), 2.55 (m, 2H), 0.94-1.27 (m, 1H), 0.51-0.55 (m, 2H), 0.19-0.47 (m, 2H). ESI-MS m/z: 356.0 [M+H].sup.+.

EXAMPLE 28

(S)-2-(2,2-dimethyl propyl)-8,9-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS028)

(90) The titled product was prepared by the same procedure as that in example 22, except that 2,2-dimethylpropionylchloride was used to replace propionylchloride.

(91) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.66 (d, J=8.0, 1H), 6.58 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 3H), 2.45 (s, 2H), 0.98 (s, 9H). ESI-MS m/z: 372.1 [M+H].sup.+.

EXAMPLE 29

(S)-2-(2-chloroethyl)-8,9-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS029)

(92) The titled product was prepared by the same procedure as that in example 22, except that 2-chloroacetylchloride was used to replace propionylchloride.

(93) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.64 (d, J=8.0, 1H), 6.52 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 6H), 3.70-3.58 (m, 3H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H). ESI-MS m/z: 364.1 [M+H].sup.+.

EXAMPLE 30

(S)-2-(2,2,2-trifluoroethyl)-8,9-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS030)

(94) The titled product was prepared by the same procedure as that in example 22, except that 2,2,2-trifluoroacetylchloride was used to replace propionylchloride.

(95) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.68 (d, J=8.1, 1H), 6.56 (d, J=8.1, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 3.02 (s, 3H), 2.85-2.70 (m, 3H). ESI-MS m/z: 384.4 [M+H].sup.+.

EXAMPLE 31

(S)-8,11-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS031)

31.1 Preparation of N-(thiophene-2-ethyl)-2,5-dimethoxy-phenylacetamide

(96) 1 g of 2,5-dimethoxyphenylacetic acid was dissolved in anhydrous dichloromethane, added with a condensing agent of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) in batches under agitating, and then with 2 eq of triethylamine, followed by addition of 1 eq of thiophene-2-ethylamine. The reaction was performed at room temperature for 3 hours. After that, the reaction mixture was quenched by water, and extracted with dichloromethane. The organic phase was evaporated to dryness and the residue was purified by column chromatography to give the product. Yield, 72%.

(97) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.40 (d, J=7.8 Hz, 1H), 6.93 (d, J=7.8 Hz, 1H), 6.90 (s, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 3.85 (s, 6H), 3.66 (s, 2H), 3.58 (t, J=12.0 Hz, 2H), 2.78 (t, J=12.0 Hz, 2H). ESI-MS m/z: 306.0 [M+H].sup.+.

31.2, Preparation of (S)-8,11-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS031)

(98) (S)-4-(2,5-dimethoxybenzyl)-4,5,6,7-tetrahydro-thieno(3,2-c)pyridine was mixed with formaldehyde/formic acid (5 mL/7.5 mL/1 mmol substrate), and reacted at 90 C. under nitrogen for 2 hours. The reaction mixture was evaporated to remove most of the solvent, adjusted with saturated NaHCO.sub.3 to be alkaline, and extracted triply with dichloromethane. The organic phase was evaporated to dryness, and the residue was purified by column chromatography to give the product.

(99) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.64 (d, J=8.0, 1H), 6.58 (d, J=8.0, 1H), 6.12 (s, 1H), 3.91 (d, J=14.8 Hz, 1H), 3.81 (s, 6H), 3.66 (dd, J=10.8 Hz, J=3.9 Hz, 1H), 3.53 (d, J=14.5 Hz, 1H), 3.27-3.21 (m, 1H), 3.14-3.04 (m, 2H), 2.82-2.70 (m, 3H). ESI-MS m/z: 302.0 [M+H].sup.+.

EXAMPLE 32

(S)-2-methyl-8,11-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS032)

(100) The titled product was prepared by the same procedure as that in example 31, except that 5-methylthiophene-2-ethylamine was used to replace thiophene-2-ethylamine.

(101) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.64 (d, J=8.0, 1H), 6.59 (d, J=8.0, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 183 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.37 (s, 3H). ESI-MS m/z: 316.0 [M+H].sup.+.

EXAMPLE 33

(S)-2-ethyl-8,11-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS033)

(102) The titled product was prepared by the same procedure as that in example 31, except that 5-ethylthiophene-2-ethylamine was used to replace thiophene-2-ethylamine.

(103) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.64 (d, J=8.8, 1H), 6.58 (d, J=8.8, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.26 (t, J=7.2 Hz, 3H). ESI-MS m/z: 330.0 [M+H].sup.+.

EXAMPLE 34

(S)-2-(2-methyl propyl)-8,11-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS034)

(104) The titled product was prepared by the same procedure as that in example 31, except that 5-(2-methylpropyl)thiophene-2-ethylamine was used to replace thiophene-2-ethylamine.

(105) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.64 (d, J=8.0, 1H), 6.58 (d, J=8.0, 1H), 6.12 (s, 1H), 3.95 (d, J=14.4 Hz, 1H), 3.83 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.63 (m, 1H), 0.86 (t, J=7.2 Hz, 6H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 35

(S)-2-(cyclopropylmethyl)-8,11-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS035)

(106) The titled product was prepared by the same procedure as that in example 31, except that 5-cyclopropylmethylthiophene-2-ethylamine was used to replace thiophene-2-ethylamine.

(107) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.64 (d, J=8.0, 1H), 6.59 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 3H), 2.55 (m, 2H), 0.94-1.27 (m, 1H), 0.51-0.55 (m, 2H), 0.19-0.47 (m, 2H). ESI-MS m/z: 356.0 [M+H].sup.+.

EXAMPLE 36

(S)-2-(2-chloroethyl)-8,11-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS036)

(108) The titled product was prepared by the same procedure as that in example 31, except that 5-(2-chloroethyl)thiophene-2-ethylamine was used to replace thiophene-2-ethylamine.

(109) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.64 (d, J=8.0, 1H), 6.58 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 6H), 3.70-3.58 (m, 3H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H). ESI-MS m/z: 364.1 [M+H].sup.+.

EXAMPLE 37

(S)-2-(2,2,2-trifluoroethyl)-8,11-dimethoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS037)

(110) The titled product was prepared by the same procedure as that in example 31, except that 5-(2,2,2-trifluoroethyl)thiophene-2-ethylamine was used to replace thiophene-2-ethylamine.

(111) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.1, 1H), 6.56 (d, J=8.1, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.81 (s, 6H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hzr 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 3.02 (s, 3H), 2.85-2.70 (m, 3H). ESI-MS m/z: 384.4 [M+H].sup.+.

EXAMPLE 38 cl (S)-2,4-dimethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS038)

(112) The titled product was prepared by the same procedure as that in example 1, except that 5-methylthiophene-2-ethylketone was used to replace 2-thienal.

(113) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 3H), 2.85-2.70 (m, 1H), 2.37 (s, 3H), 1.25 (d, J=7.2 Hz, 3H). ESI-MS m/z: 316.4 [M+H].sup.+.

EXAMPLE 39

(S)-2,5-dimethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS039)

(114) The titled product was prepared by the same procedure as that in example 1, except that 5-methyl-2-thienal and nitroethane were used to replace 2-thienal and nitromethane.

(115) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.12 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 2H), 2.37 (s, 3H), 1.12 (d, J=7.2 Hz, 3H). ESI-MS m/z: 316.4 [M+H].sup.+.

EXAMPLE 40

(S)-2,7-dimethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS040)

(116) The titled product was prepared by the same procedure as that in example 1, except that metaldehyde was used to replace paraformaldehyde.

(117) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.12 (s, 1H), 3.99 (d, J=14.8 Hz, 1H), 3.90 (m, 1H), 3.83 (s, 3H), 3.10-3.02 (m, 2H), 2.80-2.65 (m, 4H), 2.37 (s, 3H), 1.28 (d, J=7.2 Hz, 3H). ESI-MS m/z: 316.4 [M+H].sup.+.

EXAMPLE 41

(S)-2-methyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizin-7(5H)-one (AS041)

(118) The titled product was prepared by the same procedure as that in example 1, except that chloroformylchloride was used to replace paraformaldehyde.

(119) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.12 (s, 1H), 5.11 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.58-3.48 (m, 2H), 3.10-3.02 (m, 2H), 2.84-2.80 (m, 2H), 2.37 (s, 3H). ESI-MS m/z: 316.4 [M+H].sup.+.

EXAMPLE 42

(S)-1,2-dimethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS042)

(120) The titled product was prepared by the same procedure as that in example 1, except that 4,5-dimethyl-2-thienal was used to replace 2-thienal.

(121) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.10-3.02 (m, 2H), 2.74-2.63 (m, 4H), 2.37 (s, 3H), 2.20 (s, 3H). ESI-MS m/z: 316.4 [M+H].sup.+.

EXAMPLE 43

(S)-2,8-dimethoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS043)

(122) The titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-2-thienal was used to replace 2-thienal.

(123) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 5.76 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.10-3.02 (m, 2H), 2.74-2.63 (m, 4H). ESI-MS m/z: 318.4 [M+H].sup.+.

EXAMPLE 44

(S)-2-fluoro-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS044)

(124) The titled product was prepared by the same procedure as that in example 1, except that 5-fluoro-2-thienal was used to replace 2-thienal.

(125) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.50 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.88 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.10-3.02 (m, 2H), 2.74-2.63 (m, 4H). ESI-MS m/z: 306.4 [M+H].sup.+.

EXAMPLE 45

(S)-2-methyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[2,3-a]quinolizine (AS045)

(126) The titled product was prepared by the same procedure as that in example 1, except that 5-methyl-3-thienal was used to replace 2-thienal.

(127) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.1, 1H), 6.56 (d, J=8.1, 1H), 6.14 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.36 (s, 3H). ESI-MS m/z: 302.0 [M+H].sup.+.

EXAMPLE 46

(S)-2,8-dimethoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[2,3-a]quinolizine (AS046)

(128) The titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-3-thienal was used to replace 2-thienal.

(129) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 5.76 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.10-3.02 (m, 2H), 2.74-2.63 (m, 4H). ESI-MS m/z: 318.4 [M+H].sup.+.

EXAMPLE 47

(S)-8-methoxy-9-acetoxy-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS047)

(130) The titled product was prepared by the same procedure as that in example 1, except that 7-acetoxy-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.

(131) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.28 (d, J=8.0, 1H), 6.94 (d, J=8.0, 1H), 6.78 (d, J=8.1, 1H), 6.60 (d, J=8.1, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68-3.54 (m, 2H), 3.29-3.24 (m, 2H), 3.16-3.08 (m, 21-1), 2.85-2.70 (m, 2H), 2.29 (s, 3H). ESI-MS m/z: 329.0 [M+H].sup.+.

EXAMPLE 48

(S)-8-methoxy-9-(2-hydroxyethoxy)-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS048)

(132) The titled product was prepared by the same procedure as that in example 1, except that 7-(2-hydroxyethoxy)-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.

(133) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.28 (d, J=8.0, 1H), 6.94 (d, J=8.0, 1H), 6.78 (d, J=8.1, 1H), 6.60 (d, J=8.1, 1H), 4.15-4.10 (m, 2H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68-3.54 (m, 4H), 3.29-3.24 (m, 2H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 2H). ESI-MS m/z: 332.0 [M+H].sup.+.

EXAMPLE 49

(S)-8-methoxy-9-(2-dimethylaminoethoxy)-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS049)

(134) The titled product was prepared by the same procedure as that in example 1, except that 7-(T-dimethylaminoethoxy)-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.

(135) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.28 (d, J=8.0, 1H), 6.94 (d, J=8.0, 1H), 6.78 (d, J=8.1, 1H), 6.60 (d, J=8.1, 1H), 4.15-4.10 (m, 2H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68-3.54 (m, 4H), 3.29-3.24 (m, 2H), 3.16-3.08 (m, 2H), 2.85 (s, 6H), 2.80-2.70 (m, 2H). ESI-MS m/k: 359.1 [M+H].sup.+.

EXAMPLE 50

(S)-8-methoxy-9-amino-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS050)

(136) The titled product was prepared by the same procedure as that in example 1, except that 7-acetamido-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.

(137) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.18 (d, J=8.1, 1H), 6.70 (d, J=8.1, 1H), 6.48 (d, J=8.0, 1H), 6.31 (d, J=8.0, 1H), 6.22 (s, 2H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68-3.54 (m, 2H), 3.29-3.24 (m, 2H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 2H). ESI-MS m/z: 287.0 [M+H].sup.+.

EXAMPLE 51

(S)-8-methoxy-9-acetamido-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS051)

(138) The titled product was prepared by the same procedure as that in example 1, except that 7-acetamido-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.

(139) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.28 (d, J=8.0, 1H), 7.30-7.20 (m, 2H), 6.78 (d, J=8.1, 1H), 6.60 (d, J=8.1, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 311), 3.68-3.54 (m, 2H), 3.29-3.24 (m, 2H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 2H), 2.17 (s, 3H). ESI-MS m/z: 329.0 [M+H].sup.+.

EXAMPLE 52

(S)-8-methoxy-9-methylsulfonylamido-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS052)

(140) The titled product was prepared by the same procedure as that in example 1, except that 7-methylsulfonylamido-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.

(141) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.28 (d, J=8.0, 1H), 6.78 (d, J=8.1, 1H), 6.70 (d, J=8.1, 1H), 6.60 (d, J=8.1, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68-3.54 (m, 2H), 3.29-3.24 (m, 2H), 3.16-3.08 (m, 2H), 2.93 (s, 3H), 2.85-2.70 (m, 2H). ESI-MS m/z: 365.0 [M+H].sup.+.

EXAMPLE 53

(S)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]furo[3,2-a]quinolizine (AF001)

(142) The titled product was prepared by the same procedure as that in example 1, except that 2-furfural was used to replace 2-thienal.

(143) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.24 (d, J=5.4 Hz, 1H), 6.86 (d, J=5.4 Hz, 1H), 6.62 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 3.91 (d, J=14.8 Hz, 1H), 3.81 (s, 3H), 3.66 (dd, J=10.8 Hz, J=3.9 Hz, 1H), 3.53 (d, J=14.5 Hz, 1H), 3.27-3.21 (m, 1H), 3.14-3.04 (m, 2H), 2.82-2.70 (m, 3H). ESI-MS m/z: 272.1 [M+H].sup.+.

EXAMPLE 54

(S)-2-methyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]furo[3,2-a]quinolizine (AF002)

(144) The titled product was prepared by the same procedure as that in example 1, except that 5-methyl-2-furfural was used to replace 2-thienal.

(145) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.14 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.37 (s, 3H). ESI-MS m/z: 286.0 [M+H].sup.+.

EXAMPLE 55

(S)-2-ethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]furo[3,2-a]quinolizine (AF003)

(146) The titled product was prepared by the same procedure as that in example 1, except that 5-ethyl-2-furfural was used to replace 2-thienal.

(147) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.14 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.26 (t, J=7.2 Hz, 3H). ESI-MS m/z: 300.1 [M+H].sup.+.

EXAMPLE 56

(S)-2-(2-methylpropyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]furo[3,2-a]quinolizine (AF004)

(148) The titled product was prepared by the same procedure as that in example 6, except that 5-(2-methylpropyl)-2-furfural was used to replace 2-thienal.

(149) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.0, 1H), 6.51 (d, J=8.0, 1H), 6.14 (s, 1H), 3.95 (d, J=14.4 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.63 (m, 1H), 0.86 (t, J=7.2 Hz, 6H). ESI-MS m/z: 328.1 [M+H].sup.+.

EXAMPLE 57

(S)-2-cyclopropylmethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]furo[3,2-a]quinolizine (AF005)

(150) The titled product was prepared by the same procedure as that in example 1, except that 5-cyclopropylmethyl-2-furfural was used to replace 2-thienal.

(151) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.14 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 3H), 2.55 (m, 2H), 0.94-1.27 (m, 1H), 0.51-0.55 (m, 2H), 0.19-0.47 (m, 2H). ESI-MS m/z: 326.1 [M+H].sup.+.

EXAMPLE 58

(S)-2-(2-chloroethyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]furo[3,2-a]quinolizine (AF006)

(152) The titled product was prepared by the same procedure as that in example 1, except that 5-(2-chloroethyl)-2-furfural was used to replace 2-thienal.

(153) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.60 (d, J=8.0, 1H), 6.49 (d, J=8.0, 1H), 6.12 (s, 1H), 3.93 (d, J=14.4 Hz, 1H), 3.81 (s, 3H), 3.70-3.58 (m, 3H), 3.54 (d, J=14.4 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.75 (m, 5H). ESI-MS m/z: 334.1 [M+H].sup.+.

EXAMPLE 59

(S)-2-methyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]furo[2,3-a]quinolizine (AF007)

(154) The titled product was prepared by the same procedure as that in example 45, except that 5-methyl-3-furfural was used.

(155) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.1, 1H), 6.56 (d, J=8.1, 1H), 6.14 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.36 (s, 3H). ESI-MS m/z: 286.0 [M+H].sup.+.

EXAMPLE 60

(S)-2-ethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]furo[2,3-a]quinolizine (AF008)

(156) The titled product was prepared by the same procedure as that in example 1, except that 5-ethyl-3-furfural was used to replace 2-thienal.

(157) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.1, 1H), 6.56 (d, J=8.1, 1H), 6.14 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H), 1.25 (t, J=7.0 Hz, 3H). ESI-MS m/z: 300.1 [M+H].sup.+.

EXAMPLE 61

(S)-2-(2-chloroethyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]furo[2,3-a]quinolizine (AF009)

(158) The titled product was prepared by the same procedure as that in example 1, except that 5-(2-chloroethyl)-3-furfural was used to replace 2-thienal.

(159) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.62 (d, J=8.1, 1H), 6.56 (d, J=8.1, 1H), 6.14 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.71 (m, 2H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 5H). ESI-MS m/z: 350.1 [M+H].sup.+.

EXAMPLE 62

(S)-2,3-dimethoxy-5,7,8,13,13b,14-hexahydroindolo[2,3:3,4]pyrido[1,2-b]isoquinoline (A1001)

(160) The titled product was prepared by the same procedure as that in example 31, except that tryptamine was used to replace thiophene-2-ethylamine and 3,4-dimethoxyphenylacetic acid was used to replace 2,5-dimethoxyphenylacetic acid.

(161) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.13-7.08 (m, 4H), 6.82 (s, 1H), 6.76 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.90 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 335.2 [M+H].sup.+.

EXAMPLE 63

(S)-3-hydroxy-4-methoxy-5,7,8,13,13b,14-hexahydroindolo[2,3:3,4]pyrido[1,2-b]isoquinoline (A1002)

(162) The titled product was prepared by the same procedure as that in example 1, except that tryptamine was used to replace thiophene-2-ethylamine.

(163) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.13-7.08 (m, 4H), 6.66 (d, J=8.0 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.90 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 335.2 [M+H].sup.+.

EXAMPLE 64

(S)-3-hydroxy-4,10-dimethoxy-5,7,8,13,13b,14-hexahydroindolo[2,3:3,4]pyrido[1,2-b]isoquinoline (A1003)

(164) The titled product was prepared by the same procedure as that in example 1, except that 5-methoxytryptamine was used to replace thiophene-2-ethylamine.

(165) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.06 (dd, J=8.0 Hz, 1H), 6.89 (dd, J=8.0 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 6.60 (m, 2H), 4.11 (d, J=14.8 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 351.1 [M+H].sup.+.

EXAMPLE 65

(S)-3-hydroxy-4-methoxy-10-methyl-5,7,8,13,13b,14-hexahydroindolo[2,3:3,4]pyrido[1,2-b]isoquinoline (A1004)

(166) The titled product was prepared by the same procedure as that in example 1, except that 5-methyltryptamine was used to replace thiophene-2-ethylamine.

(167) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.03 (dd, J=8.0 Hz, 1H), 6.99 (dd, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.60 (m, 2H), 4.11 (d, J=14.8 Hz, 1H), 3.85 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.33 (s, 3H). ESI-MS m/z: 335.1 [M+H].sup.+.

EXAMPLE 66

(S)-3-hydroxy-4-methoxy-10-fluoro-5,7,8,13,13b,14-hexahydroindolo[2,3: 3,4]pyrido[1,2-b]isoquinoline (AIM)

(168) The titled product was prepared by the same procedure as that in example 1, except that 5-fluorotryptamine was used to replace thiophene-2-ethylamine.

(169) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.20 (dd, J=8.0 Hz, 1H), 6.99 (dd, J=8.0 Hz, 1H), 6.70 (s, 1H), 6.62 (d, J=8.1, 1H), 6.56 (d, J=8.1, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.85 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.33 (s, 3H). ESI-MS m/z: 339.1 [M+H].sup.+.

EXAMPLE 67

(S)-3-hydroxy-4-methoxy-11-methyl-5,7,8,13,13b,14-hexahydroindolo[2,3:3,4]pyrido[1,2-b]isoquinoline (A1006)

(170) The titled product was prepared by the same procedure as that in example 1, except that 6-methyltryptamine was used to replace thiophene-2-ethylamine.

(171) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.11 (dd, J=8.0 Hz, 1H), 6.99 (dd, J=8.0 Hz, 1H), 6.70 (s, 1H), 6.60 (m, 2H), 4.08 (d, J=14.8 Hz, 1H), 3.85 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H), 2.25 (s, 3H). ESI-MS m/z: 335.1 [M+H].sup.+.

EXAMPLE 68

(S)-3-hydroxy-4,11-dimethoxy-5,7,8,13,13b,14-hexahydroindolo[2,3:3,4]pyrido[1,2-b]isoquinoline (AI007)

(172) The titled product was prepared by the same procedure as that in example 1, except that 6-methoxytryptamine was used to replace thiophene-2-ethylamine.

(173) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.99 (dd, J=8.0 Hz, 1H), 6.89 (dd, J=8.0 Hz, 1H), 6.60-6.56 (m, 2H), 6.43 (s, 1H), 4.15 (d, J=14.8 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 351.1 [M+H].sup.+.

EXAMPLE 69

(S)-5,6,8,14,14a,15-hexahydro-[1,3]dioxolo[4,5-g]indolo[2,3:3,4]pyrido[1,2-b]isoquinoline (AI008)

(174) The titled product was prepared by the same procedure as that in example 62, except that 3,4-methylenedioxyphenylacetic acid was used to replace 3,4-dimethoxyphenylacetic acid.

(175) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.13-7.08 (m, 4H), 6.82 (s, 1H), 6.76 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.90 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 336.2 [M+H].sup.+.

EXAMPLE 70

(S)-3-hydroxy-2-methoxy-5,7,8,13,13b,14-hexahydroindolo[2,3:3,4]pyrido[1,2-b]isoquinoline (A1009)

(176) The titled product was prepared by the same procedure as that in example 69, except that 3-methoxy 4-hydroxy phenylacetic acid was used to replace 3,4-methenedioxy phenylacetic acid.

(177) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.13-7.08 (m, 4H), 6.82 (s, 1H), 6.76 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.92 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 321.3 [M+H].sup.+.

EXAMPLE 71

(S)-2-hydroxy-3-methoxy-5,7,8,13,13b,14-hexahydroindolo[2,3:3,4]pyrido[1,2-b]isoquinoline (AI010)

(178) The titled product was prepared by the same procedure as that in example 69, except that 3-hydroxy 4-methoxy phenylacetic acid was used to replace 3,4-methenedioxy phenylacetic acid.

(179) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.13-7.08 (m, 4H), 6.82 (s, 1H), 6.76 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.90 (s, 3H), 3.70 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.62 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 321.3 [M+H].sup.+.

EXAMPLE 72

(S)-2,8-dimethoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]pyrrolo[2,3-a]quinolizine (AP001)

(180) The titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-3-pyrrolecarboxaldehyde was used to replace 2-thienal.

(181) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=7.5, 1H), 6.54 (d, J=7.5, 1H), 5.76 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 301.1 [M+H].sup.+.

EXAMPLE 73

(S)-3,9-dimethoxy-10-hydroxy-5,8,13,13a-tetrahydro-6H-benzo[g]pyrido[2,3-a]quinolizine (AP002)

(182) The titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-3-pyridinecarboxaldehyde was used to replace 2-thienal.

(183) .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.12 (d, J=7.4, 1H), 7.40 (s, 1H), 6.65 (d, J=8.0, 1H), 6.54 (d, J=8.0, 1H), 5.76 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 313.1 [M+H].sup.+.

EXAMPLE 74

(S)-2,10-dihydroxy-3,9-dimethoxy-5,8,13,13a-tetrahydro-6H-benzo[g]pyrido[2,3-a]quinolizine (AP003)

(184) The titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-6-hydroxy-3-pyridinecarboxaldehyde was used to replace 2-thienal.

(185) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.33 (s, 1H), 6.65 (d, J=8.0, 1H), 6.54 (d, J=8.0, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 329.1 [M+H].sup.+.

EXAMPLE 75

(S)-2,8-dimethoxy-9-hydroxy-4,7,12,12a-tetrahydro-5H-benzo[g]pyrrolo[3,2-a]quinolizine (AP004)

(186) The titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-2-pyrrolecarboxaldehyde was used to replace 2-thienal.

(187) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.68 (d, J=7.4, 1H), 6.60 (d, J=7.4, 1H), 5.98 (s, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 301.1 [M+H].sup.+.

EXAMPLE 76

(S)-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[3,2-1][1,6]naphthyridin-10-ol (AP005)

(188) The titled product was prepared by the same procedure as that in example 1, except that 6-methoxy-2-pyridinecarboxaldehyde was used to replace 2-thienal.

(189) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.68 (d, J=7.4, 1H), 6.65 (d, J=8.0, 1H), 6.54 (d, J=8.0, 1H), 6.43 (d, J=7.4, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 313.1 [M+H].sup.+.

EXAMPLE 77

(S)-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[3,2-1][1,6]naphthyridine-2,10-diol (AP006)

(190) The titled product was prepared by the same procedure as that in example 1, except that 5-hydroxy-6-methoxy-2-pyridinecarboxaldehyde was used to replace 2-thienal.

(191) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.43 (s, 1H), 6.65 (d, J=8.0, 1H), 6.54 (d, J=8.0, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.27-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.70 (m, 3H). ESI-MS m/z: 329.1 [M+H].sup.+.

EXAMPLE 78

(S)-2-hydroxy-3-methoxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS001)

78.1 Preparation of thiophene-2-acetic acid

(192) 1 g of ethyl thiophene-2-acetate was dissolved in 4 mL of ethanol, added with 8 ml of 4N NaOH aqueous solution, and agitated at room temperature for 1 hour. The reaction mixture was adjusted with 1N HCl aqueous solution to a pH of 1, and extracted with dichloromethane. The organic phase was evaporated to dryness to give an oily product, thiophene-2-acetic acid. Yield, about 100%.

(193) ESI-MS m/z: 141.0 [MH].sup..

78.2 Preparation of 3-methoxy-4-benzyloxybenzaldehyde

(194) 10 g of 3-methoxy-4-hydroxybenzaldehyde was dissolved in 100 mL of acetone, added with anhydrous K.sub.2CO.sub.3 (3 eq), followed by dropwise addition of benzylbromide (1.1 eq) under agitating. Then, the mixture was placed in an oil bath and refluxed for 6 hours. After the reaction was completed, the reaction mixture was vacuum filtered and the filtrate was evaporated to dryness. Saturated NaHCO.sub.3 aqueous solution was added, and the resultant mixture was extracted with dichloromethane. The organic phase was evaporated to dryness to give the product. Yield, 95%.

(195) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.50-7.40 (m, 5H), 7.25 (s, 1H), 7.10 (s, 1H), 5.11 (s, 2H), 3.85 (s, 3H). ESI-MS m/z: 243.0 [M+H].sup.+.

78.3 Preparation of 1-benzyloxy-2-methoxy-4-(2-nitrovinyl)benzene

(196) The titled product was prepared by the same procedure as that in step 1.1 of example 1, except that the product obtained from the last step was used to replace 2-thienal.

(197) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.50-7.40 (m, 5H), 7.25 (s, 1H), 7.20 (d, J=11.8 Hz, 1H), 7.09 (d, J=11.8 Hz, 1H), 6.95 (s, 1H), 5.11 (s, 2H), 3.85 (s, 3H). ESI-MS m/z: 286.0 [M+H].sup.+.

78.4 Preparation of 3-methoxy-4-benzyloxy phenylethylamine

(198) The titled product was prepared by the same procedure as that in step 1.2 of example 1, except that the product obtained from the last step was used to replace 2-(2-nitrovinyl)thiophene.

(199) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.50-7.40 (m, 5H), 6.83 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.77 (s, 1H), 6.95 (s, 1H), 5.11 (s, 2H), 3.85 (s, 3H), 2.88 (t, J=12.0 Hz, 2H), 2.57 (t, J=12.0 Hz, 2H). ESI-MS m/z: 258.1 [M+H].sup.+.

78.5 Preparation of N-(3-methoxy-4-benzyloxy phenylethyl)thiophene-2-acetamide

(200) The titled product was prepared by the same procedure as that in step 31.1 of example 31, except that the product obtained from the last step was used to replace thiophene-2-ethylamine and 3-methoxy-4-benzyloxyphenylacetic acid was used to replace 2,5-dimethoxyphenylacetic acid.

(201) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.43-7.35 (m, 6H), 6.93 (d, J=7.8 Hz, 1H), 6.84 (m, 2H), 6.80 (s, 1H), 6.74 (s, 1H), 5.21 (s, 6H), 3.87 (s, 3H), 3.45 (s, 1H), 3.32 (t, J=12.0 Hz, 2H), 2.78 (t, J=12.0 Hz, 2H). ESI-MS m/z: 382.1 [M+H].sup.+.

78.6 Preparation of 6-methoxy-7-benzyloxy-(thiophene-2-methyl)-3,4-dihydro-isoquinoline

(202) The titled product was prepared by the same procedure as that in step 1.10 of example 1, except that the product obtained from the last step was used to replace N-thienylethyl-2-acetyloxy-3-methoxy-4-benzyloxyphenylacetamide.

(203) ESI-MS m/z: 364.1 [M+H].sup.+.

78.7 Preparation of (S)-6-methoxy-7-benzyloxy-1-(thiophene-2-methyl)-1,2,3,4-tetrahydro-isoquinoline

(204) The titled product was prepared by the same procedure as that in step 1.11 of example 1, except that the product obtained from the last step was used to replace 2-methoxy-3-benzyloxy-6-((6,7-dihydro-thieno(3,2-c)pyridin-4-yl)-methyl)-benzyl acetate.

(205) ESI-MS m/z: 366.1 [M+H].sup.+.

78.8 Preparation of (S)-2-benzyloxy-3-methoxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine

(206) The titled product was prepared by the same procedure as that in step 31.2 of example 31, except that the product obtained from the last step was used to replace (S)-4-(2,5-dimethoxy benzyl)-4,5,6,7-tetrahydro-thieno(3,2-c)pyridine.

(207) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.45-7.38 (m, 5H), 6.68 (s, 1H), 6.58 (s, 1H), 6.42 (s, 1H), 6.74 (s, 1H), 5.21 (s, 2H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 378.1 [M+H].sup.+.

78.9 Preparation of (S)-2-hydroxy-3-methoxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS001)

(208) The titled product was prepared by the same procedure as that in step 1.14 of example 1, except that the product obtained from the last step was used to replace (S)-4-(2-chloromethyl-3-methoxy-4-benzyloxy)-4,5,6,7-tetrahydro-thieno(3,2-c)pyridine).

(209) .sup.1H NMR (CDCl.sub.3, 400 MHz): 710 (d, J=5.1 Hz, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (d, J=5.1 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 288.1 [M+H].sup.+.

EXAMPLE 79

(R)-2-hydroxy-3-methoxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS002)

(210) The titled product was prepared by the same procedure as that in example 78, except that (S,S)-Noyori catalyst was used to replace (R,R)-Noyori catalyst.

(211) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.10 (d, J=5.1 Hz, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.59 (d, J=5.1 Hz, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 288.1 [M+H].sup.+.

EXAMPLE 80

(S)-2-hydroxy-3-methoxy-10-ethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS003)

80.1 Preparation of ethyl 5-acetylthiophene-2-acetate

(212) Ethyl thiophene-2-acetate (1.7 g) and acetyl chloride (1.2 eq) were dissolved in anhydours dichloromethane (50 mL), cooled to 0 C., and added with anhydrous AlCl.sub.3 (1.2 eq) in batches. After that, the reaction mixture was placed at room temperature to further react for 2 hours. After the reaction was completed, the reaction mixture was cooled to 0 C., added slowly with a certain amount of 1N HCl aqueous solution, and extracted triply with dichloromethane. The organic phase was evaporated to dryness to give the product.

(213) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.54 (d, J=3.6 Hz, 1H), 6.96 (d, J=3.6 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 3.83 (s, 2H), 2.51 (s, 3H), 1.27 (t, J=7.2 Hz, 3H). ESI-MS m/z: 213.0 [M+H].sup.+.

80.2 Preparation of ethyl 5-ethylthiophene-2-acetate

(214) 1.06 g of ethyl 5-acetylthiophene-2-acetate was dissolved in 5 mL trifluoroacetic acid, added slowly with 4 eq of triethylsilane at room temperature and reacted overnight. After the reaction was completed, the solvent was evaporated and purification was preformed by column chromatography.

(215) .sup.1H NMR (300 MHz, CDCl.sub.3): 6.84 (d, J=3.6 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.83 (s, 2H), 2.82 (q, J=7.2, 2H), 1.29-1.26 (m, 6H). ESI-MS m/z: 199.0 [M+H].sup.+.

80.3 Preparation of 5-ethylthiophene-2-acetic acid

(216) The titled product was prepared by the same procedure as that in step 78.1 of example 78, except that the product obtained from the last step was used to replace ethyl thiophene-2-acetate.

(217) .sup.1H NMR (300 MHz, CDCl.sub.3): 6.84 (d, J=3.6 Hz, 1H), 6.76 (d, J=3.6 Hz, 1H), 3.53 (s, 2H), 2.82 (q, J=7.2 Hz, 2H), 1.26 (t, J=7.2 Hz, 3H). ESI-MS m/z: 169.0 [MH].sup.+.

80.4 Preparation of (S)-2-hydroxy-3-methoxy-10-ethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS003)

(218) The titled product was prepared by the same procedure as that in example 78, except that the product obtained from the last step was used to replace thiophene-2-acetic acid.

(219) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.80 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). ESI-MS m/z: 316.1 [M+H].sup.+.

EXAMPLE 81

(R)-2-hydroxy-3-methoxy-10-ethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS004)

(220) The titled product was prepared by the same procedure as that in example 80, except that (S,S)-Noyori catalyst was used to replace (R,R)-Noyori catalyst.

(221) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). ESI-MS m/z: 316.1 [M+H].sup.+.

EXAMPLE 82

(S)-2-hydroxy-3-methoxy-10-n-propyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS005)

(222) The titled product was prepared by the same procedure as that in example 80, except that propionyl chloride was used to replace acetyl chloride.

(223) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.78 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.65 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). ESI-MS m/z: 330.1 [M+H].sup.+.

EXAMPLE 83

(S)-2-hydroxy-3-methoxy-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS006)

(224) The titled product was prepared by the same procedure as that in example 80, except that 2-methylpropionyl chloride was used to replace acetyl chloride.

(225) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.82 (m, 1H), 0.91-0.89 (m, 6H). ESI-MS m/z: 344.1 [M+H].sup.+.

EXAMPLE 84

(S)-2-hydroxy-3-methoxy-10-n-butyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS007)

(226) The titled product was prepared by the same procedure as that in example 80, except that n-butyryl chloride was used to replace acetyl chloride.

(227) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.81 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 1.62 (m, 2H), 1.32 (m, 2H), 0.90 (t, J=7.2 Hz, 3H). ESI-MS m/z: 344.1

EXAMPLE 85

(S)-2-hydroxy-3-methoxy-10-(3-methylbutyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS008)

(228) The titled product was prepared by the same procedure as that in example 80, except that 3-methylbutyryl chloride was used to replace acetyl chloride.

(229) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.80 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 1.62-1.58 (m, 3H), 0.90 (m, 6H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 86

(S)-2-hydroxy-3-methoxy-10-n-amyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS009)

(230) The titled product was prepared by the same procedure as that in example 80, except that valeryl chloride was used to replace acetyl chloride.

(231) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 1.62-1.58 (m, 2H), 1.32-1.28 (m, 4H), 0.90 (t, J=7.2 Hz, 3H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 87

(S)-2-hydroxy-3-methoxy-10-(4-methylamyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS010)

(232) The titled product was prepared by the same procedure as that in example 80, except that 4-methylvaleryl chloride was used to replace acetyl chloride.

(233) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 1.62-1.58 (m, 3H), 1.28-1.25 (m, 2H), 0.90 (t, J=7.2 Hz, 6H). ESI-MS m/z: 372.1 [M+H].sup.+.

EXAMPLE 88

(S)-2-hydroxy-3-methoxy-10-cyclopropylmethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS011)

(234) The titled product was prepared by the same procedure as that in example 80, except that cyclopropylformyl chloride was used to replace acetyl chloride.

(235) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 0.94 (m, 1H), 0.51-0.55 (m, 2H), 0.19-0.47 (m, 2H). ESI-MS m/z: 342.1 [M+H].sup.+.

EXAMPLE 89

(S)-2-hydroxy-3-methoxy-10-cyclobutylmethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS012)

(236) The titled product was prepared by the same procedure as that in example 80, except that cyclobutylformyl chloride was used to replace acetyl chloride.

(237) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 2.34 (m, 1H), 2.05-1.78 (m, 6H). ESI-MS m/z: 356.1 [M+H].sup.+.

EXAMPLE 90

(S)-2-hydroxy-3-methoxy-10-(2-chloroethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS013)

(238) The titled product was prepared by the same procedure as that in example 80, except that 2-chloroacetyl chloride was used to replace acetyl chloride.

(239) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.74 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (m, 3H), 3.51 (d, J=14.8 Hz, 1H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 2.34 (m, 1H), 1.90 (m, 2H). ESI-MS m/z: 350.1 [M+H].sup.+.

EXAMPLE 91

(12aS)-2-hydroxy-3-methoxy-10-(2-chloropropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS014)

(240) The titled product was prepared by the same procedure as that in example 80, except that 2-chloropropionyl chloride was used to replace acetyl chloride.

(241) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.74 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (m, 3H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 2.34 (m, 1H), 2.05-1.78 (m, 6H), 1.64 (t, J=7.2 Hz, 3H). ESI-MS m/z: 364.1 [M+H].sup.+.

EXAMPLE 92

(S)-2-hydroxy-3-methoxy-10-(3-chloropropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS015)

(242) The titled product was prepared by the same procedure as that in example 80, except that 3-chloropropionyl chloride was used to replace acetyl chloride.

(243) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.74 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (m, 3H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 5H), 2.69-2.60 (m, 2H), 1.90 (m, 2H). ESI-MS m/z: 364.1 [M+H].sup.+.

EXAMPLE 93

(S)-2-hydroxy-3-methoxy-10-(4-chlorobutyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS016)

(244) The titled product was prepared by the same procedure as that in example 80, except that 4-chlorobutyryl chloride was used to replace acetyl chloride.

(245) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.74 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (m, 3H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 5H), 2.69-2.60 (m, 2H), 1.77 (m, 2H), 1.59 (m, 2H). ESI-MS m/z: 378.1 [M+H].sup.+.

EXAMPLE 94

(S)-2-hydroxy-3-methoxy-10-(2,2,2-trifluoroethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS017)

(246) The titled product was prepared by the same procedure as that in example 80, except that 2,2,2-trifluoroacetyl chloride was used to replace acetyl chloride.

(247) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.80 (s, 1H), 6.73 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.54 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.70 (m, 5H). ESI-MS m/z: 370.1 [M+H].sup.+.

EXAMPLE 95

(S)-2-hydroxy-3-methoxy-10-(3,3,3-trifluoropropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS018)

(248) The titled product was prepared by the same procedure as that in example 80, except that 3,3,3-trifluoropropionyl chloride was used to replace acetyl chloride.

(249) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.80 (s, 1H), 6.73 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.54 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.70 (m, 5H), 2.14 (m, 2H). ESI-MS m/z: 370.1 [M+H].sup.+.

EXAMPLE 96

(S)-2-hydroxy-3-methoxy-10-(3,3-difluoropropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS019)

(250) The titled product was prepared by the same procedure as that in example 80, except that 3,3-difluoropropionyl chloride was used to replace acetyl chloride.

(251) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.80 (s, 1H), 6.73 (s, 1H), 6.59 (s, 1H), 5.15 (m, 1H), 4.11 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.54 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.70 (m, 5H), 1.98 (m, 2H). ESI-MS m/z: 366.1 [M+H].sup.+.

EXAMPLE 97

(S)-2,3-dimethoxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS020)

(252) The titled product was prepared by the same procedure as that in example 78, except that 3,4-dimethoxyphenylacetic acid was used to replace 3-methoxy-4-benzyloxy-phenylacetic acid.

(253) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.10 (s, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 6H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 325-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 302.1 [M+H].sup.+.

EXAMPLE 98

(S)-2,3-dimethoxy-10-ethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS021)

(254) The titled product was prepared by the same procedure as that in example 80, except that 3,4-dimethoxyphenylacetic acid was used to replace 3-methoxy-4-benzyloxyphenylacetic acid.

(255) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.80 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 6H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). ESI-MS m/z: 330.1 [M+H].sup.+.

EXAMPLE 99

(S)-2,3-dimethoxy-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS022)

(256) The titled product was prepared by the same procedure as that in example 98, except that 2-methylpropionyl chloride was used to replace acetyl chloride.

(257) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 6H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.82 (m, 1H), 0.91-0.89 (m, 6H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 100

(S)-2,3-dimethoxy-10-(2-chloroethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS023)

(258) The titled product was prepared by the same procedure as that in example 98, except that 2-chloroacetyl chloride was used to replace acetyl chloride.

(259) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.74 (s, 1H), 6.59 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 6H), 3.56 (m, 3H), 3.51 (d, J=14.8 Hz, 1H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 2.34 (m, 1H), 1.90 (m, 2H). ESI-MS m/z: 364.1 [M+H].sup.+.

EXAMPLE 101

(S)-2,3-methylenedioxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS024)

(260) The titled product was prepared by the same procedure as that in example 78, except that 3,4-methylenedioxyphenylacetic acid was used to replace 3-methoxy-4-benzyloxyphenylacetic acid.

(261) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.12 (s, 1H), 6.88 (s, 1H), 6.81 (s, 1H), 6.59 (s, 1H), 6.07 (s, 2H), 4.05 (d, J=14.8 Hz, 1H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 286.0 [M+H].sup.+.

EXAMPLE 102

(S)-2,3-methylenedioxy-10-ethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS025)

(262) The titled product was prepared by the same procedure as that in example 98, except that 3,4-methylenedioxyphenylacetic acid was used to replace 3,4-dimethoxyphenylacetic acid.

(263) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.88 (s, 1H), 6.81 (s, 1H), 6.29 (s, 1H); 6.07 (s, 2H), 4.05 (d, J=14.8 Hz, 1H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.24 (t, J=7.2 Hz, 3H). ESI-MS m/z: 314.1 [M+H].sup.+.

EXAMPLE 103

(S)-2,3-methylenedioxy-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS026)

(264) The titled product was prepared by the same procedure as that in example 102, except that 2-methylpropionyl chloride was used to replace acetyl chloride.

(265) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.88 (s, 1H), 6.81 (s, 1H), 6.29 (s, 1H), 6.07 (s, 2H), 4.05 (d, J=14.8 Hz, 1H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.81 (m, 1H), 0.94 (d, J=7.2 Hz, 6H). ESI-MS m/z: 342.1 [M+H].sup.+.

EXAMPLE 104

(S)-2,3-methylenedioxy-10-(2-chloroethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS027)

(266) The titled product was prepared by the same procedure as that in example 102, except that 2-chloroacetyl chloride was used to replace acetyl chloride.

(267) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.88 (s, 1H), 6.81 (s, 1H), 6.30 (s, 1H), 6.07 (s, 2H), 4.05 (d, J=14.8 Hz, 1H), 3.65-3.56 (m, 3H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H). ESI-MS m/z: 348.1 [M+H].sup.+.

EXAMPLE 105

(S)-2-hydroxy-3-methoxy-10-methyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS028)

(268) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-methylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(269) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.78 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H), 2.35 (s, 3H). ESI-MS m/z: 302.0 [M+H].sup.+.

EXAMPLE 106

(S)-2-hydroxy-3-methoxy-10-(2-chloromethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS029)

(270) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-chloromethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(271) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.64 (s, 2H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 302.0 [M+H].sup.+.

EXAMPLE 107

(S)-2-hydroxy-3-methoxy-10-(2-fluoro methyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS030)

(272) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-fluoromethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(273) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 5.18 (d, J=16 Hz, 2H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 320.0 [M+H].sup.+.

EXAMPLE 108

(S)-2-hydroxy-3-methoxy-10-(2-methylol)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS031)

(274) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-methylolthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(275) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.80 (s, 2H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 318.1 [M+H].sup.+.

EXAMPLE 109

(S)-2-hydroxy-3-methoxy-10-(methoxymethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS032)

(276) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-methoxymethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(277) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.63 (s, 2H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.30 (s, 3H), 3.25-108 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 332.1 [M+H].sup.+.

EXAMPLE 110

(S)-2-hydroxy-3,10-dimethoxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS033)

(278) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-methoxythiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(279) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 318.1 [M+H]+.

EXAMPLE 111

(S)-2-hydroxy-3-methoxy-9,10-dimethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS034)

(280) The titled product was prepared by the same procedure as that in example 80, except that ethyl 4,5-dimethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(281) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.10 (s, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H), 2.36 (s, 3H), 2.22 (s, 3H). ESI-MS m/z: 316.1 [M+H].sup.+.

EXAMPLE 112

(S)-2-hydroxy-3-methoxy-9-methyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS035)

(282) The titled product was prepared by the same procedure as that in example 80, except that ethyl 4-methylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(283) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.02 (s, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H), 2.20 (s, 3H). ESI-MS m/z: 302.0 [M+H].sup.+.

EXAMPLE 113

(S)-2-hydroxy-3-methoxy-9-ethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS036)

(284) The titled product was prepared by the same procedure as that in example 80, except that ethyl 4-ethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(285) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.02 (s, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 4H), 1.23 (t, J=7.2 Hz, 3H). ESI-MS m/z: 302.0 [M+H].sup.+.

EXAMPLE 114

(12aS)-2-hydroxy-3-methoxy-8-methyl-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS037)

(286) The titled product was prepared by the same procedure as that in example 103, except that acetaldehyde was used to replace formaldehyde.

(287) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.08 (d, J=14.8 Hz, 1H), 3.99 (q, J=6.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 2H), 2.90-2.81 (m, 2H), 2.69-2.60 (m, 2H), 1.82 (m, 1H), 1.28 (d, J=6.8 Hz, 3H), 0.91-0.89 (m, 6H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 115

(12aS)-2-hydroxy-3-methoxy-5-methyl-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS038)

(288) The titled product was prepared by the same procedure as that in example 83, except that 2-methyl-2-(3-methoxy-4-hydroxyphenyl)ethylamine was used to replace 3-methoxy-4-hydroxyphenylethylamine.

(289) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.08 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 2H), 2.90-2.81 (m, 2H), 2.69-2.60 (m, 3H), 1.82 (m, 1H), 1.24 (d, J=6.8 Hz, 3H), 0.91-0.89 (m, 6H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 116

(12aS)-2-hydroxy-3-methoxy-6-methyl-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS039)

(290) The titled product was prepared by the same procedure as that in example 83, except that 1-methyl-2-(3-methoxy-4-hydroxyphenyl)ethylamine was used to replace 3-methoxy-4-hydroxyphenylethyl amine.

(291) 1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.08 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 2H), 2.90-2.81 (m, 2H), 2.69-2.46 (m, 3H), 1.82 (m, 1H), 1.24 (d, J=6.8 Hz, 3H), 0.91-0.89 (m, 6H). ESI-MS m/z: 358.1 [M+H].sup.+.

EXAMPLE 117

(12aS)-2-hydroxy-3-methoxy-5-fluoro-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS040)

(292) The titled product was prepared by the same procedure as that in example 83, except that 2-fluoro-2-(3-methoxy-4-hydroxyphenyl)ethylamine was used to replace 3-methoxy-4-hydroxyphenylethylamine.

(293) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.78 (s, 1H), 6.74 (s, 1H), 6.56 (s, 1H), 4.72 (dt, J=17.8 Hz, J=6.9 Hz, 1H), 4.03 (d, J=14.8 Hz, 1H), 3.84 (s, 3H), 3.53 (d, J=10.8 Hz, 1H), 3.46 (d, J=14.8 Hz, 1H), 3.08-2.90 (m, 2H), 2.79-2.64 (m, 4H), 1.82 (m, 1H), 0.91-0.89 (m, 6H). ESI-MS m/z: 362.1 [M+H].sup.+.

EXAMPLE 118

(S)-2-hydroxy-3-methoxy-10-ethyl-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[2,3-g]quinolizine (DS041)

(294) The titled product was prepared by the same procedure as that in example 80, except that 5-ethylthiophene-3-acetic acid was used to replace 5-ethylthiophene-3-acetic acid.

(295) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.24 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.88 (s, 3H), 3.68 (dd, J=10.8 Hz, J=3.8 Hz, 1H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.65 (m, 5H), 1.23 (t, J=7.2 Hz, 3H). ESI-MS m/z: 316.0 [M+H].sup.+.

EXAMPLE 119

(S)-2-hydroxy-3-methoxy-10-(2-chloroethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[2,3-g]quinolizine (DS042)

(296) The titled product was prepared by the same procedure as that in example 80, except that 5-(2-chloroethyl)thiophene-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(297) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.65 (d, J=8.1, 1H), 6.54 (d, J=8.1, 1H), 6.24 (s, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.88 (s, 3H), 3.68-3.70 (m, 3H), 3.54 (d, J=14.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.16-3.08 (m, 2H), 2.85-2.65 (m, 5H). ESI-MS m/z: 350.1 [M+H].sup.+.

EXAMPLE 120

(S)-2-hydroxy-3-methoxy-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[2,3-g]quinolizine (DS043)

(298) The titled product was prepared by the same procedure as that in example 80, except that 5-(2-methyl propyl)thiophene-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(299) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.19 (s, 1H), 4.04 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.82 (m, 1H), 0.91-0.89 (m, 6H). ESI-MS m/z: 344.1 [M+H].sup.+.

EXAMPLE 121

(S)-2-hydroxy-3,10-dimethoxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS044)

(300) The titled product was prepared by the same procedure as that in example 80, except that 5-methoxythiophene-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(301) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 5.79 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 318.1 [M+H].sup.+.

EXAMPLE 122

(S)-2-hydroxy-3-methoxy-5,8,12,12a-tetrahydro-6H-benzo[a]furo[3,2-g]quinolizine (DF001)

(302) The titled product was prepared by the same procedure as that in example 80, except that furan-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(303) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.10 (d, J=5.1 Hz, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 6.19 (d, J=5.1 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 272.1 [M+H].sup.+.

EXAMPLE 123

(S)-2-hydroxy-3-methoxy-10-ethyl-5,8,12,12a-tetrahydro-6H-benzo[a]furo[3,2-g]quinolizine (DF002)

(304) The titled product was prepared by the same procedure as that in example 80, except that 5-ethylfuran-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(305) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.80 (s, 1H), 6.75 (s, 1H), 6.19 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). ESI-MS m/z: 300.1 [M+H].sup.+.

EXAMPLE 124

(S)-2-hydroxy-3-methoxy-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]furo[3,2-g]quinolizine (DF003)

(306) The titled product was prepared by the same procedure as that in example 80, except that 5-(2-methylpropyl)furan-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(307) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.22 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.82 (m, 1H), 0.91-0.89 (m, 6H). ESI-MS m/z: 328.1 [M+H].sup.+.

EXAMPLE 125

(S)-2-hydroxy-3-methoxy-10-cyclopropylmethyl-5,8,12,12a-tetrahydro-6H-benzo[a]furo[3,2-g]quinolizine (DF004)

(308) The titled product was prepared by the same procedure as that in example 80, except that 5-cyclopropylmethylfuran-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(309) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.20 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 0.94 (m, 1H), 0.51-0.55 (m, 2H), 0.19-0.47 (m, 2H). ESI-MS m/z: 326.1 [M+H].sup.+.

EXAMPLE 126

(S)-2-hydroxy-3-methoxy-10-(2-chloroethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]furo[3,2-g]quinolizine (DF005)

(310) The titled product was prepared by the same procedure as that in example 80, except that 5-(2-chloroethyl)furan-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(311) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.74 (s, 1H), 6.19 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (m, 3H), 3.51 (d, J=14.8 Hz, 1H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 2.34 (m, 1H), 1.90 (m, 2H). ESI-MS m/z: 334.1 [M+H].sup.+.

EXAMPLE 127

(S)-2-hydroxy-3,10-dimethoxy-5,8,12,12a-tetrahydro-6H-benzo[a]furo[3,2-g]quinolizine (DF006)

(312) The titled product was prepared by the same procedure as that in example 80, except that 5-methoxyfuran-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(313) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.20 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 302.1 [M+H].sup.+.

EXAMPLE 128

(S)-2-hydroxy-3-methoxy-10-ethyl-5,8,12,12a-tetrahydro-6H-benzo[a]furo[2,3-g]quinolizine (DF007)

(314) The titled product was prepared by the same procedure as that in example 80, except that 5-ethylfuran-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(315) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.80 (s, 1H), 6.75 (s, 1H), 5.94 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). ESI-MS m/z: 300.1 [M+H].sup.+.

EXAMPLE 129

(S)-2-hydroxy-3-methoxy-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzo[a]furo[2,3-g]quinolizine (DF008)

(316) The titled product was prepared by the same procedure as that in example 80, except that 5-(2-methylpropyl)furan-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(317) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 5.99 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.51 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 3H), 2.69-2.60 (m, 2H), 1.82 (m, 1H), 0.91-0.89 (m, 6H). ESI-MS m/z: 328.1 [M+H].sup.+.

EXAMPLE 130

(S)-2-hydroxy-3-methoxy-10-(2-chloroethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]furo[2,3-g]quinolizine (DF009)

(318) The titled product was prepared by the same procedure as that in example 80, except that 5-(2-chloroethyl)furan-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(319) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.74 (s, 1H), 5.99 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (m, 3H), 3.51 (d, J=14.8 Hz, 1H), 2.85-2.74 (m, 3H), 2.69-2.60 (m, 2H), 2.34 (m, 1H), 1.90 (m, 2H). ESI-MS m/z: 350.1 [M+H].sup.+.

EXAMPLE 131

(S)-2-hydroxy-3-methoxy-5,8,12,12a-tetrahydro-6H-benzo[a]pyrrolo[3,2-g]quinolizine (DP001)

(320) The titled product was prepared by the same procedure as that in example 80, except that pyrrole-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(321) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 5.89 (d, J=5.1 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 271.1 [M+H].sup.+.

EXAMPLE 132

(S)-2-hydroxy-3,10-dimethoxy-5,8,12,12a-tetrahydro-6H-benzo[a]pyrrolo[3,2-g]quinolizine (DP002)

(322) The titled product was prepared by the same procedure as that in example 80, except that 5-methoxypyrrole-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(323) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.10 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 301.1 [M+H].sup.+.

EXAMPLE 133

(S)-2-hydroxy-3,10-dimethoxy-5,8,12,12a-tetrahydro-6H-benzo[a]pyrrolo[2,3-g]quinolizine (DP003)

(324) The titled product was prepared by the same procedure as that in example 80, except that 5-methoxypyrrole-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(325) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.02 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 301.1 [M+H].sup.+.

EXAMPLE 134

(S)-2-hydroxy-3-methoxy-5,8,13,13a-tetrahydro-6H-benzo[a]pyrido[3,2-g]quinolizine (DP004)

(326) The titled product was prepared by the same procedure as that in example 80, except that pyridine-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(327) .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.33 (d, J=9.1 Hz, 1H), 7.73 (d, J=7.3 Hz, 1H), 7.03 (m, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 6.02 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (in, 2H). ESI-MS m/z: 283.1 [M+H].sup.+.

EXAMPLE 135

(S)-2,10-dihydroxy-3,9-dimethoxy-5,8,13,13a-tetrahydro-6H-benzo[a]pyrido[3,2-g]quinolizine (DP005)

(328) The titled product was prepared by the same procedure as that in example 80, except that 4-methoxy-5-hydroxypyridine-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(329) .sup.1H NMR (CDCl.sub.3, 400 MHz): 8.33 (d, J=9.1 Hz, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 329.1 [M+H].sup.+.

EXAMPLE 136

(S)-2-hydroxy-3,10-dimethoxy-5,8,13,13a-tetrahydro-6H-benzo[a]pyrido[2,3-g]quinolizine (DP006)

(330) The titled product was prepared by the same procedure as that in example 80, except that 6-methoxypyridine-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.

(331) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.63 (d, J=7.1 Hz, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 6.43 (d, J=7.1 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 313.1 [M+H].sup.+.

EXAMPLE 137

(S)-2-methyl-9-(2-methylpropyl)-4,7,11,11a-tetrahydro-5H-thieno[3,2-a]thieno[3,2-g]quinolizine (SS001)

(332) The titled product was prepared by the same procedure as that in example 78, except that 5-methyl-2-thienal was used to replace 3-methoxy-4-benzyloxybenzaldehyde and 5-(2-methyl propyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.

(333) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.15 (s, 1H), 6.10 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.56 (d, J=10.8 Hz, 1H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 4H), 2.36 (s, 3H), 1.82 (m, 1H), 0.91-0.89 (m, 6H). ESI-MS m/z: 318.1 [M+H].sup.+.

EXAMPLE 138

(S)-2-methyl-9-(2-chloroethyl)-4,7,11,11a-tetrahydro-5H-thieno[3,2-a]thieno[3,2-g]quinolizine (SS002)

(334) The titled product was prepared by the same procedure as that in example 78, except that 5-(2-chloroethyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.

(335) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.15 (s, 1H), 6.10 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.60-3.55 (m, 3H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 4H), 2.36 (s, 3H). ESI-MS m/z: 324.0 [M+H].sup.+.

EXAMPLE 139

(S)-2-methyl-9-(2-chloroethyl)-4,7,11,11a-tetrahydro-5H-thieno[3,2-a]furo[3,2-g]quinolizine (SF001)

(336) The titled product was prepared by the same procedure as that in example 78, except that 5-(2-chloroethyl)furan-2-acetic acid was used to replace thiophene-2-acetic acid.

(337) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.16 (s, 1H), 6.11 (s, 1H), 4.00 (d, J=14.8 Hz, 1H), 3.84 (s, 3H), 3.63-3.56 (m, 3H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 4H), 2.36 (s, 3H). ESI-MS m/z: 308.0 [M+H].sup.+.

EXAMPLE 140

(S)-2-methyl-9-(2-chloroethyl)-4,7,11,11a-tetrahydro-5H-furo[3,2-a]thieno[3,2-g]quinolizine (FS001)

(338) The titled product was prepared by the same procedure as that in example 78, except that 5-methyl-2-furfural was used to replace 3-methoxy-4-benzyloxybenzaldehyde and 5-(2-chloroethyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.

(339) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.15 (s, 1H), 6.09 (s, 1H), 4.04 (d, J=14.8 Hz, 1H), 3.84 (s, 3H), 3.60-3.56 (m, 3H), 3.48 (d, J=14.9 Hz, 1H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 4H), 2.37 (s, 3H). ESI-MS m/z: 308.0 [M+H].sup.+.

EXAMPLE 141

(S)-11-(2-methylpropyl)-6,9,13,13a-tetrahydro-5H-indolo[2,3-a]thieno[3,2-g]quinolizine (IS001)

(340) The titled product was prepared by the same procedure as that in example 78, except that tryptamine was used to replace 3-methoxy-4-benzyloxyphenylethylamine and 5-(2-methylpropyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.

(341) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.20-7.13 (m, 4H), 6.56 (s, 1H), 4.04 (d, J=14.8 Hz, 1H), 3.64 (d, J=10.8 Hz, 1H), 3.47 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 4H), 2.69-2.60 (m, 2H), 1.82-1.77 (m, 1H), 0.96 (s, 6H). ESI-MS m/z: 337.4 [M+H].sup.+.

EXAMPLE 142

(S)-11-(2-chloroethyl)-6,9,13,13a-tetrahydro-5H-indolo[2,3-a]thieno[3,2-g]quinolizine (IS002)

(342) The titled product was prepared by the same procedure as that in example 78, except that tryptamine was used to replace 3-methoxy-4-benzyloxyphenylethylamine and 5-(2-chloroethyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.

(343) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.20-7.13 (m, 411), 6.56 (s, 1H), 4.08 (d, J=14.8 Hz, 1H), 3.70-3.64 (m, 3H), 3.47 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 4H), 2.69-2.60 (m, 4H), 1.82-1.77 (m, 1H). ESI-MS m/z: 343.7 [M+H].sup.+.

EXAMPLE 143

(S)-3-methoxy-11-(2-methylpropyl)-6,9,13,13a-tetrahydro-5H-indolo[2,3-a]thieno[3,2-g]quinolizine (IS003)

(344) The titled product was prepared by the same procedure as that in example 78, except that 6-methoxytryptamine was used to replace 3-methoxy-4-benzyloxyphenylethylamine and 5-(2-methylpropyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.

(345) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.08-7.03 (m, 311), 6.56 (s, 1H), 4.04 (d, J=14.8 Hz, 1H), 3.64 (d, J=10.8 Hz, 1H), 3.47 (d, J=14.8 Hz, 1H), 3.25-3.08 (m, 411), 2.69-2.60 (m, 2H), 1.82-1.77 (m, 1H), 0.96 (s, 611). ESI-MS m/z: 367.4 [M+H].sup.+.

EXAMPLE 144

(S)-3-methoxy-11-(2-chloroethyl)-6,9,13,13a-tetrahydro-5H-indolo[2,3-a]thieno[3,2-g]quinolizine (IS004)

(346) The titled product was prepared by the same procedure as that in example 78, except that 6-methoxytryptamine was used to replace 3-methoxy-4-benzyloxy phenylethylamine and 5-(2-chloroethyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.

(347) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.08 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.56 (s, 1H), 6.21 (s, 1H), 4.04 (d, J=14.8 Hz, 1H), 3.86 (s, 1H), 3.64 (d, J=10.8 Hz, 1H), 3.70-3.64 (m, 3H), 3.25-3.08 (m, 411), 2.69-2.60 (m, 4H), 1.82-1.77 (m, 1H). ESI-MS m/z: 373.8 [M+H].sup.+.

EXAMPLE 145

(S)-2-hydroxy-3-methoxy-10-(2-hydroxyethoxymethyl)-5,8,12,12a-tetra hydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS045)

(348) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(2-hydroxyethoxymethyl)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(349) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.49 (d, J=13.6 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.80 (s, 3H), 3.67-3.55 (m, 6H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 373.1 [M+H].sup.+.

EXAMPLE 146

(S)-2-hydroxy-3-methoxy-10-(dimethylaminomethyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS046)

(350) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(dimethylaminomethyl)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(351) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.80 (s, 3H), 3.67-3.55 (m, 4H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H), 2.10 (s, 6H). ESI-MS m/z: 345.1 [M+H].sup.+.

EXAMPLE 147

(S)-2-hydroxy-3-methoxy-10-(morpholine-N-methyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS047)

(352) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(morpholine-N-methyl)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(353) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.80 (s, 3H), 3.67-3.50 (m, 8H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H), 2.55-2.50 (t, J=12 Hz, 4H). ESI-MS m/z: 387.1 [M+H].sup.+.

EXAMPLE 148

(S)-2-hydroxy-3-methoxy-10-((N-methyl)-piperazine-N-methyl)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS048)

(354) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-((N-methyl)piperazine-N-methyl)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(355) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.80 (s, 3H), 3.67-3.50 (m, 4H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H), 2.55-2.50 (t, J=12 Hz, 4H), 2.42-2.38 (t, J=12 Hz, 4H), 2.17 (s, 3H). ESI-MS m/z: 400.2 [M+H].sup.+.

EXAMPLE 149

(S)-4,7,12,12a-tetrahydro-5H-thieno[3,2-a]benzooxazole[6,5-g]quinolizin e (SBE01)

(356) The titled product was prepared by the same procedure as that in example 31, except that benzooxazole-5-acetic acid was used to replace 2,5-dimethoxyphenylacetic acid.

(357) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.62 (s, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.75 (s, 1H), 6.70 (d, J=7.8 Hz, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.67-3.50 (m, 2H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 283.0 [M+H].sup.+.

EXAMPLE 150

(S)-10-(2-methylpropyl)-5,8,12,12a-tetrahydro-6H-benzofuro[6,5-a]thieno[3,2-g]quinolizine (FBS01)

(358) The titled product was prepared by the same procedure as that in example 80, except that 2-methylpropionyl chloride was used to replace acetyl chloride and benzofuran-5-acetic acid was used to replace 3-methoxy-4-benzyloxyphenylethylamine.

(359) .sup.1H NMR (CDCl.sub.3, 400 MHz): 7.42 (d, J=7.8 Hz, 1H), 7.30 (s, 1H), 7.12 (s, 1H), 6.75 (s, J=7.8 Hz, 1H), 6.14 (s, 1H), 4.10 (d, J=14.8 Hz, 1H), 3.56 (m, 2H), 3.25-3.08 (m, 3H), 2.78-2.70 (m, 2H), 2.60 (d, J=12.8 Hz, 2H), 1.82 (m, 1H), 0.91-0.89 (m, 6H). ESI-MS m/z: 338.0 [M+H].sup.+.

EXAMPLE 151

(S)-2-methyl-8-methoxy-9-((2-morpholino)ethoxy)-4,7,12,12a-tetrahydro-5H-benzo[g]thieno[3,2-a]quinolizine (AS053)

(360) The titled product was prepared by the same procedure as that in example 3, except that 7-(morpholine-N-ethoxy)-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.

(361) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.78 (d, J=8.1, 1H), 6.70 (d, J=8.1, 1H), 6.22 (s, 1H), 4.11 (t, J=13.0 Hz, 1H), 3.95 (d, J=14.8 Hz, 1H), 3.83 (s, 3H), 3.68-3.64 (m, 6H), 3.29-3.24 (m, 2H), 3.16-3.08 (m, 4H), 2.85-2.70 (m, 2H), 2.51 (t, J=13.0 Hz, 4H), 2.23 (s, 3H). ESI-MS m/z: 415.0 [M+H].sup.+.

EXAMPLE 152

(S)-2-hydroxy-3-methoxy-10-(acetyldimethylamino)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine (DS049)

(362) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(acetyldimethylamino)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(363) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.80 (s, 3H), 3.67-3.50 (m, 2H), 3.49 (s, 6H), 3.42 (s, 2H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 373.1 [M+H].sup.+.

EXAMPLE 153

(S)-2-hydroxy-3-methoxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine-10-acetic acid (DS050)

(364) The titled product was prepared by the same procedure as that in example 80, except that 5-(carboxyethyl)thiophene-2-acetic acid was used to replace ethyl 5-ethylthiophene-2-acetate.

(365) .sup.1H NMR (CDCl.sub.3, 400 MHz): 10.80 (b, 1H), 6.79 (s, 1H), 6.75 (s, 1H), 6.23 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.80 (s, 3H), 3.67-3.50 (m, 2H), 3.42 (s, 2H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 346.0 [M+H].sup.+.

EXAMPLE 154

(S)-2-hydroxy-3-methoxy-10-(ethylol)-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine-10-acetic acid (DS051)

(366) The titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(ethylol)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.

(367) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.18 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.80 (s, 3H), 3.67-3.50 (m, 4H), 3.42 (s, 2H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.74-2.81 (t, J=12.8 Hz, 2H), 2.69-2.60 (m, 2H). ESI-MS m/z: 332.0 [M+H].sup.+.

EXAMPLE 155

Methyl(S)-2-hydroxy-3-methoxy-5,8,12,12a-tetrahydro-6H-benzo[a]thieno[3,2-g]quinolizine-10-acetate (DS052)

(368) The titled product was prepared by the same procedure as that in example 80, except that 5-(methoxycarbonylethyl)thiophene-2-acetic acid was used to replace ethyl 5-ethylthiophene-2-acetate.

(369) .sup.1H NMR (CDCl.sub.3, 400 MHz): 6.79 (s, 1H), 6.75 (s, 1H), 6.23 (s, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.87 (s, 3H), 3.69 (s, 3H), 3.60-3.52 (m, 2H), 3.42 (s, 2H), 3.25-3.08 (m, 3H), 2.90-2.81 (m, 1H), 2.69-2.60 (m, 2H). ESI-MS m/z: 359.0 [M+H].sup.+.

(370) Pharmacological Experiments

(371) 1. In the present invention, pharmacological experiments were conducted with respect to the affinity of diarylo[a,g]quinolizines of formulae (I) on dopamine D1, dopamine D2, 5-HT.sub.1A and 5-HT.sub.2A receptors. The experimental materials required for the pharmacological experiments were commercially purchased, unless otherwise specified.

(372) (1) Determination of the affinity of the diarylo[a,g]quinolizines of formula (I) and derivatives thereof on dopamine D1, dopamine D2, 5-HT.sub.1A and 5-HT.sub.2A receptors.

(373) 1) The Experimental Method

(374) The compound of the invention at different concentrations (10.sup.5 M-10.sup.11 M), an isotope receptor ligand and a receptor protein were loaded into a reaction tube, incubated at 30 C. in a water bath for 60 min, and then terminated in a refrigerator. The mixture was filtered through suction filtration using GF/C glass fiber paper on a Millipore filter (millipore) cell sample collector, and dried. The resulting sample was placed into a 0.5 mL tube, added with 500 L of liquid scintillation fluid, and counted for measuring the intensity of radioativity.

(375) 2) The Expertimental Materials

(376) (1) materials for receptor construction and cell culture: Escherichia coli. DH5strain; insect virus transfer vector pVL1393 plasmid; BaculoGold linear Chinese baculovirus DNA, purchased from ParMingen company; mkD1RcDNA; rD2R cDNA; various restriction endonucleases, TaqDNA polymerase, T4 ligase, etc., LB medium; insect cell culture TNM-FH.

(377) (2) The Experimental Materials for Binding Receptor

(378) For dopamine D1 receptor: isotope receptor ligand [.sup.3H]-SCH23390 (85.0 Ci/mmol) (D1-selective, purchased from Amersham Corporation), D1 receptor protein expressed in HEK-293 cells;

(379) For dopamine D2 dopamine receptor: isotope receptor ligand [.sup.3H]Spiperone (77.0 Ci/mmol) (D2-selective, purchased from Amersham Corporation), D2 receptor protein expressed in HEK-293 cells;

(380) For 5-HT.sub.1A receptor: isotope receptor ligand [3H]8-OH-DPAT; 5-HT.sub.1A receptor protein expressed in HEK-293 cells;

(381) For 5-HT.sub.2A receptor: isotope receptor ligand [3H]-Ketanserin; 5-HT.sub.2A receptor protein expressed in HEK-293 cells;

(382) Firstly, the above receptor proteins were dissolved in DMSO and then diluted with double distilled water to the appropriate concentration (10.sup.5 M-10.sup.11 M).

(383) (+) Butaclamo was purchased from RBI Company, GF/C glass fiber filter paper was purchased from Whatman Co., liquid scintillation fluid (dopamine D1, D2 receptors)/liposoluble scintillation fluid (5-HT.sub.1A. 5-HT.sub.2A receptor), Beckman LS-6500 multi-function liquid scintillation counter.

(384) 3. The Test Results are Shown in Tables 1 and 2.

(385) Table 1 results of the affinity of some representative compounds on dopamine D1 and D2 receptors

(386) TABLE-US-00002 D1 receptor D2 receptor Compound inhibition % Ki (nM) IC.sub.50 (nM) inhibition % Ki (nM) IC.sub.50 (nM) AS003 99.80 37.94 2.21 73.99 4.30 40.31 ND ND AS004 86.32 114.84 22.38 229.68 44.76 6.97 ND ND AS005 98.23 47.57 6.18 86.81 11.28 62.98 ND ND AS022 69.25 ND ND 5.21 ND ND AS023 89.62 357.20 7.83 714.40 15.66 22.17 ND ND AS032 96.00 158.94 28.91 416.4 26.87 13.75 ND ND AS050 99.02 685.43 72.20 1520.9 356.52 22.63 ND ND AS051 76.38 ND ND 1.29 ND ND DS001 86.98 4.30 171.80 8.49 88.02 15.16 396.08 68.22 DS003 98.16 26.33 0.37 48.06 0.68 98.50 40.83 3.80 180.33 16.78 DS005 96.74 61.75 6.88 112.69 12.57 96.31 38.63 2.15 170.60 9.50 DS006 94.29 128.14 9.53 233.85 17.39 99.50 7.54 0.23 32.66 0.98 DS007 97.62 62.19 7.13 113.49 13.00 99.53 17.61 1.95 76.32 8.46 DS013 98.64 16.43 2.81 112.69 12.57 98.37 34.36 2.72 145.64 7.19 DS015 96.10 77.00 2.85 144.38 5.35 97.19 18.38 2.30 55.15 6.89 DS016 95.84 158.42 10.70 297.04 20.06 93.54 49.94 7.8 149.81 23.39 DS008 88.78 ND ND 90.45 79.54 4.83 238.62 14.67 : no test data for the test. ND: Not Dectected.

(387) Table 2 results of the affinity of some representative compounds on 5-HT.sub.1A and 5-HT.sub.2A receptors

(388) TABLE-US-00003 5-HT.sub.1A receptor 5-HT.sub.2A receptor Compound inhibition % Ki (nM) IC.sub.50 (nM) inhibition % Ki (nM) IC.sub.50 (nM) AS003 91.91 405.01 87.1 514.1 110.6 90.43 1074.70 22.4 2230.5 46.5 AS004 51.69 ND ND 44.24 ND ND AS005 98.58 129.82 3.03 162.40 3.80 76.11 ND ND AS022 6.60 ND ND 32.31 ND ND AS023 76.45 ND ND 60.08 ND ND AS032 74.09 ND ND 30.01 ND ND AS050 49.26 ND ND 74.25 ND ND AS051 33.90 ND ND 46.59 ND ND AI001 88.22 728.23 104.19 911.02 130.36 50.46 ND ND DS003 92.10 997.76 189.57 1248.15 237.09 45.15 ND ND DS005 85.33 1966.00 228.96 2459.45 286.45 29.55 ND ND DS006 83.71 ND ND 50.31 ND ND DS007 87.03 863.79 77.32 1080.60 96.73 53.34 ND ND DS013 89.84 553.09 81.59 691.92 102.07 34.81 ND ND DS015 92.24 118.7 23.02 147.68 28.64 ND ND ND ND: Not detected

(389) It can be seen from the above that the tested compounds have very strong affinity on dopamine D1 and D2 receptors. Further, some compounds of the present invention exhibit a strong affinity on 5-HT.sub.1A.

INDUSTRIAL APPLICATION

(390) The diarylo[a,g]quinlizines of the invention have relatively low toxicity and good solubility.

(391) The preparation method for the diarylo[a,g]quinlizines and derivatives of the invention has advantages of, for example, mild reaction condition, abundant and readily available raw materials, simple operation and post-treatment, good selectivity, etc.

(392) The diarylo[a,g]quinlizines and derivatives thereof according to the invention have excellent selectivity among different subtypes of serotonin receptors and dopamine receptors.

(393) Therefore, the compounds of the invention can be used in preparing a medicament for treating a disease relating to nervous system, especially to the dopamine receptors D1 and D2 as well as serotonin receptors 5-HT.sub.1A and 5-HT.sub.2A.