CA2355469A1 - Dibenzo[a,g]quinolizinium derivatives and the salts thereof - Google Patents

Abstract

The present invention provides a 5,6-dihydrodibenzo[a,g]quinolizinium derivative and the salts thereof of formula (I) which specifically inhibits the sterol 14-reductase which is involved in the distal pathway of cholester ol biosynthesis, and the use of the compound of formula (I) for treating hypercholesterolaemia or hyperlipidaemia, wherein R1, R2, R3, R4, X and 2 ar e defined in the claims.

Description

DIBENZO[a,g]Q!UINOLIZINIUM DERIVATIVES AND
'THE SALTS THEREOF
The present invention relates to 5,6-dihydrodibenzo[a,g]quinolizinium derivatives and the salts thereof. More specifically, the present invention relates to 5,6-dihydrodibenzo[a,g]quinolizinium derivatives and the salts thereof which specifically inhibit sterol 14.-reductase which is involved in the distal pathway of cholesterol biosynthesis, and thus exert cholesterol biosynthesis inhibiting effect.
The present invention also relates to the use of 5,6-dihydrodibenzo[a,g]-quinolizinium derivatives a~c~d the salts thereof which are represented by formula (I) as set forth below for treating hypercholesterolemia or hyperlipidaemia.
BACKGROUND ART
Cholesterol is an important vital constituent of cell membrane in mammal and is involved in cell division, growth, development and control of differentiation, and also is a precursor of various essential metabolites (for example, steroid hormones, bile acids). However, it may cause hyperlipidaemia which leads to atherosclerosis if its intake or production within the body is excess.
Hyperlipidaemia leads to cardiovascular disease which is a leading cause of death in humans. It is usually caused when cholesterol or triglyceride exceeds a proper level (i.e., total cholesterol level for adults at the age of between 30 and 40 is about 200 mg/dl), and then, is deposited to the inner wall of an artery to form atheroma plaques, thereby blood flow being inhibited which causes cardiac failure or cerebral stroke. Cholesterol is synthf;sized mainly in the liver in mammals and the synthetic pathway thereof is started from acetyl-CoA and is completed after at least 32 steps of enzymatic reactions.

Cholesterol biosyrnthesis which occurs in mammal can be summarized according to the enzyme reaction patterns in which each intermediate is formed as in the following reaction scheme 1.
Reaction Scheme 1 I
Acetate(C2) --~~ Mevalonate (C6) I- 1--~ Squalene (C30) III
------~ Lanosterol (C30) ---a Cholesterol (C27) In the above reaction scheme, steps I and II undergo polymerization, and steps II and III undergo cvyclization. In step IV, transformation, demethylation, isomerization or reduction of steroid ring is proceeded. Cholesterol biosynthesis is carefully controlled by flue mufti-step regulation, i.e., the so-called multivalent coordinate regulation. For example, 3-~i-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) is the main rate-limiting enzyme in the cholesterol biosynthesis. It reduces HMG-CoA synthesized from acetyl-CoA during the early stage of the biosynthetic pathway starting from acetate (C2) to mevalonate (C6) and is inhibited in vivo by the final product, cholesterol. More specifically, the activity of this enzyme is controlled by dietary cholesterol, oxysteroids and mevalonate derivatives in a feed-back inhibition manner. For the past decade, the lipid-lowering agents have been developed based on their inhibiting activities against this enzyme. Most of currently marketed therapeutic agents for hyperlipidaemia which have; been developed based on such mechanism include, for example, statins such as lovastatin, pravastatin, simvastatin, atorvastatin, and cerivastatin. However, if cholesterol biosynthesis is suppressed by inhibiting the activity of HMG CoA reductase which is the rate limiting enzyme at the early stage of cholesterol biosynthesis, there may be many side effects that the synthesis of many important biomolecules such as dolicol, isopentenyl pyrophosphate, haem A, and ubiquinone which are also derived from mevalonate are suppressed together.
Therefore, it may be <~dvantageous to block cholesterol biosynthesis at a step distal to HMG-CoA reductase in order to prevent depletion of such essential intermediates.
Accordingly, recent researches have been focused on the development of new type of therapeutic agents for hyperlipidaemia which can effectively block only the post-squalene steps without interfering HMG-CoA reductase activity.
For example, the activation mechanisms of the distal enzymes responsible for the post-squalene pathway in the cholesterol biosynthesis which comprises the sequence of 'squalene -i lanosterol -i ;~ymosterol --~ desmosterol -i cholesterol' have been studied, and some attempts to screen and develop a drug which can specifically inhibit the activity of the 'target enzyme responsible for the distal pathway of cholesterol biosynthesis, have been made. Especially, based on the inhibitory activity of squalene epoxidase responsible for the pathway of 'squalene --~
lanosterof, a benzylamine series compound, NB598 has been developed by Banyu Pharmaceutical Co. of Japan; Squalenestatin I has been developed by the researchers of Glaxo Wellcome Limited, a British company on the basis of its inhibition of squalene synthase which is responsible for the synthesis of squalene from famesyl pyrophosphate. RPRI 07393 has been developed as a potent squalene synthase inhibitor by researchers at Rhone-Poulenc, France. Further, Taton et al.
have reported MDL 28,81 ~~ having 8-azadecaline ring based on the inhibition of 2,3-oxidosqualene cyclase responsible for the cyclization reaction in which squalene epoxide is converted into methylsterol (See, Biochem. Biophys. Res.
Commun. 1986, 138, 764-70~. These NB598, Squalenestatin I, RPR107393 and MDL 28,815 which inhibit the activities of enzymes responsible for the post-mevalonate pathway in the cholesterol biosynthetic pathway have a merit that they can selectively inhibit the cholesterol biosynthesis without effecting on the production of other important intermediates which are derived from mevalonate, differently from the drugs that target HMG-CoA reductase responsible for the early stage of cholesterol biosynthesis.
However, these agents have not yet been commercialized as therapeutic agents for hyperlipidaemia.
DISCLOSURE OF THE INVENTION
The present inventors have conducted an extensive research for many years in order to develop a novel class of cholesterol biosynthetic inhibitor which specifically inhibits the enzynne involved in the step of 'lanosterol -i cholesterol.
As a result, the inventors have surprisingly discovered that 5,6-dihydrodibenzo-[a,g]quinolizinium derivatives and the salts thereof which are represented by formula (I) as set forth hereinafter strongly inhibit the activity of sterol 14-reductase which catalyzes the reduction of 4,4-dimethyl-8,14-dien-3 (3-0l and thus have completed the present invention.
Based on this findings, it was possible to provide a cholesterol biosynthesis inhibitor which comprises :i,6-dihydrodibenzo[a,g]quinolizinium derivatives and the salts thereof which are represented by formula (I) as the main component which specifically inhibits the sterol 14-reductase in the distal pathway of the cholesterol biosynthesis.
It is therefore an object of the present invention to provide 5,6-dihydrodibenzo[a,g]quinoLizinium derivatives or the salts thereof which are represented by formula (I) as set forth below.
Another object of the present invention is to provide a cholesterol biosynthesis inhibitor which comprises 5,6-dihydrodibenzo[a,g]quinolizinium derivatives and the salts thereof which are represented by formula (I).
Further object of tlhe present invention is to provide a pharmaceutical composition for treating; hyperlipidaemia which comprises 5,6-dihydro-dibenzo[a,g]quinolizinium derivatives and the salts thereof which are represented by formula (I) and a pharmaceutically acceptable excipient.
Still another object of the present invention is to provide a method for treating hyperlipidaemia by inhibiting cholesterol biosynthesis, especially inhibiting sterol 14-reducta.se with the above pharmaceutical composition.
Further objects and. advantages of the invention will become apparent through reading the remainder of the specification.
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the detailed description of the preferred embodiment in addition to the scope of the invention defused by the Claims.
Hereinbelow, the application will be illustrated in more detail.
5,6-Dihydrodibenzo[a,g]quinolizinium derivatives and the salts thereof according to the present invention have the similar chemical structure to the coridaline-series alkaloids in the form of quaternary ammonium salt which are major active components of Corydalis Turtschaninowii Besser. Corydalis Turtschaninawii Besser is an annual plant widely distributed in the mountains and fields of Korea and has been used in the prescription of sedative agent or hemostatic agent in herbal medicine. This coridaline in the form of a quaternary S ammonium salt has been known to have a week sedative action and a strong gastric juice secretion action, and UK Patent No. 1,265,627 and German Patent No.
2,043,218 disclose its use as an anti-ulcer agent.
The inventors of the present invention have discovered the novel compound of the present invention in the course of screening new cholesterol biosynthesis inhibitor.
This discovery was fiully supported by a screening method for the activity of sterol 14-reductase that was established by the inventors since the inventors have started the research for a new drug.
The detailed screening method will be explained in detail in the working examples. Thus, the principle thereof will be briefly explained below.
That is, sterol 14-reductase is one of the main regulatory enzymes for lanosterol -1 cholesterol pathway and is responsible for reduction of the double bond formed when a methyl group attached to the carbon at I4-position of lanosterol is demethylated. First, a screening system for sterol 14-reductase was constructed in which 4,4.-dimethyl-Sa-cholesta-7,14-dien-3(3-0l is used as a substrate and then, the effect on the activity of sterol 14-reductase was investigated in the screening system. It is possible to obtain the correlation that a substance inhibiting the activity of sterol 14-reductase inhibits cholesterol biosynthesis by comparing the results obtained from the screening tests with those of the actual animal experiments.

_7_ Dibenzo[a,g]quinolizinium derivative for the purpose of the present invention can be represented by the formula (I) below.
~~CHZZ

wherein, R' and R2 which may be the same or different from each other, represent a hydroxy group or an alko:Ky group having 1 to 4 carbons or R' and RZ
together represent a methylenedioxy group;
R3 represents a hydroxy group or an alkoxy group having 1 to 4 carbons;
R4 represents a hydrogen atom, an alkyl group having 1 to 8 carbons, or an alkenyl group having 3 to 8 carbons;
X represents inorganic acid ion, organic acid ion or halide, more particularly, nitrate, sulfate, acetate, tartrate, maleate, succinate, citrate, fumarate, aspartate, salicyla.te, glycerate, ascorbate, fluoride, chloride, iodide or bromide, Z represents an alkyl group having 5 to 12 carbon, or an alkenyl group having 4 to 6 carbon, a N b~enzotriazolyl group, a quinolinyl group, a furyl group, a substituted furyl group, or a group represented by the formula ZZ Z' A_ Z3 \\B
i Z'4 Zs _g_ wherein Z', Z2, Z3, Z4 and ~'.5 which may be the same or different from each other, represent a hydrogen atom, halogen, an alkyl group having 1 to S carbons, a trifluoromethyl group, a phenyl group, a substituted phenyl group, a vitro group, an alkoxy group having 1 to 4 carbons, a methylenedioxy group, a trifluoro-methoxy group, a hydroxy group, a~ benzyloxy group, a phenoxy group, a vinyl group, a benzenesulfonylmethyl group or a methoxycarbonyl group; and A and B which may be the same or different from each other, represent carbon or nitrogen.
The cholesterol biosynthesis inhibitor according to the present invention, especially S,6-dihydrodibenzo[a,g]quinolizinium derivatives or the salts thereof as the inhibitor of sterol 14-reductase can preferably be represented by Table 1 below:
Table 1 R:z R~
( r NIX

I

I ~
O~CHzZ
R~

Rs Formulu Iu omp.n . R R R~ Z X m.p.('C) R

1 OMe OMe OMe Et -CHz(CHz),oCHaCI 150 Me 2 OMe OMe OMe Et \ / Me CI 102 Me F F

3 OMe OMe OMe Et \ / F CI 72 lO

F F

4 OMe OMe OMe Et Cl 210 F
\ /

o~v 5 OMe OMe OMe Et \ / Me CI 100 oMe 15 6 OMe OMe OMe Et CI 85 ~9 \ /

M~

7 OMe OMe OMe Et \ / CI 175 NOz 8 OMe OMe OMe Et \ / ~ CI 82 9 OMe OMe OMe Et \ / CF, CI 115 ~~ _ 10 OMe OMe OMe Et \ / F CI 76 11 OMe OMe OMe Et \ / CI 117 CFa 12 OMe OMe OMe Et \ / CI 70 OMe Rl R2 R3 R4 Z A m.p.('C) omp.no F F

13 OMe OMe OMe Et ~ ~ cF3 CI 85 F F

14 OMe OMe OMe Et ~ ~ oen CI 71 Ma 15 OMe OMe OMe Et ~ ~ CI 72 Me 16 OMe OMe OMe Et ~ ~ n CI 83 17 OMe OMe OMe Et c~ CI 114 N

18 OMe OMe OMe Et ~ ~ CI 165 ci 1g OMe OMe OMe Et ~ ~ Br Ct 186 F'~

IS _-.
20 OMe OMe~ OMe Et \ ~ CI 72 21 OMe OME; OMe Et ~ ~ ~ CI 76 o ~

~

22 OMe OMe OMe Et ~ ~ oMa CI 75 F

23 OMe OMe OMe Et ~ ~ CI 92 C

24 OMe OMe OMe Et ~ ~ CI 131 Me N02 O~N

2S 25 OMe OMe OMe Et ~ ~ ~ CI 98 Me 26 OMe ONIe OMe Et -CH=CHz CI 91 R~ R2 Rg R4 Z A m.p.
( ~
) omp.no 27 OMe OIMe OMe Et ~ ~ Ma CI 167 Ma 28 OMe OIMe OMe Et ~ ~ Ma CI 87 Me I
N

29 OMe OMe OMe Et ~ N CI 89 Me 30 OMe OMe OMe Et ~ ~ CI 85 Me _ 31 OMe OMe OMe Et ~ ~ Me CI 87 32 OMe OMe OMe Et ~ ~ CI 76 Ma 33 OMe O~Me OMe Et CI 85 ~
~

F'c 34 OMe O~Me OMe Et CI 95 ~
~

Br OMe 35 OMe OMe OMe Et CI 135 ~
~

oMa ~ OMe CIMe OMe Et I ~ ~ CI 104 N

OMe 37 OMe C)Me OMe Et ~ ~ oMe CI 110 OMe S~h 38 OMe OMe OMe Et ~ I CI 100 ~ X

39 OMe OMe OMe Et 0 CI 85 Noz ci 40 OMe OMe OMe Et I ~ ) CI 105 mp.no R' RZ R3 R4 Z A m.p.('C) Me 41 OMe ONfe OMe Et ~c~ CI 195 42 OMe OMIe OMe Et ~ ~ ocF3 CI 103 43 OMe OMIe OMe Et ~ ~ CI 110 i SIMe~
44 OMe OMe OMe Et ~

c~

45 -0-CH2-0- OMe Et -CH~(CHi),oCH3i 115 ' Me 46 -0-CHrO- OMe Et ~ ~ Me I 155 Ma F F

47 -0-CHrO- OMe Et ~ ~ F I 11y F F

48 -0-CHz-0- OMe Et ~ ~ oMe I 132 OMe 0=N
49 -0-CHI-0- OMe Et ~ I 115 ~ i ~

50 -0-CHz-0- OMe Et ~ ~ CF, I 142 Et 51 -0-CHz-0- OMe \ / I 134 F F

52 -0-CHs-0. OMe Et ~ ~ ~ cF, I 136 F F

53 -0-CHz-0- OMe Et ~ ~ ~n I 115 WO 00/37468 PCT/1tR99/00030 omp.noR' RZ R3 Rq Z A m.p.
( ~
) 54 -0-CHrO- 0Me Et ~ N G I 139 Ma 55 OEt OEt OMe Et ~ ~ Me CI 132 Me F F

56 OEt OEi; OMe Et ~ ~ F CI 100 F

F F

57 OEt OEi OMe Et ~ ~ CF, CI 113 F F

58 OEt OEt OMe Et ~ ~ Ci CI 126 N

F F

59 OH OH OMe Et ~ ~ F CI 82 F F

is F F

60 OH OH OMe Et ~ ~ CF, CI gg i F F

61 OEt OEt OEt Et -CHz(CHx),oCH9CI 174 62 OEt OEt OEt Et ~ ~ cF, CI 142 -_ 63 OEt OEi OEt Et ~ ~ CI 127 F F

64 OEt OEt OEt Et ~ ~ cF, CI 110 F F

~ ~ ~

65 OEt OEi: OEt Et C~ CI 136 N

Me 66 OPr OPr OPr Et -~-Me CI 133 Me .oynp.no.R,' H2 R,3 R4 Z A m.p.('C) f 67 OPr OPr OPr Et ~ F CI 122 S 68 OPr OPr OPr Et ~ ~ cF, CI 151 Me 89 OMe OMe OMe Et --~-E-Me HS04 123 Me F F
70 OMe OMe OMe Et ~ ~ F CH~CO~108 F

lO 71 OMe OMe OMe Et ~ ~ ci NO; 127 N

The compounds represented by the formula (I) according to the present invention can be synthesi2;ed starting from the compound of formula (II) below 15 according to the reaction scheme 2 described below.
Reaction Scheme 2 R2 ~ R2 ~ O CH9 I / N+ X I
R~ I ~ Acetonylatfon R' / I N Aikylation OMe ~ I ~ OMe ( II ~ / R' (jll~ / Ra Rz _ HO 1 R~ I / I N+ X DeproteCtion HO I / ~t~l~ x O-Alkytatfon R4 I ~ OMe R4 I ~ OH
R3 ( V ) I / Ra s 30 R I ~ + x _ R~ w _ R~ / N\ ~ I / N+ x OH ZCHy-X R I
R ~ R4 I ~ O~CHZZ
~ R3 ( I ~ / Ra wherein, R', R2, R3, R4, :X and Z are the same as defined in the compound of formula (I) above.
In the first step of the reaction scheme, 5,6-dihydrodibenzo[a,g]quinoli-zinium salt of formula (II) is reacted with acetone in the presence of a base such as sodium hydroxide to give 8-acetonyl-5,6-dihydrodibenzo[a,g]quinolizine compound of the formula (ITI).
In the second step, 8-acetonyl-5,6-dihydrodibenzo[a,g]quinolizine compound and alkyl halide (R4-X) are reacted at SO ~ 100 °C in a polar solvent such as acetonitrile or a non-polar solvent such as toluene to give 13-alkyl-5,6-dihydrodibenzo[a,g]quinolizinium salt of formula (IV).
The third step of the above reaction scheme involves the cleavage reaction of 2,3-methylenedioxy ring or deprotection reaction of 2,3-dimethoxy group in which the compound of formula (IV) is reacted with Lewis acid such as anhydrous aluminum chloride at 80 ~ 160 °C and then subjected to hydrolysis reaction with a dilute acid. According to the reaction conditions, 13-alkyl-2,3-dihydroxy compound may be produced as a major product along with 2,3,9-trihydroxy-, or 2,3,9,10-tetrahydroxy compound and these compounds can be separated by recrystallization or column chromatography. However, it may be possible to use the compound in the fourth step reaction without further separation process.
The fourth step involves a reaction in which the compound of formula (V) obtained from the previous step is selectively alkylated at 2,3-positions with an alkylating reagent such as dimethyl sulfate or iodomethane or reacted with dibromomethane to give 13-alkyl-9-hydroxy-5,6-dihydrodibenzo[a,g]quinolizinium salt of formula (VI) wherein a methylenedioxy ring is introduced.

In the fifth reaction step, the compound of formula (VI) thus obtained is reacted with electrophiles {Z;CHZ-X) to give 9-substituted 5,6-dihydrodibenzo[a,g]-quinolizinium salt.
The compound of formula (IV) used in preparing the compound of formula (I) may also be synthesized under the different reaction condition according to the reaction scheme 3 below.
Reaction Scheme 3 Rz R2 R' I ~ Nw X Reduction R~ I ~ ~ Alkylation OMe ~ I I \ OMe ( h ~ / R3 (VB) / Rs z R \ R2 \ _ i Oxidat'ron R~ I ~ N\ X
R4 \ OMe R
R3 (IV) wherein, R', R2, R3, R4 and X are the same as defined in the compound of formula (I) above.
According to the reaction scheme 3, 1.0 mol of 5,6-dihydrodibenzo[a,g]-quinolizinium salt of the formula (II) is reacted with 1.0 to 3.0 mol of NaBH4 and 2.0 to 4.0 mol of potassium carbonate in an alcoholic solvent to give a compound of the formula (VII) and the; compound thus obtained is then reacted with 1.0 to 3.0 mol of electrophiles (R4-X) in an organic solvent to give 13-alkyl-dibenzo-[a,g]quinolizinium salt of the formula (VIII). Compound (VIII) is then oxidized with N-chlorosuccin imide (NCS) or N-bromosuccin imide to give I 3-substituted 5,6-dihydrodibenzo[a,g]quinolizinium salt of the formula (IV).
In addition, the compound of formula (I) may also be synthesized under the different reaction condition. according to the reaction scheme 4 below.
Reaction Scheme 4 Rz Rz W
R~ I ~ N~ X Pyrolysis R~ I ~ I N~ X _ R4 ~ .\ Q~Me R4 ~ OH
R3 ~ / R3 Rz 2CHz-X R~ I i R4 I I ~. ~~CH2Z
<I) ~ R' wherein, R', R2, R3, R4 , X and Z are the same as defined in the compound of formula {I) above.
According to the reaction scheme 4, 1.0 mol of the compound of the formula (IV) is subjected to pyrolysis in the presence of a non-polar solvent such as decaline or in the absence of a solvent at a high temperature of 100 to 300 °C
to give a compound of the formula (VT) and the compound thus obtained is then reacted with 1.0 to 2.0 mol of ele;ctrophiles (ZCH2-X) to give 9-substituted 5,6-dihydrodibenzo[a,g]quinoliizinium salt of the formula (I).
9-Substituted 5,6-dilnydrodibenzo[a,g]quinolizinium salt of the formula (I) may be transformed into various salts such as halide, sulfate, nitrate, acetate, cinnamate, tinate, tannate, maleate, succinate, citrate, fumarate or fatty acid salt, _18_ etc. on the basis of the salts used in the purification process of the reaction scheme described below.
Reaction Scheme 5 RZ ~ R2 ~ O CH3 R1 I / N+ x R~ I / N
I
R4 ~ ~ O~CHpZ R4 I ~ O~CH2Z
C I ) / Rs SIX) / Rs RZ
I / N+ Y
H_Y R~
R~ I I w O.GH~
~X) / Ra wherein, R', R2, R3 , R , :K and Z are the same as defined in the compound of formula (I) above; and Y represent halide, sulfate, nitrate, acetate, tinnate, tannate, maleate, succinate, citrate, fumarate, or fatty acid salt ion.
In the above rea.ctian scheme, substituted 5,6-dihydrodibenzo[a,g]-quinolizinium salt of the formula (I) is reacted with acetone in the presence of a base such as sodium hydroxide to give 8-acetonyl-5,6-dihydrodibenzo[a,gJ-quinolizine compound of the formula (IX) and the compound thus obtained is reacted with a suitable inorganic acid, organic acid or fatty acid to give various 5,6-dihydrodibenzo[a,g]-quinolizinium compounds of formula (X).
Among 5,6-dihydrodibenzo[a,g]-quinolizinium salts of formula (I), the compound wherein R', RZ, R3, R4 and X each represents a methoxy group, a methoxy group, a methoxy group, an ethyl group and chloride, and Z represents 4-(tert-butyl)phenyl; the compound wherein R', R2, R3, R4 and X each represents a methoxy group, a methoxy group, a methoxy group, an ethyl group and chloride, and Z represents 4-pentaflu.orophenyl; the compound wherein R', RZ, R3, R4 and X
each represents a methoxy group, a methoxy group, a methoxy group, an ethyl group and chloride, and Z represents 4-trifluoromethylphenyl; and the compound wherein R'-R2, R3, R4 and X each represents a methylenedioxy group, a methoxy group, an ethyl group and iodide, and Z represents 4-trifluoromethylphenyl are preferred in an aspect of the pharmaceutical efficacy.
The compound of formula (I) markedly inhibits the cholesterol biosynthesis in the cultured human liver cell culture (HepG2 cell line). In order to investigate the effect of the compour.~d of formula (I) of the invention, the compound was orally administered into male Syrian Golden Hamsters having weights of 90 ~ 11 Og for two weeks and blood w;as then taken from each animal. Plasma lipids, i.e., total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were analyzed using an automatic analy;~er (Automatic analyzer model Hitachi 71 SO). As the results, total cholesterol, LI)L-cholesterol, and triglyceride levels were significantly decreased while HDL-cholesterol value was not significantly changed. In addition, the compound resulted in decrease in a certain degree in the glucose value within the serum.
The compound of" formula (I) may be formulated into a pharmaceutical composition with pharmaceutically acceptable excipients or carriers.
Especially, the composition can desirably be used as the therapeutic agents for treating hypercholesterolemia and hyperlipidaemia by inhibiting sterol 14-reductase.
The composition may be formmlated into a tablet, a syrup or an injection formulation, and thus, can be administ:eyed orally or parenterally. An effective dose will vary depending upon the kind of the excipients or carriers within the range for ixeating hypercholesterolemia and hyperlipidaemia with a dose of 0.1 ~ 50 mg/kg/day of active ingredient being preferable in case of oral administration.

The present invention will be described in greater detail by way of the following examples and synthetic examples. The examples are provided for the purpose of illustration only and should not be construed as limiting the invention which is properly delineated in the Claims.
S3r~~thetic Egamnles Hereinbelow, synthetic examples for the derivative of the compounds represented by the above formula (I) will be described.
Ezamule 1: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-dodecoxy-13-ethyl-10-metrioxybenzo[g]quinolizinium chloride (Compound No. 1 ) l OG of 5,6-dihydro-2,3-methylenedioxybenzo[a]-9,10-dimethoxy-13-ethyl-benzo[g]quinolizinium chloride and l Og of aluminum chloride were suspended in 70 ml of dichloromethane and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. A 15%
hydrochloric acid solution was added to the mixture and the precipitate produced was filtered, washed and dried to give 9g of 5,6-dihydro-2,3-dihydroxybenzo[a]-ethyl-9-hydroxy-10-metho:Kybenzo[g]quinolizinium chloride as a light orange crystal.
lOG of 5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo[g]quinolizinium chloride were suspended in 150 ml of water and 20 g of a 50% sodium hydroxide solution and 20 ml of dimethylsulfate were added thereto. After the mixture v~ras stirred for S hours, a 15% hydrochloric acid solution was added to adjust pH to neutral. The precipitate thus produced was filtered to give 8g of 5,6-diihydro-2,3-dimethoxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo-[g)quinolizinium chloride as a light brown crystal.
1 G of 5,6-dihydro-2,:3-dimethoxybenzo[a]-13-ethyl-9-hydroxy-10-methoxy-benzo[g]quinolizinium chloride, 0.45g of sodium iodide, and 0.41 g of potassium carbonate were dissolved in 10 ml of acetonitrile. After 0.7g of dodecyl bromide was then added thereto, tl:~e mixture was refluxed for 8 hours. Undissolved by-products were filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was then dissolved in chloroform and washed with 10 ml of water. The solution was dried over magnesium sulfate to remove IO water and the residue was then purified by silica gel column chromatography eluting with a mixed solvent of chloroform/methanol ( 15 :1 ) to give 0.24 g of the titled compound as a brov~nn crystal (m.p.: 150 °C).
1H-NMR (300MHz, CDCI,,) ~ : 0.87(t, J= 6.9Hz, 3H), 1.26(m, 12H), 1.50(m, 4I~, 1.68(t, J= 7.2Hz, 3H}, 1.98(m, 4H), 3.35(m, 2H), 3.41(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.01 (s, 3H), 4.50(t, J = 6.9Hz, 2H), 5.10(m, 2H), 6.91 (s, 1H), 7.29(s, lI~, 8.01(d, J= 9.3Hz, 1H), 8.13(d, J= 9.3Hz, 2H), 10.00(s, 1H) gamyle 2: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-[4-(tert-butyl)benzyloxy]-13-ethyl-10-methoxybenzo[g]quinolizinium chloride (C'.ompound No. 2) The process of E:~ample 1 was repeated except that 0.6g of 4-(tert-butyl)benzyl bromide was employed in place of dodecyl bromide to give 0.47g of the titled compound as a brown crystal (m.p.: 102 °C).
'H-NMR (300MHz, CDC13) ~: 1.29(s, 9H), 1.69(t, J= 7.2Hz, 3H), 3.20(m, 2H), 3.39(m, 2H), 3.94(s, 3H), 3.99(s, 3H), 4.11(s, 3H), 4.98(m, 2H), 5.53(s, 2H), 6.95(s, 1H), 7.23(s, 1H), 7.42(d, J = 8.lHz, 2H), 7.64(d, J= 8.lHz, 2H), 8.04(d, J= 9.3Hz, 1H), 8.87(d, J= 9.3Hz, 1H), 10.00(s, 1H) zam 1~ a 3: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluoro)benzyloxybenzo[g]quinolizinium chloride (Compound No. 3) The process of Ex~unple 1 was repeated except that 0.7g of 2,3,4,5,6-pentafluorobenzyl bromide was employed in place of dodecyl bromide to give 0.80g of the titled compound as a brown crystal (m.p.: 72 °C).
'H-NMR (300MHz, CDCll3) 8: 1.67(t, J= 7.8Hz, 3H), 3.37(m, 2H), 3.42(m, 2H), 3.96(s, 1H), 4.01(s, 3H), 4.08(s, 3H), 5.06(m, 2H), 5.86(s, ZH), 6.93(s, 1H), 7.28(s, 1H), 7.92(d, J= 9.3Hz, 1H), 8.04(d, J= 9.3Hz, 1H), 10.12(s, 1H).
Ega pi 4: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-9-[4-fluoro-2-(trifluoromethyl)benzyloxy]-10-methoxybenzo[g]-quinoliziniLUn chloride (Compound No. 4) The process of Example 1 was repeated except that 0.68g of 4-fluoro-2-(trifluoromethyl)benzyl bronude was employed in place of dodecyl bromide to give 0.76g of the titled compound as a brown crystal (m.p.: 210 °C).
'H-NMR (300MHz, CDC13) a: 1.68{t, J= 6.6Hz, 3H), 3.28(m, 2H), 3.41(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.05(s, 3H), 5.05(m, 2H), 5.77(s, 2H), 6.94(s, 1H), 7.26(s, 1H), 7.40(m, 1H), 7.46(m, 1H), 7.97(d, 1H, J=9.3Hz), 8.04(d, J =
9.3Hz, 1H), 8.50(m, 1H), 10.06(s, lI~.
Ezam~, a 5: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(4,5-dimethoxy-~2-nitro)benzyloxy-13-ethyl-10-methoxybenzo [g]-quinolizinimn chloride (Compound No. 5) The process of Exarr,~ple 1 was repeated except that 0.758 of 4,5-dimethoxy-2-nitrobenzyl bromide was Employed in place of dodecyl bromide to give 0.368 of the titled compound as a brown crystal (m.p.: 100 °C).
'H-NMR (300MHz, CDC'l~) 8: 1.60(t, J= 7.2Hz, 3H), 3.21(m, 2H), 3.39(m, 2H), 3.96(s, 3H), 3.98(s, 3H), 4.00(s, 3H), 4.13(s, 3H), 4.22(s, 3H), 5.18(m, 2H), 5.79(s, 2H), 6.91(s, 1H), 7.22(s, 1H), 7.43(s, 1H), 7.69(s, 1H), 7.91(d, J=
9.OHz, 1H), 8.00{d, J= 9.OHz, 1H), 10.36(s, 1H).
Egam In a 6: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-methyl-3-nitro)benzyloxybenzo[gJquinolizinium chloride (Compound No. 6) The process of Exeunple 1 was repeated except that 0.51 g of 4-methyl-3-nitrobenzyl chloride was employed in place of dodecyl bromide to give 0.38g of the titled compound as a brown crystal (m.p.: 85 °C).
'H-NMR (300MHz, CD(:13) ~: 1.70(t, J= 6.9Hz, 3H), 2.62(s, 3H), 3.27(m, 2H), 3.38(m, 2H), 3.'~6(s, 3H), 4.01(s, 3H), 4.14(s, 3H), S.O1(m, 2H), 5.78(s, 2H), 6.91(s, 1H), 7.25(s, 1H), 7.45(d, J = 7.8Hz, 1H), 7.92(d, J= 9.6Hz, 1H), 8.00(d, J = 9.6Hz, 1H), 8.24(d, J= 9.3Hz, 1H), 8.33(m, 1H), 10.30(s, 1H) Ezam lie 7: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-S~-( 2-methoxy-5-nitro)benzyloxybenzo [gJ quinolizinium chloride (C;ompound No. 7) The process of Example 1 was repeated except that 0.67g of 2-methoxy-5-nitrobenzyl bromide was employed in place of dodecyl bromide to give O.SSg of the titled compound as a brov~m crystal (m.p.: 175 °C).

1H-NMR (300MHz, CDC13) a: 1.69(t, J= 6.3Hz, 3H), 3.31(m, 2H), 3.42(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.07(s, 3H), 4.08(s, 3H), 5.13(m, 2H), 5.74(s, 2H), 6.92(s, 1H), 7.9~;(d, J= 9.3Hz, 1H), 8.02(d, J= 9.3Hz, 1H), 8.25(d,J=
2.7Hz, 1H), 8.271;d, J= 3.OHz, 1H), 8.54(d, J= 3.OHz, lI-~, 10.09(s, 1H) Egamp l~ a 8: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-vinyl)benzyloxybenzo[g]quinolizinium chloride (Compound. No. 8) The process of Example 1 was repeated except that 0.41 g of 4-vinylbenzyl chloride was employed in place of dodecyl bromide to give 0.338 of the titled compound as a brown crystal (m.p.: 82 °C).
'H-NMR (300MHz, CDCl3) 8: 1.69(t, J= 6.8Hz, 3H), 3.29(m, 2H), 3.40(m, 2H), 3.95(s, 3H), 4.00(s, 3H), 4.12(s, 3H), 5.01(m, 2H), 5.40(m, 2H), 5.68(s, 2H), 6.72(m, 1HC), 6.92(s, 1H), 7.25(s, 2ITJ, 7.38(m, 4~, 7.94(d, J =
9.3Hz, 1H), 7.99(d, J= 9.3Hz, 1H), 10.00(s, 1H).
Ezam In a 9: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-~(4-trifluoromethyl)benzyloxybenzo[g]quinolizinium chloride (Compound No. 9) The process of Example 1 was repeated except that 0.65g of 4-(trifluoromethyl)benzyl bromide was employed in place of dodecyl bromide to give 0.72g of the titled compound as a brown crystal (m.p.: 11 S °C).
1H-NMR (300MHz, CDCI~) 8: 1.66(t, J= 7.SHz, 3H), 3.27(m, 2H), 3.38(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.10(s, 3H), 5.08(m, 2H), 5.79(s, 2H), 6.91(s, 1H), 7.26(s, 1H), 7.66(d, J= 9.3Hz, 2H), 7.88(d, J= 9.3Hz, 2H), 7.97(d, J=
7. 8Hz, 1 H), 8. 03 (d, J= 7. 8Hz, 1 f~, 10. 24(s, 1 H) Egam In a 10: Preparation of 5,6-dihydro-Z,3-dimethoxybenzo[a]-9-(2-chloro-4-fluro)benzyloxy-13-ethyl-I 0-methoxybenzo[g]quinolizinium chloride (Compound No. 10}
S
The process of Example 1 was repeated except that 0.49g of 2-chloro-4-fluorobenzyl bromide was employed in place of dodecyl bromide to give 0.19g of the titled compound as a brown crystal (m.p.: 76 °C).
~H-NMR (300MHz, CDCI~) 8: 1.61(t, J= 6.3Hz, 3H), 3.31(m, 2H), 3.40(m, 2H), 3.96(s, 3H), 4.01(s, 3H), 4.12(s, 3H), 4.91(m, 2H), 5.76(s, 2H), 6.99(s, 1H), 7.22(s, 1H), 7.34(m, 3H), 7.99(d, J = 9.3Hz, 1H), 8.08(d, J= 9.3Hz, 1H), 9.79(s, 1H) i5 ~ zam~~ 11: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-( 3 -trifluoromethyl)b enzyloxyb enzo [g]quinolizinium chloride (Compound No. I 1 ) The process of Example 1 was repeated except that 0.65g of 3-(trifluoromethyl)benzyl bromide was employed in place of dodecyl bromide to give 0.42g of the titled compound as a brown crystal (m.p.: 117 °C).
1H-NMR (300MHz, CDC:13) a: 1.66(t, J= 6.8Hz, 3H), 3.34(m, 2H), 3.38(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.10(s, 3H), 5.00(m, 2H), 5.80(s, 2H), 6.91(s, 1H), 7.26(s, 1H}, 7.60(m, 3H), 7.92(d, J = 9.6Hz, IH), 8.00(d, J= 9.6Hz, 1H), 8.18(d, J= 6.9Hz, 1H), 10.23(s, 1H) aam In a I2: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(3-methoxy)benzyloxybenzo[g]quinolizinium chloride (Compound No. 12) The process of E?xample 1 was repeated except that 0.42g of 3-methoxybenzyl chloride w;~s employed in place of dodecyl bromide to give 0.548 of the titled compound as a brown crystal (m.p.: 70 °C).
S 'H-NMR (300MHz, CDC:l3) ~: 1.67(t, J= 6.8Hz, 3H), 3.21(m, 2H), 3.39(m, 2H), 3.87(s, 3H), 3.9:5(s, 3H), 4.00(s, 3H), 4.11(s, 3H), 5.00(m, ZH), 5.61(m, 2H), 6.99(s, 1H), 7.24(s, IH), 7.27(m, 4H), 7.95(d, J= 9.3Hz, 1H), 8.00(d, J= 9.3Hz, 1H), 10.10(s, IH).
zam In a 13: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,5,6-tetrafluoro-4-trifluoromethyl)benzyloxy-benzo[g]quinolizinium chloride {Compound No. 13) The process of E~:ample 1 was repeated except that 0.848 of 2,3,5,6-tetrafluoro-4-trifluoromethiyl benzyl bromide was employed in place of dodecyl bromide to give 0.48g of the titled compound as a brown crystal (m.p.: 85 °C).
1H-NMR (300MHz, CDC13) 8: 1.69(t, J=7.SHz, 3H), 3.30(m, 2H), 3.40(m, 2H), 3.96(s, 3H), 4.01(s, 3H), 4.07(s, 3H), 5.10(m, 2H), 5.96(s, 2H), 6.92(s, 1H), 7.25(s, 1H), 7.91(d, J=9.3Hz, 1H), 8.05(d, J=9.3Hz, 1H), 10.21(s, 1H) EzamQlyl4: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(4-benzyloxy)-benzyloxy-13-ethyl-10-methoxybenzo[g]quinoiizinium chloride (C:ompound No. 14) The process of :Example 1 was repeated except that 0.63g of 4-benzyloxybenzyl bromide 'Has employed in place of dodecyl bromide to give O.SSg of the titled compound as a brown crystal (m.p.: 71 °C).
'H-NMR (300MHz, CDC13) ~: 1.63(t, J=7.3Hz, 3H), 3.41(m, 4H), 3.96(s, 3H), 3.99(s, 3H), 4.03(s,, 3H), 5.02(m, 2H), S.S9(s, 2H), 5.60(s, 2H), 6.87(s, 1H), 7.02{m, 2H), 7.35(m, 6H), 7.72(m, 2H), 7.93(d, J=9.3Hz, 1H), 7.98(d, J=9.3Hz, 1H), 9.89(s, 1H) Ezam Ip a 15:" Preparation of S,6-dihydro-2,3-dimethoxybenzo[a]-9-(2,S-dimethyl)benzyloxy-13-ethyl-10-methoxybenzo[g]quinolizinium chloride (Ca~mpound No. 15) The process of Example 1 was repeated except that 0.42g of 2,5-dimethylbenzyl chloride was employed in place of dodecyl bromide to give 0.54g of the titled compound as a brown crystal (m.p.: 72 °C).
'H-NMR (300MHz, CDC13) ~: 1.68(t, J=6.3Hz, 3H), 2.40(m, 6H), 3.42(m, 4H), 3.95(s, 3H), 4.00(s, 3H), 4.10(s, 3H), 4.96(m, 2H), 5.70(s, 2H), 6.93(s, 1H), 7.13(m, 3H), 7.48(s, 1H), 7.95(d, J=9.3Hz, 1H), 8.02(d, J=9.3Hz, 1H), 9.88(s, 1H) gam~~~ Preparation of S,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10 methoxy-9-(4-phenyl)benzyloxybenzo[g]quinolizinium chloride (Compound No. 16) The process of Example 1 was repeated except that O.SSg of 4-phenylbenzyl chloride was employed in place of dodecyl bromide to give 0.51 g of the titled compound as a brown crystal {m.p.: 83 °C).

'H-NMR (300MHz, CDC13) 8: 1.65(t, J=7.SHz, 3H), 3.26(m, 2H), 3.36(m, 2H), 3.95(s, 3H), 3.99(s~, 3H), 4.13(s, 3H), 5.04(m, 2H), S.?1(s, 2H), 6.90(s, 1H), 7.24(s, 1H), 7.:37(d, J=7.2Hz, 2H), 7.41(d, J=7.SHz, 2H), 7.46(d, J=7.2Hz, 2H), 7.58(d, J=7.SHz, 2H), 7.86(d, J=9.3Hz, 1H), 7.99(d, J=9.3Hz, 1H), 10.09(s, 1H) gam lp a 17: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(6-chloro-pyridine-3 yl)methoxy-13-ethyl-10-methoxybenzo[g]quinoli-zinium chloride (Compound No. 17) The process of Example 1 was repeated except that 0.45g of 3-chloromethyl-6-chloropyridine was employed in place of dodecyl bromide to give 0.28g of the titled compound as a brown crystal (m.p.: 114 °C).
IH-NMR (300MHz, CDC:13) 8: 1.67(t, J=7.SHz, 3H), 3.26(m, 2H), 3.38(m, 2H), 3.96(s, 3H), 4.Oll;s, 3H), 4.12(s, 3H), 5.13(m, 2H), 5.78(s, 2H), 6.91(s, 1H), 7.26(s, 1H), 7.42(d, J=8.4Hz, 1H), 7.91(d, J=9.6Hz, IH), 8.00(d, J=9.6Hz, 1H), 8.52(m, 1H), 8.66(m, 1H), 10.35(s, 1H) sample 18: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(3-chloro)-benzyloxy-13-ethyl-10-methoxybenzo[g]quinolizinium chloride (Compound No. 18) The process of Example 1 was repeated except that 0.45g of 3-chlorobenzyl chloride was employed ire place of dodecyl bromide to give 0.53g of the titled compound as a brown crystal (m.p.: 165 °C).
'H-NMR (300MHz, CDC:13) 8: 1.66(t, J=7.SHz, 3I-~, 3.30(m, 2H), 3.38(m, 2I~, 3.96{s, 3H), 4.00(s, 3H), 4.11(s, 3H), 5.06(m, 2I-~, 5.70(s, 2H), 6.91(s, 1H), 7.25(s, 1H), 7.38(m, 4H), 7.92(d, J=9.3Hz, 1H), 8.00(d, J=9.3Hz, 1H), 10.17(s, 11~
Egam a 19: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(4-bromo)benzyloxy-13-ethyl-10-methoxybenzo[g]quinolizinium chloride (C:ompound No. 19) The process of Example 1 was repeated except that 0.69g of 4-bromobenzyl bromide was employed in place of dodecyl bromide to give 0.17g of the titled compound as a brown crystal (m.p.: 186 °C).
iH-NMR (300MHz, CDC13) ~: 1.66(t, J=7.8Hz, 3H), 3.22(m, 2H), 3.37(m, 2H), 3.95(s, 3H), 4.00(x;, 3H), 4.09(s, 3H), 5.04(m, 2H), 5.66(s, 2H), 6.91(s, 1H), 7.26(s, 1H), 7.:35(d, J=8.4Hz, 2H), 7.71(d, J=8.4Hz, 2H), 7.88(d, J=9.6Hz, 1 H), 8.01 (d, J=9.6Hz, 1 H), 10.13(s, 1 H) Egaml~e 20: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2-trifluoromethyl)benzyloxybenzo[g]quinolizinium chloride (Compound No. 20) The process of Example 1 was repeated except that 0.658 of 2-trifluoromethyl benzyl bromide was employed in place of dodecyl bromide to give 0.668 of the titled compound as a brown crystal (m.p.: 72 °C).
'H-NMR (300MHz, CDC13) ~: I.66(t, J=7.2Hz, 3H), 3.31{m, 2H), 3.39(m, 2H), 3.96(s, 3H), 4.00(s~, 3H), 4.04(s, 3I-~, 5.06{m, 2H), 5.82(s, 2H), 6.93(s, 1H), 7.26(s, 1H), 7.72(m, 3H), 7.94(d, J=9.6Hz, 1H), 8.01(d, J=9.6Hz, 1H), 8.39(d, J=7.2Hz, 1H), 10.03(s, 1H) Ezam to a 21: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10 methoxy-9-(3-phenoxy)benzyloxybenzo[g]quinolizinium chloride (Compound No. 21 ) The process of E;~cample 1 was repeated except that 0.60g of 3-phenoxybenzyl chloride was employed in place of dodecyl bromide to give 0.40g of the titled compound as a brown crystal (m.p.: 76 °C).

'H-NMR (300MHz, CDC:~3) 8: 1.66(t, J=7.SHz, 3H), 3.27(m, 2H), 3.37(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.03(s, 3H), 5.09(m, 2H), 5.67(s, 2H), 6.92(s, 1H), 6.99(s, 1H), 7.01,(m, 2H), 7.30(m, 6H), 7.62(m, 1H), 7.90(d, J=9.3Hz, 1H), 7.98(d, J=9.3Hz, IH), 10.10(s, IH) Egam In a 22: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-methoxy)benzyloxybenzo[g]quinolizinium chloride (Compoundl No. 22) The process of Example 1 was repeated except that 0.43g of 4-methoxybenzyl chloride was employed in place of dodecyl bromide to give 0.848 of the titled compound as a. brown crystal (m.p.: 75 °C).
1H-NMR (300MHz, CDC'.1~) ~: 1.68(t, J=7.2Hz, 3H), 3.33(m, 2H), 3.42(m, 2H), 3.93(s, 3H), 3.94(s, 3H), 4.08(s, 3H), 5.23(m, 2H), 5.73(s, 2H), 6.80(s, 1H), 6.95(s, 1H), 7.24(d, J=8.9Hz, 2H), 7.39(d, J=8.7Hz, 2H), 7.89(d, J=9.3Hz, IH), 7.97(d, J=9.3Hz, 1H), 10.00(s, 1H) Ezam~ a 23: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(2-chloro-6-fluoro)ben:zyloxy-13-ethyl-10-methoxybenzo[g]quinolizinium chloride (C.ompound No. 23) The process of Ex<unple 1 was repeated except that O.Sg of 2-chloro-6-fluorobenzyl chloride was employed in place of dodecyl bromide to give 0.54g of the titled compound as a brown crystal (m.p.: 92 °C).
'H-NMR (300MHz, CDCl3) a: 1.66(t, J=7.2Hz, 3H), 3.46(m, 4H), 3.96(s, 3H), 4.01(s, 3H), 4.12(s, 3H), 5.00(m, 2H), 5.75(s, 2H), 6.99(s, 1H), 7.11(s, IH), 7.28(m, 3H), 7.99(d, J=9.3Hz, IH), 8.08(d, J=9.3Hz, IH), 9.74(s, 1H) ~zamlhe 24: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-I3-ethyl-10-methoxy-9-(2-methyl-3-nitro)benzyloxybenzo[g]quinolizinium chloride (Compound No. 24) The process of Example 1 was repeated except that 0.51 g of 2-methyl-3-nitrobenzyl chloride was employed in place of dodecyl bromide to give 0.45g of the titled compound as a brown crystal (m.p.: 131 °C).
'H-NMR (300MHz, CDCI~) 8: 1.68(t, J=7.SHz, 3H), 2.72(s, 3H), 3.35(m, 2H), 3.56(m, 2H), 3.96{s, 3H), 4.00(s, 3H), 4.09(s, 3H), 5.00(m, 2H), 5.85(s, 2H), 6.90(s, 1H), 7.44(d, J=8.4Hz, 1H), 7.79(d, J=7.SHz, 1H), 7.92(d, J=9.3Hz, 1H), 8.03(d, J=9.3Hz, 1H), 8.42(d, J=6.9Hz, 1H), 10.04(s, 1H) Exam~l 25: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(5-methyl-2-nitro)benzyloxybenzo[g]quinolizinium chloride (Compound No. 25) The process of Example 1 was repeated except that 0.51 g of 5-methyl-2-nitrobenzyl chloride was employed in place of dodecyl bromide to give 0.75g of the titled compound as a brov~nn crystal (m.p.: 98 °C).
'H-NMR (300MHz, CD(:13) a: 1.67(t, J=7.SHz, 3H), 2.60(s, 3H), 3.27(m, 2H), 3.42(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.02(s, 3H), 5.19(m, 2H), 5.91(s, 2H), 6.92(s, 1H;), 7.26(s, 1H), 7.93(d, J=9.3Hz, 1H), 8.01(d, J=9.3Hz, IH), 8.03(m, 1H), 8.22(m, 1H), 10.23(s, 1H) EzamQle 26: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-allyloxybenzo[g]quinolizinium chloride (Compound No.
26) The process of Exannple 1 was repeated except that 0.21 g of allyl chloride was employed in place of dodecyl bromide to give 0.30g of the titled compound as a brown crystal (m.p.: 91 °C).
'H-NMR (300MHz, CDCl3) 8: 1.67(t, J=7.SHz, 3H), 3.21(m, 2H), 3.43(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.08(s, 3H), 5.11(m, 3H), 5.30(d, 1H, J=8.4Hz), 5.50(d, J=15.7Hz, 1H), 6.39(m, 1H), 6.95(s, 1H), 7.26(s, J=9.3Hz, 1 H), 7. 94(d, J=9.3Hz, 1 H), 8.00(d, 1 H), 10.14(s, 1 H) Ezam Ip a z7: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(3,4-dimethyl)bc,nzyloxy-13-ethyl-10-methoxybenzo[g)quinolizinium chloride (Compound No. 27) The process of Example 1 was repeated except that 0.438 of 3,4-dimethylbenzyl chloride wa.s employed in place of dodecyl bromide to give 0.62g of the titled compound as a brown crystal (m.p.: 167 °C).
'H-NMR (300MHz, CDCl3) 8: 1.68(t, J=7.2Hz, 3H), 2.20(m. 6H), 3.20(m, 2H), 3.42(m, 2H), 3.94(s, 3H), 4.08(s, 3H), 4.12(s, 3H), 5.16(m, 2H), 5.59(s, 2H), 6.93(s, 1H), 7.21(m, 4H), 7.94(m, 2H), 9.99(s, 1H) Exam lu a 28: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(2,4-dimethyl)benzyloxy-13-ethyl-10-methoxybenzo[gJquinolizinium chloride (Compound No. 28) The process of E:~cample 1 was repeated except that 0.43g of 2,4-dimethylbenzyl chloride ways employed in place of dodecyl bromide to give 0.59g of the titled compound as a brown crystal (m.p.: 87 °C).
'H-NMR (300MHz, CDCl3) 8: 1.68(t, J=7.2Hz, 3H), 2.36(m, 6H), 3.25(m, 2H), 3.45(m, 2H), 3.93(s, 3H), 4.07(s, 3H), 4.10(s, 3H), 5.20(m, 2H), 5.72(s, 2H), 6.96{s, 1H), 7.07(m, 3H), 7.26(s, 1H), 7.88(q, J=9.3Hz, 2H), 9.81(s, 1H) Egam~le 29: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(1H benzo-triazol-1-yl):methoxy-13-ethyl-10-methoxybenzo[g]-quinolizinium chloride (Compound No. 29) The process of Example 1 was repeated except that 0.468 of 1-chloromethyl-1H benzotriazole was employed in place of dodecyl bromide to give 0.65g of the titled compound as a brovv~l crystal (m.p.: 89 °C}.
'H-NMR (300MHz, CDC:13) 8: 1.68(t, J=7.SHz, 3H), 3.18(m, 2H), 3.40{m, 2H), 3.95(s, 3H), 4.00(;s, 3H), 4.01(s, 3H), 4.90(m, 2H), 5.80(s, 2H), 6.90(s, 1H), 7.09(s, 1H), 7.41(m, 2H), 7.67(m, 1H), 7.84(d, J=9.6Hz, 1H), 8.01(d, J=9.6Hz, 1H), 8.06(m, 1H), 8.35(d, J=8.7Hz, 1H), 10.95(s, 1H) Exam 1~ a 3~: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-9-[4-(i-propyl)b~enzyloxy]-10-methoxybenzo[g]quinolizinium chloride (Compound No. 30) The process of Example 1 was repeated except that 0.46g of 4-i-propylbenzyl chloride was employed in place of dodecyl bromide to give 0.40g of the titled compound as a brown crystal (m.p.: 85 °C).
1H-NMR (300MHz, CDC13) ~: 1.23(s, 3H), 1.26(s, 3H), 1.65(t, J=7.SHz, 3H), 2.92(m, 1H), 3.29(m, 2H), 3.37(m, 2H), 3.95{s, 3H), 4.00(s, 3H), 4.12(s, 3H), 5.00(m, 2:E~, 5.62(s, 2H), 6.92(s, 1H), 7.25(s, 1H), 7.27(m, 2H), 7.69(d, J=8.lHz, 2H), 7.93(d, J=9.3Hz, 1H), 7.99(d, J=9.3Hz, 1H), 9.98{s, 1H) ~~m In a 31: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(4-methyl)benzyloxybenzo[g]quinolizinium chloride (Compound No. 31 ) The process of Example 1 was repeated except that 0.388 of 4-methylbenzyl chloride was employed in place of dodecyl bromide to give 0.45g of the titled compound as a brown cryst:a.l (m.p.: 87 °C).
'H-NMR (300MHz, CDC'.13) 8: 1.65(t, J=7.SHz, 3H), 2.35(s, 3H), 3.28(m, 2H), 3.37(m, 2H), 3.95(s, 3H), 4.00(s, 3H), 4.12(s, 3H), 5.00(m, 2H), 5.61(s, 2H), 6.92(s, 1H), 7.21(s, 1H), 7.25(d, J=5.7Hz, 2H), 7.64(d, J=7.SHz, 2H), 7.93(d, J=9.3Hz, 1H), 7.98{d, J=9.3Hz, 1H), 9.95(s, lI~
Ez~mole 32: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(3-methyl)benzyloxybenzo[g]quinolizinium chloride (Compound No. 32) 'The process of Example 1 was repeated except that 0.38g of 3-methylbenzyl chloride was employed in place of dodecyl bromide to give 0.38g of the titled compound as a brown crystal (m.p.: 76 °C).
1H-NMR (300MHz, CDCl3) ~: 1.66(t, J=7.8Hz, 3H), 2.41(s, 3H), 3.30(m, 2H), 3.52(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.13(s, 3H), S.O1(m, 2H), 5.62(s, 2H), 6.92(s, 1H), 7.26(s, 1H), 7.29(m, 2H), 7.58(m, 2H), 7.93(d, J=9.3Hz, 1H), 8.00(d, J=9.3Hz, 1H), 9.97(s, 1H) EgamQle 33: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2-trifluoromethyl)benzyloxybenzo[g]quinolizinium chloride (C:ompound No. 33) WO 00/37468 PC'T/KR99/00030 The process of E~;ample 1 was repeated except that 0.388 of 2-trifluoromethylbenzyl chloride was employed in place of dodecyl bromide to give 0.42g of the titled compound as a brown crystal (m.p.: 8S °C).
'H-NMR (300MHz, CDC13) 8: 1.68(t, J=7.2Hz, 3H), 2.58(s, 3H), 3.40(m, 4H), 3.95(s, 3H), 4.00(s, 3H), 4.09(s, 3H), 4.90(m, 2H), 5.69(s, 2H), 6.92(s, 1H), 7.24(s, 1H), 7.26~(m, 2H), 7.79(m, 2H), 7.94(d, J=9.3Hz, 1H), 8.01(d, J=9.3Hz, 1H), 9.8'~0(s, 11~
Ezamp 1~ a 34: Preparation of S,6-dihydro-2,3-dimethoxybenzo[a]-9-(3-bromo)-benzyloxy-1:3-ethyl-10-methoxybenzo[g]quinolizinium chloride (Compound ~No. 34) The process of Example 1 was repeated except that 0.688 of 3-bromobenzyl chloride was employed in place of dodecyi bromide to give O.S2g of the titled compound as a brown crystal (m.p.: 9S °C).
'H-NMR (300MHz, CDC13,) a: 1.60(t, J=7.SHz, 3H), 3.31(m, 2H), 3.52(m, 2H), 3.96(s, 3~, 4.00(s, 3H), 4.11(s, 3H), 5.06(m, 2H), 5.69(s, 2H), 6.91(s, 1H), 7.26(s, IH), 7.32(m, 2H), 7.49(m, 1H), 7.88(m, 1H), 7.92(d, J=9.3Hz, 1H), 8.00(d, J=9.3Hz, 1H), 10.15(s, IH) Example 35: Preparation of S,6-dihydro-2,3-dimethoxybenzo[a]-9-(3,S-dimethoxy)be;nzyloxy-13-ethyl-10-methoxybenzo[g]quinolizinium chloride (Compound No. 3S) The process of Ex;nnple 1 was repeated except that O.Slg of 3,S-dimethoxybenzyl chloride was employed in place of dodecyl bromide to give 0.26g of the titled compound as a brown crystal (m.p.: 135 °C).

1H-NMR (300MHz, CDCl3) 8: 1.68(t, J=7.8Hz, 3H), 3.25(m, 2H), 3.36(m, 2H), 3.84(s, 6H), 3.95(x,, 3H), 4.00(s, 3H), 4.11(s, 3H), 5.04(m, 2H), 5.56(s, 2H), 6.42(s, IH), 6.9:Z(s, 1H), 6.97(d, J=2.4Hz, 2H), ?.24(s, IH), 7.95(d, J=9.3Hz, 1H), 8.00(d, J=9.3Hz, 1H), 10.11(s, IH) Egam~ 1~ a 36: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(~quinolin-2-yl)methoxybenzo[g]quinolizinium chloride (Compound No. 36) The process of Examvple 1 was repeated except that 0.58g of 2-chloromethyl quinoline was employed ire place of dodecyl bromide to give 0.468 of the titled compound as a brown crystal (m.p.: 104 °C).
'H-NMR (300MHz, CDC13) 8: 1.68(t, J=7.SHz, 3H), 3.27(m, 2H), 3.40(m, 2H), 3.97(s, 3H), 4.00(s, 3H), 4.09(s, 3H), 5.10(m, 2H), 5.96(s, 2H), 6.92(s, 1H), 7.25(s, 1H), 7.Sfi(m, 2H), 7.73(m, 2H), 7.94(m, 2H), 8.19(d, J=8.4Hz, 1H), 8.35(d, J=8.4Hz, 1H), 10.23(s, 1H) ~zample 37: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-~(3,4,5-trimethoxy)benzyloxybenzo[g]quinolizinium chloride (Compound No. 37) The process of Example 1 was repeated except that 0.598 of 3,4,5-trimethoxybenzyl chloride was employed in place of dodecyl bromide to give 0.60g of the titled compound as a~ brown crystal (m.p.: 110 °C).
1H-NMR (300MHz, CDC'.l;) b: 1.68(t, J---7.SHz, 3H), 3.18(m, ZH), 3.41(m, 2H), 3.84(s, 3H), 3.87(s, 3H), 3.95(s, 3H), 3.95(s, 3H), 4.00(s, 3H), 4.14(s, 3H), 5.10(m, 2H), 5.61.(s, 2H), 6.61(s, 1H), 6.90(s, 1H), 7.I6(s, 1H), 7.25(s, IH), 7.99(d, J=9.6Hz, 1H), 8.00(d, J=9.6Hz, 1H), 10.21(s, IH) ] zam~~ a 38: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-[4-(phenylsulfonylmethyl)benzyloxy]benzo[g]-quinolizinium chloride (Compound No. 38) The process of Example 1 was repeated except that 0.89g of 1-bromomethyl-2-[(phenylsulfonylmethyl)benzene was employed in place of dodecyl bromide to give 0.688 of the titled compound as a brown crystal (m.p.: 100 °C).
'H-NMR (300MHz, CDCl3) d: 1.67(t, J=7.8Hz, 3H), 3.28(m, 2H), 3.41(m, 2H), 3.96(s, 3H), 3.99(:>, 3H), 4.26(s, 3H), 4.96(m, 4H), 5.67(s, 2H), 6.88(s, 1H), 7.03(s, 1H), 7.29(m, 2H), 7.44(m, 4H), 7.47(m, 2H), 7.61(m, 2H), 7.98(d, J=9.3Hz, 1H), 8.08(d, J=9.3Hz, 1H), 8.17(d, J=6.6Hz, 1H), 10.00(s, 1H) Ezam In a 3,_9-_ Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(5-nitrofuran-2-yl)methoxybenzo[g]quinolizinium chloride (Compound No. 39) The process of Example 1 was repeated except that 0.56g of 2-bromomethyl-5-nitrofuran was employed in place of dodecyl bromide to give 0.188 of the titled compound as a brown crystal (m.p.: 85 °C).
'H-NMR (300MHz, CDC'.13) 8: 1.69(t, J=7.2Hz, 3H), 3.26(m, 2H), 3.38(m, 2H), 3.96(s, 3H), 4.01(s, 3H), 4.18(s, 3H), 5.13(m, 2H), 5.80(s, 2H), 6.91(s, 1H), 7.26(s, 1H), 7.31(d, J=3.6Hz, 1H), 7.46(d, J=3.6Hz, 1H), 7.94(d, J=9.6Hz, 1H), 8.03(d, J=9.6Hz, 1H), 10.30(s, 1H) Egamole 40: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(6-chloro)-piperonylo~y-13-ethyl-10-methoxybenzo[g]quinolizinium chloride (Compound No. 40) The process of Example 1 was repeated except that 0.568 of 6-chloropiperonyl chloride was employed in place of dodecyl bromide to give 0.75g of the titled compound as a. brown crystal (m.p.: 10~ °C;).
'H-NMR (300MHz, CDC;13) ~: 1.70(t, J=7.8Hz, 3H), 3.38(m, 4H), 3.96(s, 3H), 3.99(s, 3H), 4.1'l(s, 3H), 4.82(m, 2H), 5.00{m, 2H), 5.59(s, 2H), 6.95(s, 1H), 7.26(s, 1H), 7.42(s, 1H), 7.51(s, 1H), 7.95(d, J=9.3Hz, 1H), 8.09(d, J=9.3Hz, 1H), 9.89(s, 1H) zam~e 41: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-~(2-methyl)propenoxybenzo[g]quinolizinium chloride (Compound No. 41 ) The process of Ex~unple 1 was repeated except that 0.258 of 3-chloro-2-methylpropene was employed in place of dodecyl bromide to give 0.46g of the titled compound as a brown crystal (m.p.: 195 °C).
'H-NMR (300MHz, CDCl3) a: 1.68(t, J=7.8Hz, 3H), 2.01(s, 3H), 3.39(m, 4H), 3.96(s, 3H), 4.00(s, 3H), 4.08(s, 3H), 5.05(m, 4H), 5.40(m, 2H), 6.93(s, 1H), 7.26(s, 1H), 7.91(d, J=9.3Hz, 1H), 7.98(d, J=9.3Hz, 1H), 10.01(s, 1H) Ezamnle 42: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9'-(4-trifluoromethoxy)benzyloxybenzo[g]quinolizinium chloride {C:ompound No. 42) The process of lExample 1 was repeated except that 0.69g of 4-trifluoromethoxy benzyl bromide was employed in place of dodecyl bromide to give 0.49g of the titled compound as a brown crystal (m.p.: 103 °C).
'H-NMR (300MHz, CD~Cl3) 8: 1.63(t, .I=7.5Hz, 3H), 3.25(m, 2H), 3.46(m, 2H), 3.94(s, 3H), 4.00(s., 3H), 4.11(s, 3H), 5.24(m, 2H), 5.76(s, 2H), 6.84(s, 1H), 7.24(s, 1H), 7.:!5(d, J=9.6Hz, 2H), 7.29(d, J=9.6Hz, 2H), 7.93(d, J=9.3Hz, 1H), 7.96(d, J=9.3Hz, 1H), 10.54(s, 1H) Ezam lp a 43__ Preparation ~of S,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-9-(2-iodo)benzyloxy-10-methoxybenzo[g]quinolizinium chloride {Compound No. 43) The process of Example 1 was repeated except that 0.68g of 2-iodobenzyl chloride was employed in place of dodecyl bromide to give O.SOg of the titled compound as a brown crystal (m,p.: 110 °C).
'H-NMR (300MHz, CDCl3) 8: 1.60(t, J=8.3Hz, 3H), 3.35(m, 2H), 3.50(m, 2H), 3.96(s, 3H), 4.00(,;, 3H), 4.11(s, 3H), 5.00(m, 2H), 5.65(s, 2H), 6.94(s, lI-~, 7.07(m, 2H), 7.4T(m, 2H), 7.96(d, J=9.3Hz, 1H), 8.02(d, J=9.3Hz, 1H), 10.00(s, 1H) Egam Ire a 44: Preparation of S,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-SP-[(3-trimethylsilyl)propen-2-yl]oxybenzo[g]
quinoliziniu~rn chloride (Compound No. 44) The process of Example 1 was repeated except that 0.448 of 2-chloromethyl-3-trimethylsilyl-1-propene was employed in place of dodecyl bromide to give 0.59g of the titled compound as a brown crystal (m.p.: 195 °C).
'H-NMR (300MHz, CDC'l~) 8:1.63(t, J 7.8Hz, 3H), 3.32(m, 2H), 3.41(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.08(s, 3H), 5.05(m, 6H), 6.92(s, 1H), 7.26(s, 1H), 7.90(d, J--9.3Hz, 1H), 7.98(d, J 9.3Hz, 1H), 10.01(s, 1H) ~zamyle 45: Preparation of S,6-dihydro-2,3-methylenedioxybenzo[a]-9-dodecoxy-13~-ethyl-10-methoxybenzo[g]quinolizinium iodide (Compound No. 45) lOG of S,6-dihydro-2,3-r~ethylenedioxybenzo[a]-9,10-dimethoxy-13-ethylbenzo[g]quinolizinium chloride was subjected to pyrolysis under nitrogen atmosphere at a temperature of 180 °C and then dissolved in methanol.
Undissolved by-products were filtered off and the residue was then purified by silica gel column chromatography eluting with a mixed solvent of methanol /dichloromethane (10:1 ) to give 6g of S,6-dihydro-2,3-methylenedioxybenzo[a]-ethyl-9-oxy-10-methoxy- be:nzo[g]quinolizinium salts as an orange crystal.
1 G of S,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-9-oxy-10-methoxy-benzo[g]quinolizinium, 0.43g of sodium iodide, and 0.398 of potassium carbonate were dissolved in 10 ml of acetonitrile. After 0.71 g of dodecyl bromide was added thereto, the mixtwe was refluxed for 10 hours. Undissolved by-products were filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was then dissolved in chloroform and washed with 10 ml of water. The organic solution was dried over magnesium sulfate to remove water and concentrated. The residue was then purified by silica gel column chromatography eluting with a mixed solvent of chloroform/methanol ( 1 S :1 ) to give 0.40 g of the titled compound as a brown crystal (m.p.: 17S °C).
~H-NMR (300MHz, CDCl3) 8: 0.88(t, J=6.9Hz, 3H), 1.28(m, 12H), 1.53(m, 4H), 1.69(t, J=7.2Hz, 3H), 1.98(m, 4H), 3.35(m, 2H), 3.41(m, 2H), 4.41(s, 2S 3H), 4.50(t, J=6.9Hz, 2H), 5.10(m, 2H), 6.12(s, 2H), 6.93(s, 1H), 7.30(s, 1 H), 8.00(d, J=9.31Hz, 1 H), 8.14(d, J=9.3Hz, 1 H), 10.01 (s, 1 H) Ezam to a 46: Preparation o~f 5,6-dihydro-2,3-methylenedioxybenzo[a]-9-[(4-tert-butyl)benzyloxy]-13-ethyl-10-methoxybenzo[g]quinolizinium iodide (Compound No. 46) The process of Example 4S was repeated except that 0.6Sg of 4-(tert-butyl)benzyl bromide was employed in place of dodecyl bromide to give 0.82g of the titled compound as a brown crystal {m.p.: I 55 °C).
1H-NMR (300MHz, CDCl3) 8: 1.29(s, 9H), 1.69(t, J=7.2Hz, 3H), 3.22(m, 2H), 3.40(m, 2H), 4.11(s, 3H), 4.98(m, 2H), 5.53(s, 2H), 6.15(s, 2H), 6.97(s, 1H), 7.21(s, 1H), 7.44(d, J=8.lHz, 2H), 7.65(d, J=8.lHz, 2H), 8.05(d, J=9.3Hz, 1H), 8.88(d, J=9.3Hz, 1H), 10.02(s, 1H) Egam le 47: Preparation of 5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluoro)benzyloxybenzo[g]-quinoliziniutn iodide (Compound No. 47) The process of Example 45 was repeated except that 0.75g of 2,3,4,5,6-pentafluorobenzyl bromide was employed in place of dodecyl bromide to give 0.92g of the titled compound as a brown crystal (m.p.: 112 °C).
'H-NMR (300MHz, CDCI,;) 8: 1.69(t, J=7.8Hz, 3H), 3.38(m, 2H), 3.40(m, 2H), 4.10(s, 3H), 5.06(rr~, 2I-~, 5.86(s, 2I-n, 6.12(s, 2H), 6.94(s, 1H), 7.29(s, 1H), 7.93(d, J=9.3Hz, :lH), 8.04(d, J=9.3Hz, 1H), 10.10(s, 1H) Ezam In a 48: Preparation of 5,6-dihydro-2,3-methylenedioxybenzo[a]-9-(4,5-dimethoxy-2;-nitro)benzyloxy-I 3-ethyl-I 0-methoxybenzo[g]-., quinoliziniurn iodide (Compound No. 48) The process of Ex2unple 45 was repeated except that 0.79g of 4,5-dimethoxy-2-nitrobenzyl bromide was employed in place of dodecyl bromide to give 0.49g of the titled compound as a brown crystal (m.p.: 132 °C).
'H-NMR (300MHz, CDCI,;) a: 1.61(t, J=7.2Hz, 3H), 3.20(m, 2H), 3.39(m, 2H), 3.98(s, 3H), 4.01(s, 3H), 4.22(s, 3H), 5.18(m, 2I-~, 5.79(s, 2H), 6.13(s, 2H), 6.91(s, 1H), 7.23(s, 1H), 7.44(s, 1H), 7.70(s, 1H), 7.90(d, J=9.OHz, 1H), 8.00(d, J=9.OHz, 1H), 10.31(s, 1H) S ~zam In a 49: Preparation of S,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-~9-(4-methyl-3-nitro)benzyloxybenzo[g]quinolizinium iodide (Compound No. 49) The process of Example 4S was repeated except that O.S3g of 4-methyl-3-nitrobenzyl chloride was employed in place of dodecyl bromide to give O.SOg of the titled compound as a brown. crystal (m.p.: 11 S °C).
1H-NMR (300MHz, CDC13) 8: 1.67(t, J=6.9Hz, 3H), 2.61(s, 3H), 3.26(m, 2H), 3.35(m, 2H), 4.14(s, 3H), S.O1(m, 2H), 5.78(s, 2H), 6.13(s, 2H), 6.90(s, 1S 1H), 7.23(s, 1HC), 7.44(d, J=7.8Hz, 1H), 7.92(d, J=9.6Hz, 1H), 8.00{d, J=9.6Hz, 1H), 8.24(d, J=9.3Hz, 1H), 8.35(m, 1H), 10.18(s, 1H) zam 1~ a 50: Preparation of S,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(4-trifluoromethyl)benzyloxy benzo[g]quinolizinium iodide (Compound No. SO) The process of Example 4S was repeated except that 0.688 of 4-trifluoromethyl benzyl bromide was employed in place of dodecyl bromide to give 0.7Sg of the titled compound as a brown crystal (m.p.: 142 °C).
1H-NMR (300MHz, CDC13) 8: 1.67(t, J=7. SHz, 3H), 3.24(m, 2H), 3.37{m, 2H), 4.10(s, 3H), 5.08(rn, 2H), 5.79(s, 2H), 6.15(s, 2H), 6.91(s, 1H), ?.26(s, 1H), 7.64(d, J=9.3Hz, 2H), 7.86(d, J=9.3Hz, 2H), 7.98(d, J=7.8Hz, 1H), 8.03(d, J=7.8Hz, 1H), 10.16(s, 1H) Edam le 51: Preparation ~of 5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(3-trifluoromethyl)benzyloxybenzo[g]quinolizinium iodide (Compound No. 51 ) The process of Example 45 was repeated except that 0.688 of 3-(trifluoromethyl)benzyl bromude was employed in place of dodecyl bromide to give 0.53g of the titled compound as a brown crystal (m.p.: 134 °C).
~H-NMR (300MHz, CDCl3) ~: 1.67(t, J=6.8Hz, 3H), 3.34(m, 2H), 3.38{m, 2H), 4.10(s, 3H), 5.00(rn, 2H), 5.80(s, 2H), 6.14(s, 2H), 6.91(s, 1H), 7.26(s, 1H), 7.62(m, 3H), 7.92(d, J=9.6Hz, 1H), 8.00(d, J=9.6Hz, 1H), 8.17(d, J=6.9Hz, 1H), 10.14{s, 1H) Egam In a 52: Preparation of 5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,5,6-tetrafluoro-4-trifluoromethyl)benzyloxy-benzo[g]quvzolizinium iodide (Compound No. 52) The process of ExaJnple 45 was repeated except that 0.898 of 2,3,5,6-tetrafluoro-4-trifluoromethyl benzyl bromide was employed in place of dodecyl bromide to give 0.99g of the: titled compound as a brown crystal (m.p.: 136 °C).
'H-NMR (300MHz, CDCl.3) 8: 1.67(t, J=7.SHz, 3H), 3.32(m, 2H), 3.40(m, 2H), 4.07(s, 3H), 5.10(n~, 2H), 5.94(s, 2H), 6.11(s, 2H), 6.92(s, 1H), 7.25(s, 1H), 7.90(d, J=9.3Hz, 1H), 8.04(d, J=9.3Hz, 1H), 10.18(s, 1H) Egam Ip a 53: Preparation of 5,6-dihydro-2,3-methylenedioxybenzo[a]-13-ethyl-10-methoxy-9-(4-phenyl)benzloxybenzo[g]quinolizinium iodide (Compound No. 53) The process of Example 45 was repeated except that O.S8g of 4-phenylbenzyl chloride was employed in place of dodecyl bromide to give 0.69g of the titled compound as a brown crystal (m.p.: 115 °C).
iH-NMR (300MHz, CDCl3) d: 1.66(t, J--7.SHz, 3H), 3.24(m, 2H), 3.34(m, 2H), 4.13(s, 3H), 5.04(nn, 2H), 5.71(s, 2H), 6.17(s, 2H), 6.90(s, 1H), 7.24(s, 1H), 7.38(d, J=7.2Hz, 2H), 7.42(d, J=7.SHz, 2H), 7.46(d, J=7.2Hz, 2H), 7.58(d, J=7.SHz, 2H), 7.86(d, J=9.3Hz, 1H), 8.00(d, J=9.3Hz, 1H), 10.12(s, 1H) ~zampile 54: Preparation of 5,6-dihydro-2,3-methylenedioxybenzo[a]-9-(6-chloropyridinyl-3-yl)methoxy-13-ethyl-10-methoxybenzo[g]-quinoliziniwn iodide (Compound No. 54) The process of Example 45 was repeated except that 0.468 of 3-chloromethyl-6-chloropyridvne was employed in place of dodecyl bromide to give 0.448 of the titled compound as a brown crystal (m.p.: 139 °C).
1H-NMR (300MHz, CDCI:,) 8: 1.68(t, J=7.SHz, 3H), 3.26(m, 2H), 3.38(m, 2H), 4.12(s, 3IT), 5.14(n~, 2H), 5.78(s, 2H), 6.11(x, 2H), 6.91(s, 1H), 7.26(s, 1H), 7.42(d, J=8.4Hz, 1H), 7.90(d, J=9.6Hz, 1H), 8.00(d, J=9.6Hz, 1H), 8.52(m, 1H), 8.681;m, 1H), 10.25(s, 1H) ~zamlhe 55: Preparation of 5,6-dihydro-2,3-diethoxybenzo[a]-9-[4-(tert-butyl)benzyloxy]-13-ethyl-I 0-methoxybenzo[g]quinolizinium chloride (Compound No. 55) To a solution of 10g of 5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo[g]quinolizinium chloride in 100 ml of acetonitrile 8.1 g of potassium carbonate and 9.1 g of ethyl iodide. The mixture was refluxed for hours. Undissolved by-products were filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was then dissolved in chloroform and washed with 50 ml of water. The organic solution was dried over magnesium sulfate to remove water, filtered, and concentrated. The residue was then purified by silica gel column chromatography eluting with a mixed solvent of methanol/dichloromethane (2:1 ) to give 8.5 g of 5,6-dihydro-2,3-diethoxybenzo[a]-13-ethyl-9-hydroxy-10-methoxybenzo[g]quinolizinium chloride as a light brown crystal.
To a solution of lg of 6,6-dihydro-2,3-diethoxybenzo[a]-13-ethyl-9-hydroxy-10-methoxy-benzo[g]quinol!~izinium chloride in lOmg acetonitrile were added, 0.388 of sodium iodide, and ~0.35g of potassium carbonate. After 0.58g of 4-(tert-butyl)benzyl bromide was added thereto, the mixture was refluxed for 3 hours.
Undissolved by-products were filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was then dissolved in chloroform and washed with 10 ml of water. The organic solution was dried over magnesium sulfate to remove water, filtered, and concentrated. The residue was then purified by silica gel column chromatography eluting with a mixed solvent of chloroform/methanol ( 15:1;1 to give 0.72 g of the titled compound as a brown crystal (m.p.: 132 °C).
1H-NMR (300MHz, CDC13) ~ : 1.29(s, 9H), 1.67(m, 9H), 3.24(m, 2H), 3.40(m, 2H), 4.04(m, 4H), 4.11(s, 3H), 4.99(m, 2H), 5.54(s, 2H), 6.94(s, 1H), 7.23(s, 1H), 7.40(d, J=9.3Hz, 2H), 7.66(d, J=9.3Hz, 2H), 8.04(d, J=9.3Hz, 1H), 8.87(d, J=9.3Hz, 1H), 10.11(s, 1H) Egam Ip a 56: Preparation of 5,6-dihydro-2,3-diethoxybenzo[a]-13-ethyl-10-methoxy-9-(2;,3,4,5,6-pentafluoro)benzyloxybenzo[g]quinolizinium chloride (Co:mpound No. 56) The process of Example 55 was repeated except that 0.67g of 2,3,4,5,6-pentafluorobenzyl bromide was employed in place of 4-(tent-butyl)benzyl bromide to give 0.828 of the titled ccrmpound as a brown crystal (m.p.: 100 °C).
'H-NMR (300MHz, CDC1.3) 8: 1.67(m, 9H), 3.36(m, 2H), 3.42(m, 2H), 4.01(m, S 4H), 4.08(s, 3H), ~~.06(m, 2H), 5.86(s, 2H), 6.93(s, 1H), 7.28(s, IH), 7.92(d, J=9.3Hz, 1H), 8.04(d, J=9.3Hz, 1H), 10.12(s, 1H) ~~m lp a 57: Preparation of S,6-dihydro-2,3-diethoxybenzo[a]-9-(2,3,5,6-tetra-fluoro-4-trifl~aoro methyl)benzyloxy-13-ethyl-10-methoxy-benzo[g]-quinolizinium chloride (Compound No. S7) The process of Example SS was repeated except that 0.80g of 2,3,5,6-tetrafluoro-4-trifluoromethyl benzyl bromide was employed in place of 4-(tert-butyl)benzyl bromide to give 0.68g of the titled compound as a brown crystal (m.p.:
113 °C).
1H-NMR (300MHz, CDCl3) d: 1.69(m, 9H), 3.34(m, 2H), 3.40(m, 2H), 3.96(m, 4H), 4.07(s, 3H), 5.12(rn, 2H), 5.96(s, ZH), 6.92(s, 1H), 7.25(s, 1H), 7.92(d, 1H, J=9.6Hz), 8.06(d, 1H, J=9.6Hz), 10.24(s, 1H) ~zamyl~~, Preparation of S,6-dihydro-2,3-diethoxybenzo[a]-9-(6-chloro-pyridinyl-3-yl)methoxy-13-ethyl-10-methoxybenzo[g]-quinolizinium chloride (Compound No. S8) The process of Example SS was repeated except that 0.42g of 3-chloro-6-chloropyridine was employed in place of 4-(tent-butyl)benzyl bromide to give 0.42g of the titled compound as a brown crystal (m.p.: 126 °C).
'H-NMR (300MHz, CDC13) a: 1.68(m, 9H), 3.26(m, 2H), 3.38(m, 2H}, 4.01(m, 4H), 4.12(s, 3H), 5.11(m, 2H), 5.78(s, 2H), 6.91(s, 1H), 7.26(s, 1H), 7.45(d, J=9.3Hz, IH), 7.91(d, J=9.6Hz, 1H), 8.00(d, J=9.6Hz, 1H), 8.52(m, 1H), 8.64(m, 1H), 10.30(s, 1H) Egam 1~ a 59: Preparation of 5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluoro)benzyloxybenzo[g)-quinoLizinium chloride (Compound No. 59) To a solution of lg of 5,6-dihydro-2,3-dihydroxybenzo[a)-13-ethyl-9-hydroxy-10-methoxy-benzo[g]quinolizinium chloride in l Omg of acetonitrile were IO added 0.44g of sodium iodide, and 0.41 g of potassium carbonate. After 0.77g of 2,3,4,5,6-pentafluorobenzyl bromide was added thereto, the reaction mixture was stirred for 24 hours in an ice bath. After pH was adjusted to neutral with an aqueous hydrochloric acid solution, undissolved by-products were filtered off and the filtrate was concentrated under reduced pressure to remove the solvent.
The residue was then dissolved in chloroform and washed with 10 ml of water. The organic solution was dried over magnesium sulfate to remove water filtered, and concentrated. The residue was then purified by silica gel column chromatography eluting with a mixed solvent of chloroform/methanol ( 15:1 ) to give 0.34 g of the titled compound as a brown crystal (m.p.: 82 °C).
1H-NMR (300MHz, DMSO~-ds) a: 1.47(t, 3H), 3.12(m, 2H), 3.34(m, 2H), 4.01(s, 3H), 4.82(m, 2H), 5.72(s, 2H), 7.17(s, IH), 7.31(s, 1H), 8.19(d, J=7.2Hz, 1H), 8.22(d, J=7.2Hz, 1H), 9.95(s, 1H) Exams 1~ a 60: Preparation of 5,6-dihydro-2,3-dihydroxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,5,6-tetrafluoro-4-trifluoromethyl)benzyloxy-benzo[g]quinolizinium chloride (Compound No. 60) The process of Example 59 was repeated except that 0.92g of 2,3,5,6-tetrafluoro-4-trifluoromethyl benzyl bromide was employed in place of 2,3,4,5,6-pentafluorobenzyl bromide to give 0.25g of the titled compound as a brown crystal (m.p.: 88 °C).
1H-NMR (300MHz, DMSC)-ds) &. 1.48(t, J=6.3Ha, 3H), 3.18{m, 2H), 3.37(m, 2H), 4.07(s, 3H), 4.91(rn, 2H), 5.77(s, 2H), 6.84(s, 1H), 7.11(s, 1H), 8.01(d, J=9.3Hz, 1H), 8.07(d, J=9.3Hz, 1H), 9.99(s, 1H) am Ip a 61: Preparation of 5,6-dihydro-2,3-diethoxybenzo[a]-9-dodecoxy-10-ethoxy-13-e~thylbenzo[g]quinolizinium chloride (Compound No.
61) To a solution of lOg of 5,6-dihydro-2,3-methylenedioxybenzo[a]-9,10-dimethoxy-13-ethyl-benzo[g]quinolizinium chloride in 100mg of dichloromethane was suspended 30g of aluminum chloride and the mixture was stirred for 1 hour.
The reaction mixture was concentrated under reduced pressure to remove the solvent. A 15% aqueous hydrochloric acid solution was added to the mixture and the precipitate produced was filtered, washed with water, and dried to give 7.Sg of 5,6-dihydro-2,3-dihydroxybe:nzo[a]-9,10-dihydroxy-13-ethylbenzo[g]quinolizinium chloride as dark brown crystal.
To a solution of 1 Og of 5,6-dihydro-2,3-dihydroxybenzo[a]-9,10-dihydroxy-13-ethylbenzo- [g]quinolizini.um chloride in 100 ml of acetonitrile were added 12.1 g of potassium carbonate and 14.3g of ethyl iodide. The mixture was refluxed for 5 hours. Undissolved by-products were filtered off and the filtrate was concentraed under reduced pressure to remove the solvent. The residue was then dissolved in chloroform and washed with 50 ml of water. The organic solution was dried over magnesium sulfate to remove; water, filterated, and concentrated. The residue was then purified by silica gel column chromatography eluting with a mixed solvent of methanol/dichloro-methane {2:1 ) to give 7.8 g of 5,6-dihydro-2,3-diethoxybenzo[a]-10-ethoxy-13-ethyl-9-hydroxybenzo(g]quinolizinium chloride as a light brown crystal.
To a solution of lg of 5,6-dihydro-2,3-die~thoxybenzo[a]-10-ethoxy-13-ethyl-9-hydroxy-benzo[g]quinoli2;inium chloride in lOmg of acetonitrile were added 0.37g of sodium iodide and 0.34g of potassium carbonate. After 0.62g of dodecyl bromide was then added thereto, the mixture was refluxed for 10 hours.
Undissolved by-products were filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was then dissolved in chloroform and washed with I 0 ml of water. The organic solution was dried over magnesium sulfate to remove water, filtered, and concentrated. The residue was then purified by silica gel column chromatography eluting with a mixed solvent of chloroform/methanol (15:1 ) to give 0.378 of the titled compound as a brown crystal (m.p.: 174 °C).
1H-NMR (300MHz, CDC13) ~ : 0.87(t, J=6.9Hz, 3H), 1.24(m, 12H), 1.50(m, 4H);
1.68(m, 12H), 1.S>8(m, 4H), 3.34(m, 2H), 3.48(m, 2H), 4.01(m, 8H), 4.52(t, J=6.9Hz, 2H), 5.20(m, 2H), 6.93(s, 1H), 7.30(s, 1H), 8.04(d, J=9.3Hz, 1H), 8.1:1(d, J=9.3Hz, 2H), 10.07(s, 1H) gam I"~ Preparation of 5,6-dihydro-2,3-diethoxybenzo(a]-10-ethoxy-13-ethyl-9-(4-trifluoromethyl)benzyloxy benzo[g]quinolizinium chloride (Compound No. 62) The process of Example 61 was repeated except that 0.598 of 4-trifluoromethyl benzyl bromide was employed in place of dodecyl bromide to give 0.83g of the titled compound as a brown crystal (m.p.: 142 °C).
1H-NMR (300MHz, CDCl3) ~: 1.69(m, 12H), 3.26(m, 2H), 3.34(m, 2H), 4.00(m, 12H), 5.08(m, :pH), 5.80(s, 2H), 6.93(s, 1H), 7.25(s, 1H), 7.68(d, J=9.6Hz, 2H), i'.84(d, J=9.6Hz, 2H), 7.96(d, J=7.4Hz, IH), 8.04(d, J=7.4Hz, 1 H), 10.21 (s, 1 H) Examhe 63: Preparation of 5,6-dihydro-2,3-diethoxybenzo[a]-10-ethoxy-13-ethyl-9-(3-trifluoromethyl)benzyloxybenzo[g]quinolizinium chloride (Compound No. 63) The process of Example 61 was repeated except that 0.59g of 3-trifluoromethylbenzyl bromide was employed in place of dodecyl bromide to give 0.588 of the titled compound as a brown crystal (m.p.: 127 °C).
'H-NMR (300MHz, CDC13) d: I.70(m, 12H), 3.32(m, 2H), 3.38(m, 2H), 4.10(m, 12H), 5.00(m, 2Hf), 5.85(s, 2H), 6.92(s, 1H), 7.26(s, 1H), 7.62(m, 3H), 7.92(d, J=9.6Hz, IH), 8.00(d, J=9.6Hz, 1H), 8.18(d, J=6.9Hz, 1H), 10.17(s, 1H) Ezample 64: Preparation of 5,6-dihydro-2,3-diethoxybenzo[a]-10-ethoxy-13-ethyl-9-(2,?t,5,6-tetrafluoro-4-trifluoromethyl)-benzyloxy benzo[g]quir~olizinium chloride (Compound No. 64) The process of Example 61 was repeated except that 0.77g of 2,3,5,6-tetrafluoro-4-trifluoromethyl benzyl bromide was employed in place of dodecyl bromide to give 0.688 of the titled compound as a brown crystal (m.p.: 110 °C).
'H-NMR (300MHz, CDCl3) ~ 1.b4(m, 12H), 3.30(m, 2H), 3.40(m, 2H), 4.07(m, 12H), 5.10(m, 2E>], 5.98(s, 2H), 6.92(s, 1H), 7.25(s, 1H), 7.92(d, J=9.6Hz, 1H), 8.06(d, J=9.6Hz, 1H), 10.20(s, 1H) Egam lie 65: Preparation of 5,6-dihydro-2,3-diethoxybenzo[a]-9-(6-chloro-pyridine-3-yl)imethoxy-10-ethoxy-13-ethylbenzo[g]-quinolizinium chloride (Compound No. 65) The process of Example 61 was repeated except that 0.4g of 3-chloromethyl-6-chloropyridine was employed in place of dodecyl bromide to give 0.37g of the titled compound as a brovv~i crystal (m.p.: I 36 °C).
'H-NMR (300MHz, CDCl3) ~ 1.68(m, 12H), 3.24(m, 2H), 3.38(m, 2H), 4.12(m, 12H), 5.13(m, 2H), 5.78(s, 2H), 6.90(s, 1H), 7.26{s, 1H), 7.41(d, J=9.3Hz, 1H), '7.92(d, J=9.6Hz, 1H), 8.00(d, J=9.6Hz, 1H), 8.54(m, 1H), 8.66(m, 1H~, 10.23(s, 1H) Ezamp~le 66: Preparation of 5,6-dihydro-2,3-dipropoxybenzo[a]-9-(4-(tert-butyl )benzyloxy]-13-ethyl-10-propoxybenzo[g]quinolizinium chloride (Compound No. 66) To a solution of 1 Og of 5,6-dihydro-2,3-dihydroxybenzo[a]-9,10-dihydroxy-13-ethylbenzo-[g]quinolizi~ium chloride in 100 ml of acetonitrile 12.1 g of potassium carbonate and 15.68 of propyl iodide. The mixture was relluxed for 8 hours. Undissolved by-products were filtered off and the filtrate was concentraed under reduced pressure to remove the solvent. The residue was then dissolved in chloroform and washed with 50 ml of water. The organic solution was dried over magnesium sulfate to remove water, filtered and concentrated. The residue was then purified by silica gel column chromatography eluting with a mixed solvent of methanol/dichloromethane; (2:1 ) to give 7.8 g of 5,6-dihydro-2,3-dipropoxybenzo[a]-13-ethy:l-9-hydroxy-10-propoxybenzo[g]quinolizinium chloride as a light brown crystal.
To a solution of 1 g of 5,6-dihydro-2,3-dipropoxybenzo[a]-13-ethyl-9-hydroxy-10-propoxy-benzo~[g]quinolizinium chloride in l Omg of acetonitrile were added 0.348 of sodium iodide and 0.31 g of potassium carbonate. After 0.51 g of 4-(tert-butyl)benzyl bromide 'was added thereto, the mixture was refluxed for 5 hours.
Undissolved by-products were filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was then dissolved in chloroform and washed with 10 ml of water. The solution was dried over magnesium sulfate to remove water, filtered, and concentrated. The residue was then purified by silica gel collumn chromatography eluting with a mixed solvent of chloroforrn/methanol ( 15 :1 ) to give 0.68 g of the titled compound as a brown crystal (m.p.: 133 °C).
1H-NMR (300MHz, CDC13) b: 1.29(s, 9H), 1.48(m, 9H), 1.72(m, 6H), 3.24(m, 2H), 3.45(m, ZH), 4.18{m, 6H), 4.99(m, 2H), 5.53(s, 2H), 6.95{s, 1H), 7.23(s, 1H), 7.44(d, J=9.6Hz, 2H), 7.66(d, J=9.6Hz, 2H), 8.07(d, J=9.3Hz, 1H), 8.87(d, J=9.3Hz, 1H), 10.05(s, 1H) Egamhe 67:. Preparation of 5,6-dihydro-2,3-dipropoxybenzo[a]-13-ethyl-9-(2,3,4,5,6-pentafluoro)benzyloxy-10-propoxybenzo[g]
quinolizinium chloride (Compound No. 67) The process of Exannple 66 was repeated except that 0.59g of 2,3,4,5,6-pentafluorobenzyl bromide was employed in place of 4-(tert-butyl)benzyl bromide to give 0.908 of the titled compound as a brown crystal (m.p.: i 22 °C).
'H-NMR (300MHz, CDC1,3) ~: 1.49(m, 9H), 1.59(m, 6H), 3.36(m, 2H), 3.40(m, 2H), 4.15(m 6H), 5.06(m, 2H), 5.84(s, 2H), 6.93(s, 1H), 7.28(s, 1H), 7.91(d, J=9.6Hz, 1H), 8.05(d, J=9.6Hz, 1H), 10.08(s, 1H) exam le 68: Preparation of 5,6-dihydro-2,3-dipropoxybenzo[a]-13-ethyl-10-propoxy-9-(4-trifluoromethyl)benzyloxybenzo[g]quinolizinium chloride (C'ompound No. 68) The process of Ex<nnple 66 was repeated except that 0.54g of 4-trifluoromethylbenzyl bromide was employed in place of 4-(tert-butyl)benzyl bromide to give 0.958 of the titled compound as a brown crystal (m.p.: 151 °C).

1H-NMR (300MHz, CDC13) cfi: 1.50(m, 9I-~, 1.69(m, 6H), 3.24(m, 2H), 3.36(m, 2H), 4.10(m, 6H), 5.08{m, 2I-~, 5.79(s, 2H), 6.91(s, 1H), 7.26(s, 1H), 7.64(d, J=9.3H::, 2H), 7.86(d, J=9.3Hz, 2H), 7.96(d, J=7.8Hz, 1H), 8.02(d, J=7.8Hz, 1 H), 10.21 (s, 1 H) Ezaml le 69: Preparation of S,6-dihydro-2,3-dimethoxybenzo[a]-9-[4-(tert-butyl)-benzyloxy]-13-ethyl-10-methoxybenzo[g]quinolizinium bisulfate (Compound No. 69) IO
1 G of 8-acetonylated S,6-dihydro-2,3-dimethoxybenzo[a]-9-[4-{tert-butyl)benzyloxy]-13-ethyl-10-methoxybenzo[g]quinolizinium chloride was introduced into 10 ml of l .Onrl sulfuric acid. After the solution was stirred at room temperature for 2 hour, the precipitate produced was filtered, washed with S
ml of water and then dried over oven to give O.S8 g of the titled compound as a brown crystal (m.p.: 123 °C).
1H-NMR (300MHz, CDCI,~) 8: 1.30(s, 9H), 1.70(t, J=7.2Hz, 3H), 3.24(m, 2H), 3.40(m, 2H), 3.92(s, 3H), 3.99(s, 3~, 4.14(s, 3H), 4.98(m, 2H), S.S6(s, 2H), 6.97(s, lI~, 7.25(s, 1H), 7.46(d, J=8.lHz, 2H), 7.62(d, J=8.lHz, 2H), 8.02(d, J=9.3Hz, 1H), 8.87(d, J=9.3Hz, 1H), 9.98(s, 1H) Ezam le 70: Preparation of S,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluoro)benzyloxybenzo[g]quinolizinium acetate (Compound No. 70) 1 G of 8-acetonylalted S,6-dihydro-2,3-dimethoxybenzo[a]-13-ethyl-10-methoxy-9-(2,3,4,5,6-pentafluorobenzyloxybenzo[g]quinolizinium chloride was introduced into 10 ml of glacial acetic acid and the mixture was stirred at at room temperature for S hours. The precipitate produced was filtered, washed with 10 ml of ether and then dried over oven to give 0.75 g of the titled compound as a brown crystal (m.p.: 108 °C).
IH-NMR (300MHz, CDC13) a: 1.62(t, J= 7.8Hz, 3H), 3.35(m, 2H), 3.29(m, 2H), 3.96(s, 1H), 4.08(s, 3H), 4.14(s, IH), 5.08(m, 2H), 5.86(s, 2H), 7.00(s, 1H), 7.23(s, 1H), 7.39(d, J=9.3Hz, 1H), 8.04(d, J=9.3Hz, IH), 9.98(s, IH) Egampile 71: Preparation of 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(6-chloro-pyridine-3-:y1)methoxy-13-ethyl-10-methoxybenzo-[gJquinoli-zinium nitrate (Compound No. 71 ) 1 G of 8-acetonyl;ated 5,6-dihydro-2,3-dimethoxybenzo[a]-9-(6-chloro pyridine-3-yl)methoxy-13-ethyl-10-methoxybenzo[gJquinolizinium chloride was introduced into 10 ml of 1.3M nitric acid and the mixture was stirred at room temperature for 2 hour. The. precipitate produced was filtered, washed with 5 ml of water and then dried over oven to give 0.82 g of the titled compound as a brown crystal (m.p.: 127 °C).
'H-NMR (300MHz, CDCl3) 8: 1.62(t, J=7.SHz, 3H), 3.22(m, 2H), 3.32(m, 2H), 3.93(s, 3H), 4.00(s, 3H), 4.14(s, 3H), 5.10(m, 2H), 5.78(s, 2H), 6.90(s, IH), 7.26(s, 1H), 7.4~4(d, J=8.4Hz, 1H), 7.92(d, J=9.3Hz, IH), 8.00(d, J=9.3Hz, 1H), 8.5~4(m, 1H), 8.68(m, IH), I0.15(s, 1H) Ezamhe 72: Inhibiting ef~Fect of 5,6-dihydrodibenzo[a,g]quinolizinium salts on sterol 14-red~uctase in microsome state.
20 Male Sprague-Davvley rats weighing from 150 to 250g have been fed for 7 days with a diet containing 0.1%(w/w) Lovastatin and 5%(w/w) Cholestyramine.
The animals were fasted for 12 hours before excising liver tissues and then sacrificed by decapitation at midnight. An aqueous solution containing 0.25M
of sucrose was injected into the: hepatic portal vein to remove all the blood within the liver, and then, the liver was excised. The liver was homogenated with two volumes of buffer solution A {0.1 M potassium phosphate , 1 mM reduced glutathione, 0.5 mM EDTA, 20%(v/v) glycerol, pH 7.4) by repeating pestles over 10 times and then, centrifuge:d with 900 x g for 5 minutes to give a supernatant. The supernatant was centrifuged with 12,000 x g for 20 minutes. The supernatant obtained was ultracentrifuged with 105,000 x g for 90 minutes to give a microsome which was used as an enzyme source of sterol 14-reductase. Assay for sterol 14-reductase was carried out as follows:
60 mmol of 4,4-dimethyl-5a-cholesta-7,14-dien-3 ~i-of and 5,6-dihydrodibenzo-[a,gJquinolizinium salts (co;mpound no. 2) dissolved in DMSO were added to an assay mixture (total volume 1.0 ml) containing 2 mg of the microsomal protein, mM of NADPH and 25 mg of glucose plus 20 units of glucose oxidase with preincubations under nitrogen at 37 °C for 4 min. unless otherwise specified to establish anaerobic condition. Buffer A (0.1 M potassium phosphate buffer, pH
7.4, including 1 mM reduced glutathione, 0.5 mM EDTA, and 20% {v/v) glycerol) used for incubation had been equilibrated with nitrogen, and nitrogen was exchanged for air in all sexed reaction flasks prior to the start of incubations.
Incubation of the complete mixture was carried out anaerobically in sealed flasks for 10 min at 37 °C unless otherwise indicated. Incubations were terminated by the addition of 1 ml of ethanolic KOH followed by heating under reflux for 10 min.
Sterols were extracted four tunes with 4 ml of petroleum ether, and the solvent was evaporated to dryness under a nitrogen stream. The resulting residue was dissolved in 200 - 500 ~cl of n-hexane for quantification by GLC at high sensitive attenuation.
The activity of sterol 14-reductase was determined with the amount of the substrate wherein the double bonds of 14-carbon were reduced (for the amount reduced by 1 mg of the microsome prot~;in for 1 minute). When the level of compound no. 2 added to the reaction system was 0.1 to 0.3 ~cM, 50% of inhibition of the enzymatic activity was observed.
Exam Ip a 73: Effect of 5,6-dihydrodibenzo[a,g)quinolizinium salts on cholesterol biosynthesis ratio in CHO cells Chinese hamster ovary cells (CHO cell) were passage-cultivated on the flat plates. When colonies reached at 70 to 80% of area based on the total culture area, culture medium was replaced with a fresh medium and this was then used as samples for determining sterol 14-reductase activity and the cholesterol biosynthesis ratio.
Cholesterol biosynthesis ratio was determined by the Boogaard method [See, Biochem. J. 1987, 241, 345-51 ) with some modification. To the three dishes (diameter: 60 nm) containin;g the above CHO cells, the compound obtained from Example 2 were added and the mixture was then incubated for 30 minutes. After adding each 0.5 ~,Ci of 'AC-M:evalonate into the medium, incubation was continued for 2 hours. Culture medium was removed from the vessel, and the mixture was then washed 3 times with P13S at 4°C. The cells were scratched and collected in about 1.0 ml of PBS, and then subjected to centrifugation at 10,000 rpm for 5 min.
In order to determine cholesterol having radioactivity, the cell precipitates were first floated with 0.1 N NaOH. After quantifying proteins in the floats, the floated material were taken so as to contain a suitable amount of proteins. The total volume was adjusted to 1.0 mil with the buffer solution A and added 1.0 ml of 25%
ethanolic KOH solution thereto to proceed saponification reaction at 80 °C for 30 minutes. After dissolving unsaponicated sterols into n-hexane, they were separated by a thin layer liquid chromatography. The composition of the developing solvents was ethyl acetate and benzene at 95:5 ratio and cholesterol was developed as the internal standard for 50 minutes. Bands in the cholesterol-developed peak region were collected and put into a radioactive vial, and then 10 ml of scintillation cocktail solution were added thereto. The radioactivity strength of each sample was determined by a liquid scintillation counter (LSC) to give the cholesterol biosynthetic ratio. 50% of inhibitory effect was observed at the 0.1 to 0.3 ,uM
concentration of 5,6-dihydrodibenzo[a,g]quinolizinium salts (compound no. 2).
Ez,~m~]~e 74: Effect of 5,6-~dihydrodibenzo[a,g]quinoliziniurn salts on cholesterol biosynthesis in cultured human liver cell line (HepG2 cells}
Cultured human liver HepG2 cell line was grown on RPMI (Rosewell park Memorial Institute) 1640 culture medium containing 10% PBS until 60% of monolayer are formed in a 60 mm culture dish. After replacing the medium with ml of a fresh culture medium containing 10 %(v/v) LPDS (Fetal calf lipoprotein-deficient senun), the cells were further grown for 4$ hours until 90% of cultivation degree appear. The culture medium was removed and the cell was then washed with PBS. 2 ml of culture medium containing compound no. 2 (final concentration 100 ,uM) and AY-9944 (final concentration 1 ~cM) were added thereto. Then, the medium was cultivated at 3~7 °C for 1 hour under the condition of 95%
air/5%
carbonic acid gas. AY-9944 which is an inhibitor for sterol 7-reductase was used as a control drug for assuring the present experimental procedure on the inhibition of cholesterol biosynthesis. 'Thereafter, 3 ~cCi of [1,2-'°C]acetate (72 mCi/mmol) were added thereto. The cull:ivation was continued for 2 hours so that the isotope is introduced into the cell and used as a precursor for sterol to be synthesized.
Then, the culture medium was completely removed and washed with PBS twice and the cells were collected by scratching. 10 ~cg of cholesterol, 10 ,ug of lanosterol and [3H]cholesterol (30,000 dpm) were added thereto, and saponification reaction was carried out at 70 °C for an hour by adding 7.5% of methanolic KOH
solution.
Unsaponified sterol was removed by extracting them three times with 3 ml of petroleum ether and dried with nitrogen purging. The dried samples were redissolved in 200 ~cl of chloroform. An aliquot of the samples was loaded onto WO 00/37468 PCTlKR99/00030 Silicagel 60F thin layer plate; and then separated using ethyl acetate/hexane (v/v) as the developing solvent. The thin layer film was developed by exposure to Amersham Hyperfilm at -70°C for 7 days. Cholesterol band were confirmed by comparing the band appeared in the film and that appeared in the iodine-stained thin layer. After scratching the cholesterol band, it was quantified by a liquid scintillation counter.
Exam lp a 75: In vivo effect of 5,6-dihydrodibenzo[a,g]quinolizinium salts on cholesterol biosynthesis in Syrian Golden Hamster Male Syrian Golden Hamsters weighing 90 ~ 1 l Og distributed from Samyuk Animal Laboratory, Seoul, Korea were bred under the following conditions: they were maintained under reverse light cycle (light cycle: from 6 P.M to 6 A.M;
dark cycle: from 6 A.M. to 6 P.M.). The food and water were supplied at 10 A.M. The commercially available standard rodent chows were used. The hamsters were divided into 6 or 7 animals per group. The animals were fasted for 12 hours before administrating the drug. Then, 5,6-dihydrodibenzo[a,g]quinolizinium salts (compound no. 2) dissolved izi a 0.25% methyl cellulose solution was administered orally for 14 days at the indicated time per a day. After fasting animals for 24 hours from the last administration, blood was extracted using a cardiac puncture and plasma was then isolated. Plasma lipids, i.e., total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyce:ride values were analyzed using Automatic Analyzer (Hitachi 7150).
Ezam !n a 76: Preparation crf pharmaceutically available tablets of 5,6-dihydro-dibenzo[a,g]quinolizinium salts The raw drug materials corresponding to an amount of 10,000 tablets were weighted and passed into 20 mesh sieve and the mixture was then blended for 10 minutes. The mixture was. transferred to a compressor and was tableted under suitable pressure so as to give average weight of 200 mg per tablet.
1 ) Composition of the raw drug materials per tablet (200 mg) Component amount Compound No. 2 10 mg Calcium carboxymethyl celluloseS mg Lactose # 100 ( 100 mesh) 147. S mg Hydroxypropyl cellulose 5 mg Ludipress (BASF AG) 30 mg Magnesium stearate 2.5 mg 2) Composition of the raw drug materials per tablet (200 mg) Component amount Compound No. 2 10 mg Calcium carboxymethyl celluloseS mg Lactose # 100 ( 100 mesh) 147.5 mg Hydroxypropyl cellulose 5 mg Kollidon VA64 (BASF A~G) 30 mg Magnesium stearate 2.5 mg 3 ) Composition of the raw drug materials per tablet (200 mg) Component amount Compound No. 3 5 mg Calcium carboxymethyl cellulose5 mg Lactose #100 (100 mesh) 152.5 mg Hydroxypropyl cellulose 5 mg Ludipress (BASF AG) 30 mg Magnesium stearate 2.5 mg 4) Composition of the raw drug materials per tablet (200 mg) Component amount Compound No. 3 5 mg Calcium carboxymethyl cellulose5 mg Lactose # 100 ( 100 mesh) 152.5 mg Hydroxypropyl cellulose 5 mg Kollidon VA64 (BASF AG) 30 mg Magnesium stearate 2.5 mg 5) Composition of the raw drug materials per tablet (200 mg) Component amount Compound No. 68 2 mg Calcium carboxymethyl cellulose5 mg Lactose # 100 ( 100 mesh) 155.5 mg Hydroxypropyl cellulose 5 mg Ludipress (BASF AG) 30 mg Magnesium stearate 2.5 mg 6) Composition of the raw drug materials per tablet (200 mg) Component amount Compound No. 68 2 mg Calcium carboxymethyl cellulose5 mg Lactose # 100 ( 100 mesh) 155.5 mg Hydroxypropyl cellulose 5 mg Kollidon VA64 (BASF Ats) 30 mg Magnesium stearate 2.5 mg The compounds of formula (I) can effectively inhibit sterol 14-reductase which is involved in the distal pathway of cholesterol biosynthesis, and thus, are especially effective in treatvzg hypercholesterolemia.
The compounds of formula (I) above have the activities to decrease total cholesterol, LDL-cholesterol, and triglyceride levels and at the same time, to decrease glucose level in an. animal test. Therefore, they are effective in diabetic hypercholesterolaemia and hyperlipidaemia.
Table 3 represents the relative activity for sterol 14-reductase of the compound of formula (I) as set forth in Table 1. Among the compounds of Table 1, Compound Nos. 2, 3, 9 and 68 markedly inhibited the cholesterol biosynthesis in human HepG2 cell line connpared with AY9944 which is a comparative drug. In the animal test with Syrian (iolden Hamster, Compound Nos. 2, 3, 9 and 68 have markedly decreased total clholesterol, LDL-cholesterol, and triglyceride levels compared with lovastatin which is a commercially available comparative cholesterol-lowering agent.

Table 3: Relative In Yitra activity for the compound of formula (I) Comp. No. Enzyme Comp. No. Enzyme Comp. No. Enzyme Activity Activity Activity 1 +++ 25 + 49 ++

2 +++ 26 + 50 ++

3 +++ 27 + 51 ++

4 ++ 28 + 52 ++

5 +++ 29 ++ 53 ++-6 +++ 30 + 54 ++

7 ++ 31 + 55 +++

8 + 32 + 56 +++

9 +++ 33 +

10 ++ 34 ++ 58 ++

11 +++ 35 + 59 ++

12 + 36 ++ 60 +-++

13 +++ 37 + 61 +++

14 + 38 ++ 62 ++

15 + 39 ++ 63 ++

16 +++ 40 + 64 ++

17 +++ 41 + 65 ++

18 ++ 42 ++ 66 ++

19 ++ 43 ++ 67 ++

20 ++ 44 + 68 +++

21 + 45 ++ 69 ++

22 + 46 +++ 70 ++

23 ++ 47 +++ 71 ++

24 + 4g ++.~-+: 100 ~cM or more of lfCso value ++: 10 - 100 ~cM of ICSa, value +++: 1 ~cM or below of IC:SO value Table 4: In vivo activity resat for Comp. Nos. 2, 3, 9, and 68 Group No. n Total HDL LDL Triglyceride cholesterolcholesterolcholesterol(mg/dl) (m8/~) (m8/~) (mP~~) normal diet 5 130.814 59.87 37.014 79.4113 control normaldiet+ 5 107.8a9 67.013 29.112 SS.St7 lovastatin (-17.6'!0)(+11.2%) (-21.4%) (-30.1%) 6.0 mg/kg/day normal diet 5 115. 8:~ 66. 617 31.0 t 67.818 + 8 3 comp.2 (-11.5',0 (+11.4%) (-16.0%
(-14.6 /) 0.3 mg/kg/day normal diet 5 89.01 7 63.01 3.0 18.812 49.26 +

Comp. 3 (-23 .5 (+5.4%) (-49.2%) (-3 8.0%) "~o ) 0.3 mg/kg/day normal diet 5 82.417 56.213.0 20.212 44.85.5 +

Comp.9 (-37.040.)(-6.0%) (-45.4%) (-43.6%) 0.3 mg/kg/day normal diet 5 87.416 58.613 21.813 45.217 +

Comp. 68 (-33.1 (-2.0%) (-41.1%) (-43.1%) ~o) 0.3 mg/kg/day Meanwhile, the toxicity of the compounds of the present invention was investigated as follows: i.e., the compounds were suspended into propylene glycol and then orally administered into each of 5 male and female SD rats at the age of 5-weeks that were fasted for 12 hours. Under the usual breeding conditions, general symptoms, weight change and lethal case of the above rats were monitored for two weeks. At the dose over 2,000 mg/kg of the compound nos. 2, 3, 9 and 68, general symptoms and the body weight change of the animals were normal and the lethal case was not observed. The toxicity data for the representative compounds (Compound No. 2, 3, 9 and 68) is set forth in Table 5.
Table 5 Comp. No. Acute Toxicity (mg/kg) animal administratiosex LDSo n route Comp.2 rats oral male >2,000 female >2,000 Comp.3 rats oral male >2,000 female >2,000 Comp.9 rats oral male >2,500 female >2,000 Comp.68 rats oral male >3,000 female >3,000 As evident from the above descriptions, the compound of formula (I) inhibits sterol 14-reductase which is an enzyme in the distal stage of the cholesterol biosynthesis, thereby being effective in treatment of hypercholesterolemia and hyperlipidaemia and safe in an aspect of toxicity.

Claims (17)

What is claimed is

1. A 5,6-dihydrodibenzo[a,g)quinolizinium derivative represented by the formula (I) and the salt thereof.

wherein, R1 and R2 which many be the same or different from each other, represent a hydroxy group or an alkoxy group having 1 to 4 carbons or R1 and R2 together represent a methylenedioxy group;
R3 represents a hydroxy group or an alkoxy group having 1 to 4 carbons;
R4 represents a hydrogen atom, an alkyl group having 1 to 8 carbons, or an alkenyl group having 3 to 8 carbons;
X represents inorganic acid ion, organic acid ion or halide, more particularly, nitrate, sulfate, acetate, tartrate, maleate, succinate, citrate, fumarate, aspartate, salicylate, glycerate, ascorbate, fluoride, chloride, iodide or bromide, Z represents an alkyl group having 5 to 12 carbons, or an alkenyl group having 4 to 6 carbons, a N-benzotriazolyl group, a quinolinyl group, a furyl group, a substituted furyl group, or a group represented by the formula wherein Z1, Z2, Z3, Z4 and Z5 which may be the same or different from each other, represent a hydrogen atom, halogen, an alkyl group having 1 to 5 carbons, a trifluoromethyl group, a phenyl group, a substituted phenyl group, a nitro group, an alkoxy group having 1 to 4 carbons, a methylenedioxy group, a trifluoromethoxy group, a hydroxy group, a benzyloxy group, a phenoxy group, a vinyl group, a benzenesulfonylmethyl group or a methoxycarbonyl group; and A and B which may be the same or different from each other, represent carbon or nitrogen.

2. The compound of formula (I) according to Claim 1, wherein Z represents a group having the following chemical formula wherein Z1, Z2, Z3, Z4 and Z5 which may be the same or different from each other, represent a hydrogen atom, halogen, an alkyl group having 1 to 5 carbons, a trifluoromethyl group, a phenyl group, a substituted phenyl group, nitro, an alkoxy group having 1 to 4 carbons, a methylenedioxy group, a trifluoromethoxy group, a hydroxy group, a benzyloxy group, a phenoxy group, a vinyl group, a benzenesulfonylmethyl group or a methoxycarbonyl group; and A and B which may be the same or different from each other, represent carbon or nitrogen; and X represents inorganic acid ion, organic acid ion or halide.

3. The compound of formula (I) according to Claim 1, wherein R4 is ethyl group.

4. The compound of formula (I) according to Claim 1, wherein R1, R2, R3, R4 and X each represents a methoxy group, a methoxy group, a methoxy group, an ethyl group and chloride, and Z represents 4-(tert-butyl)phenyl.

5. The compound of formula (I) according to Claim 1, wherein R1, R2, R3, R4 and X each represents a methoxy group, a methoxy group, a methoxy group, an ethyl group and chloride, and Z represents 2,3,4,5,6-pentafluorophenyl.

6. The compound of formula (I) according to Claim 1, wherein R1, R2, R3, R4 and X each represents a methoxy group, a methoxy group, a methoxy group, an ethyl group and chloride, and Z represents 4-trifluoromethylphenyl.

7. The compound of formula (I) according to Claim 1, wherein R1-R2, R3, R4 and X each represents a methylenedioxy group, a methoxy group, an ethyl group and iodide, and Z represents 4-trifluoromethylphenyl.

8. A process for preparing a 5,6-dihydrodibenzo[a,g]quinolizinium derivative of formula (I) and pharmaceutically acceptable salts thereof, in which (a) the compound of formula (IV) is deprotected to give a compound of formula (V);
(b) the compound of formula (V) obtained from the previous step is selectively O-alkylated with an alkylating reagent to give monohydroxy compound of formula (VI); and (c ) the compound of formula (VI) thus obtained is reacted with alkyl substituent (ZCH2-X) to give a 5,6-dihydrodibenzo[a,g]quinolizinium derivative.

In the above formulae, R1, R2, R3, R4, X and Z are the same as defined in the compound of formula (I).

9. A process for preparing a 5,6-dihydrodibenzo[a,g]quinolizinium derivative and pharmaceutically acceptable salts thereof, in which (a) a compound of the formula (IV) is subjected to pyrolysis in the presence of a non-polar solvent or in the absence of a solvent at a high temperature of 100 to 300 °C to give a compound of the formula (VI); and (b) the compound thus obtained is then reacted with electrophiles (ZCH2-X) to give a 5,6-dihydrodibenzo[a,g]quinolizinium derivative of the formula (I).

wherein, R1, R2, R3, R4, and X are the same as defined in compound of formula (I);
and Z represent halide, sulfate, nitrate, acetate, tinnate, tannate, maleate, succinate, citrate, fumarate, or fatty acid salt.

10. A pharmaceutical composition for treating hyperlipidaemia which comprises a 5,6-dihydrodibenzo[a,g]quinolizinium derivative represented by the formula (I) and the salt thereof as an active ingredient and a pharmaceutically acceptable excipient.
wherein, R1 and R2 which may be the same or different from each other, represent a hydroxy group or an alkoxy group having 1 to 4 carbons or R1 and R2 together represent a methylenedioxy group;
R3 represents a hydroxy group or an alkoxy group having 1 to 4 carbons;
R4 represents a hydrogen atom, an alkyl group having 1 to 8 carbons, or an alkenyl group having 3 to 8 carbons;

X represents inorganic acid ion, organic acid ion or halide, more particularly, nitrate, sulfate, acetate, tartrate, maleate, succinate, citrate, fumarate, aspartate, salicylate, glycerate, ascorbate, fluoride, chloride, iodide or bromide, Z represents an alkyl group having 5 to 12 carbons, or an alkenyl group having 4 to 6 carbons, a N-benzotriazolyl group, a quinolinyl group, a furyl group, a substituted furyl group, or a group represented by the formula wherein Z1, Z2, Z3, Z4 and Z5 which may be the same or different from each other, represent a hydrogen atom, halogen, an alkyl group having 1 to 5 carbons, a trifluoromethyl group, a phenyl group, a substituted phenyl group, a nitro group, an alkoxy group having 1 to 4 carbons, a methylenedioxy group, a trifluoromethoxy group, a hydroxy group, a benzyloxy group, a phenoxy group, a vinyl group, a benzenesulfonylmethyl group or a methoxycarbonyl group; and A and B which may be the same or different from each other, represent carbon or nitrogen.

11. The pharmaceutical composition according to Claim 10, wherein Z
represents a group having the following chemical formula wherein Z1, Z2, Z3, Z4 and Z5 which may be the same or different from each other, represent a hydrogen atom, halogen, an alkyl group having 1 to 5 carbons, a trifluoromethyl group, a phenyl group, a substituted phenyl group, nitro, an alkoxy group having 1 to 4 carbons, a methylenedioxy group, a trifluoromethoxy group, a hydroxy group, a benzyloxy group, a phenoxy group, a vinyl group, a benzenesulfonylmethyl group or a methoxycarbonyl group; and A and B which may be the same or different from each other, represent carbon or a nitrogen; and X represents inorganic acid ion, organic acid ion or halide.

12. The pharmaceutical composition according to Claim 10, wherein R4 is ethyl group

13. The pharmaceutical composition according to Claim 10, wherein R1, R2, R3, R4 and X each represents a methoxy group, a methoxy group, a methoxy group, an ethyl group and chloride, and Z represents 4-(tert-butyl)phenyl.

14. The pharmaceutical composition according to Claim 10, wherein R1, R2, R3, R4 and X each represents a methoxy group, a methoxy group, a methoxy group, an ethyl group and chloride, and Z represents 4-pentafluorophenyl.

15. The pharmaceutical composition according to Claim 10, wherein R1, R2, R3, R4 and X each represents a methoxy group, a methoxy group, a methoxy group, an ethyl group and chloride, and Z represents 4-trifluoromethylphenyl.

16. The pharmaceutical composition according to Claim 10, wherein R1-R2, R3, R4 and X each represents a methylenedioxy group, a methoxy group, an ethyl group and iodide, and Z represents 4-trifluoromethylphenyl.

17. The pharmaceutical composition according to Claim 10, wherein said composition is sterol 14-reductase inhibitor.