U.S. patent application number 14/091979 was filed with the patent office on 2014-03-27 for hexahydrodibenzo[a,g]quinolizine compound, preparation method thereof, pharmaceutical composition and use thereof.
This patent application is currently assigned to SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES. The applicant listed for this patent is Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Invention is credited to Kaixian CHEN, Ying CHEN, Hualiang JIANG, Jing LI, Zeng LI, Hong LIU, Haifeng SUN, Xin XIE, Xuechu ZHEN, Liyuan ZHU.
Application Number | 20140088130 14/091979 |
Document ID | / |
Family ID | 47195431 |
Filed Date | 2014-03-27 |
United States Patent
Application |
20140088130 |
Kind Code |
A1 |
LIU; Hong ; et al. |
March 27, 2014 |
HEXAHYDRODIBENZO[A,G]QUINOLIZINE COMPOUND, PREPARATION METHOD
THEREOF, PHARMACEUTICAL COMPOSITION AND USE THEREOF
Abstract
The present invention relates to a novel
hexahydrodibenzo[a,g]quinoline compound represented by general
formula (I) and its derivatives, enantiomer, diastereoisomer,
raceme and mixtures thereof, as well as pharmaceutically acceptable
salts thereof. The present invention further relates to a method
for preparing the compound, and the compound has good prevention
and treatment effect on neurological diseases, especially diseases
associated with dopamine receptor and 5-hydroxytryptamine receptor.
The bioactivity experiment demonstrates that, the compound is
expected to be developed into a novel and potent chemical entity
for treating diseases associated with dopamine receptor and
5-hydroxytryptamine receptor, especially schizophrenia, Parkinson's
disease, drug addiction, migraine and so on. ##STR00001##
Inventors: |
LIU; Hong; (Shanghai,
CN) ; XIE; Xin; (Shanghai, CN) ; ZHEN;
Xuechu; (Shanghai, CN) ; SUN; Haifeng;
(Shanghai, CN) ; LI; Jing; (Shanghai, CN) ;
ZHU; Liyuan; (Shanghai, CN) ; LI; Zeng;
(Shanghai, CN) ; CHEN; Ying; (Shanghai, CN)
; JIANG; Hualiang; (Shanghai, CN) ; CHEN;
Kaixian; (Shanghai, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Shanghai Institute of Materia Medica, Chinese Academy of
Sciences |
Shanghai |
|
CN |
|
|
Assignee: |
SHANGHAI INSTITUTE OF MATERIA
MEDICA, CHINESE ACADEMY OF SCIENCES
Shanghai
CN
|
Family ID: |
47195431 |
Appl. No.: |
14/091979 |
Filed: |
November 27, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/CN2012/073661 |
Apr 9, 2012 |
|
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|
14091979 |
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Current U.S.
Class: |
514/280 ;
514/279; 514/284; 546/33; 546/41; 546/71 |
Current CPC
Class: |
A61P 25/36 20180101;
A61P 25/00 20180101; C07D 491/147 20130101; C07C 69/736 20130101;
A61P 43/00 20180101; C07D 455/03 20130101; A61P 25/18 20180101;
C07D 491/153 20130101; C07D 491/22 20130101; A61P 25/06 20180101;
C07D 491/056 20130101; C07D 311/20 20130101; A61P 25/30 20180101;
A61P 25/16 20180101; C07D 217/20 20130101; C07C 231/14
20130101 |
Class at
Publication: |
514/280 ; 546/71;
546/33; 546/41; 514/284; 514/279 |
International
Class: |
C07D 491/147 20060101
C07D491/147; C07D 491/22 20060101 C07D491/22; C07D 455/03 20060101
C07D455/03 |
Foreign Application Data
Date |
Code |
Application Number |
May 27, 2011 |
CN |
201110141822.8 |
Claims
1. A hexahydrodibenzo[a,g]quinoline compound of general formula
(I): ##STR00023## an enantiomer, diastereoisomer, racemate,
pharmaceutically acceptable organic salt or inorganic salt,
crystalline hydrate or solvate thereof, or mixture thereof, wherein
R.sub.2 is a hydroxy, a hydroxy-substituted C1-C6 alkyl, a
substituted or unsubstituted C1-C6 alkoxy, a halogen, a substituted
or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6
alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a
substituted or unsubstituted C3-C6 cycloalkyl, a substituted or
unsubstituted C1-C6 alkanoyl, a substituted or unsubstituted C6-C20
aryl, a substituted or unsubstituted benzyl, an amino acid or
N-protected amino acid, or --(CO) R.sub.9; when R.sub.2 is a
substituted or unsubstituted C1-C6 alkyl, a substituted or
unsubstituted C1-C6 alkoxy, a substituted or unsubstituted C2-C6
alkenyl, a substituted or unsubstituted C2-C6 alkynyl, or a
substituted or unsubstituted C3-C6 cycloalkyl, a substituent for
substitution can be a halogen or COOR.sub.10; when R.sub.2 is a
substituted or unsubstituted C1-C6 alkanoyl, a substituted or
unsubstituted C6-C20 aryl, or a substituted or unsubstituted
benzyl, a substituent for substitution is selected from the
following group: C1-C6 alkyl, a halogen, C1-C6 alkoxy; wherein
R.sub.9 is a substituted or unsubstituted C1-C6 alkyl, a
substituted or unsubstituted C2-C6 alkenyl, a substituted or
unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C6-C20
aryl, or heteroaryl selected from thiazolyl, pyrazolyl, imidazolyl,
thienyl, furyl, pyrrolyl, or pyridyl; when R.sub.9 is a substituted
or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6
alkenyl, or a substituted or unsubstituted C2-C6 alkynyl, a
substituent for substitution is a carboxyl, a substituted or
unsubstituted C6-C20 aryl, or heteroaryl selected from thiazolyl,
pyrazolyl, imidazolyl, thienyl, furyl, pyrrolyl, or pyridy; when
R.sub.9 is a substituted or unsubstituted C6-C20 aryl, a
substituent for substitution is a C1-C6 alkyl, a halogen or a C1-C6
alkoxy; R.sub.10 is H, a C6-C20 alkyl substituted or unsubstituted
C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl; when R.sub.2 is
an amino acid or N-protected amino acid, the amino acid can be
D-amino acid, L-amino acid or racemate; each of R.sub.3, R.sub.4 is
independently H, a halogen substituted or unsubstituted C1-C6
alkyl, a halogen substituted or unsubstituted C1-C6 alkoxy, a C2-C6
alkenyl, a C2-C6 alkynyl, a halogen, COOR.sub.11, or
CONR.sub.12R.sub.13, wherein R.sub.11 is H, a substituted or
unsubstituted C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a
substituted or unsubstituted C6-C20 aryl, or a substituted or
unsubstituted benzyl; when R.sub.11 is a substituted or
unsubstituted C6-C20 aryl, or a substituted or unsubstituted
benzyl, a substituent for substitution is a C1-C6 alkyl, a halogen
or a C1-C6 alkoxy; when R.sub.11 is a substituted or unsubstituted
C1-C6 alkyl, a substituent for substitution is a halogen; each of
R.sub.13, R.sub.12 is independently H, a substituted or
unsubstituted C1-C6 alkyl or they and nitrogen atom together form
azetidine, pyrrolidinyl, piperazinyl, or morpholinyl, when R.sub.13
or R.sub.12 is a substituted or unsubstituted C1-C6 alkyl, a
substituent for substitution is a halogen; each of R.sub.1,
R.sub.5, R.sub.6, R.sub.7, R.sub.8 is independently H, a hydroxy, a
hydroxy-substituted C1-C6 alkyl, a halogen-substituted or
unsubstituted C1-C6 alkyl, a halogen substituted or unsubstituted
C1-C6 alkoxy, a halogen, a C3-C6 cycloalkyl, a halogen substituted
or unsubstituted C2-C6 alkenyloxy, a halogen-substituted or
unsubstituted C3-C6 alkynyloxy, a substituted or unsubstituted
benzyloxy, a substituted or unsubstituted C6-C20 aryl,
R.sub.14COO--, R.sub.15R.sub.16N--; when R.sub.1, R.sub.5, R.sub.6,
R.sub.7, or R.sub.8 is a substituted or unsubstituted benzyloxy, or
a substituted or unsubstituted C6-C20 aryl, a substituent for
substitution is a C1-C6 alkyl, a halogen, or a C1-C6 alkoxy;
wherein R.sub.14 is H, a halogen-substituted or unsubstituted C1-C6
alkyl; each of R.sub.15 and R.sub.16 is independently selected from
H, a substituted or unsubstituted C1-C6 alkyl, a substituted or
unsubstituted C2-C6 alkenyl, or a substituted or unsubstituted
C2-C6 alkynyl or they and nitrogen atom together form azetidine,
pyrrolidinyl, piperazinyl, or morpholinyl, when R.sub.15 or
R.sub.16 is a substituted or unsubstituted C1-C6 alkyl, a
substituted or unsubstituted C2-C6 alkenyl, a substituted or
unsubstituted C2-C6 alkynyl, a substituent for substitution is a
C1-C6 alkyl, a halogen or a C1-C6 alkoxy; R.sub.1 and R.sub.2 can
together form a substituted or unsubstituted 5-7 membered
heterocycle, a substituent for substitution is a halogen, or a
halogen-substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, or
C2-C6 alkynyl; and the heterocycle contains 1-3 heteroatom(s)
selected from N, O or S; any two adjacent substituents of R.sub.5,
R.sub.6, R.sub.7 and R.sub.8 can together form a substituted or
unsubstituted 5-7 membered heterocycle, a substituent for
substitution is a halogen, or a halogen-substituted or
unsubstituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and the
heterocycle contains 1-3 heteroatom(s) selected from N, O or S; and
the configuration of chiral carbon atom in the compound of general
formula (I) is R or S configuration, provided that when the
compound of general formula (I) is racemate: (a) when R.sub.2 is
methoxyl, R.sub.3 is H, R.sub.4 is H or methyl, and at least one of
R.sub.5, R.sub.6, R.sub.7, and R.sub.8 is methoxyl or R.sub.6 and
R.sub.7 together form --O--CH.sub.2--O--, then R.sub.1 is not H,
methoxyl or BnO; (b) when R.sub.1 and R.sub.2 together form
--O--CH.sub.2--O--, and R.sub.7 or R.sub.8 is methoxyl, then
R.sub.5 is not methoxyl; (c) when R.sub.6 and R.sub.7 together form
--O--CH.sub.2--O-- and R.sub.5 and R.sub.8 are H, then R.sub.2 is
not methoxyl and R.sub.1 and R.sub.2 together do not form
--O--CH.sub.2--O--; and (d) the compound of general formula (I) is
not DC037027, ##STR00024##
2. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 1, wherein R.sub.1 is H, a
halogen-substituted or unsubstituted C1-C6 alkyl, a
halogen-substituted or unsubstituted C1-C6 alkoxy, a hydroxy, a
hydroxy-substituted C1-C6 alkyl or a halogen-substituted or
unsubstituted benzyloxy; R.sub.2 is a hydroxy, a
hydroxy-substituted C1-C6 alkyl, a halogen substituted or
unsubstituted C1-C6 alkyl, a halogen substituted or unsubstituted
C1-C6 alkoxy, or a halogen; R.sub.3 is H, or a halogen substituted
or unsubstituted C1-C6 alkyl; R.sub.4 is H, a halogen substituted
or unsubstituted C1-C6 alkyl, or a halogen substituted or
unsubstituted C1-C6 alkoxy; R.sub.5 is H, a halogen substituted or
unsubstituted C1-C6 alkyl, a halogen substituted or unsubstituted
C1-C6 alkoxy or a halogen; R.sub.6 is H, a halogen-substituted or
unsubstituted C1-C6 alkyl, a halogen-substituted or unsubstituted
C1-C6 alkoxy, a hydroxy, or a hydroxy-substituted C1-C6 alkyl;
R.sub.7 is H, a halogen-substituted or unsubstituted C1-C6 alkyl, a
halogen-substituted or unsubstituted C1-C6 alkoxy, a hydroxy, or a
hydroxy-substituted C1-C6 alkyl; R.sub.8 is H, a hydroxy, a
hydroxy-substituted C1-C6 alkyl, a halogen-substituted or
unsubstituted C1-C6 alkoxy, a halogen-substituted or unsubstituted
C1-C6 alkyl or a halogen; or R.sub.1 and R.sub.2 can together form
a C1-C6 alkyl-substituted or unsubstituted 5-7 membered
heterocycle, and the heterocycle contains 1-2 heteroatom(s)
selected from N, O or S; R.sub.6 and R.sub.7 can together form a
fluoro-, chloro- or bromo-substituted 5-7 membered heterocycle, and
the heterocycle contains 1-2 heteroatom(s) selected from N, O or
S.
3. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 2, wherein R.sub.1 is H, a C1-C6
alkyl, a C1-C6 alkoxy, a hydroxy, a hydroxy-substituted C1-C6 alkyl
or benzyloxy; R.sub.2 is a hydroxy, a hydroxy-substituted C1-C6
alkyl, a C1-C6 alkyl, a C1-C6 alkoxy or a halogen; R.sub.3 is H or
a C1-C6 alkyl; R.sub.4 is H, a C1-C6 alkyl, or a C1-C6 alkoxy;
R.sub.5 is H, a C1-C6 alkyl, a C1-C6 alkoxy or a halogen; R.sub.6
is H, a C1-C6 alkyl, a C1-C6 alkoxy, a hydroxy, or a
hydroxy-substituted C1-C6 alkyl; R.sub.7 is H, a C1-C6 alkyl, a
C1-C6 alkoxy, a hydroxy, or a hydroxy-substituted C1-C6 alkyl;
R.sub.8 is H, a hydroxy, a hydroxy-substituted C1-C6 alkyl, a C1-C6
alkoxy, a C1-C6 alkyl or a halogen; the halogen is F, Br or Cl;
R.sub.1 and R.sub.2 can together form a C1-C6 alkyl-substituted or
unsubstituted 5- or 6-membered heterocycle and the heterocycle
contains 1-2 heteroatom(s) selected from N, O or S; R.sub.6 and
R.sub.7 can together form a fluoro-, chloro- or bromo-substituted
or unsubstituted 5- or 6-membered heterocycle and the heterocycle
contains 1-2 heteroatom(s) selected from N, O or S.
4. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 1, wherein, the configuration of
chiral C atom which is not linked with R.sub.3 or R.sub.4 in the
parent nucleus of compound of general formula (I) is S.
5. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 1, wherein, the configuration of
chiral C atom which is not linked with R.sub.3 or R.sub.4 in the
parent nucleus of compound of general formula (I) is R.
6. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 1, wherein, the compound of
general formula (I) is chiral compound.
7. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 1, wherein, R.sub.5 is methoxyl,
and R.sub.6 is hydroxyl.
8. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 1, wherein, R.sub.3 is a halogen
substituted or unsubstituted C1-C6 alkyl, a halogen substituted or
unsubstituted C1-C6 alkoxy, a C2-C6 alkenyl, a C2-C6 alkynyl, a
halogen, COOR.sub.11, or CONR.sub.12R.sub.13.
9. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 1, wherein, R.sub.8 is a
hydroxy-substituted C1-C6 alkyl, or a halogen.
10. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 1, wherein, one to four of
R.sub.5, R.sub.6, R.sub.7, and R.sub.8 is a hydroxy-substituted
C1-C6 alkyl or C1-C6 alkyl.
11. The hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, racemate, pharmaceutically acceptable organic salt
or inorganic salt, crystalline hydrate or solvate thereof, or
mixture thereof according to claim 1, wherein the compound is
selected from the group consisting of: ##STR00025## ##STR00026##
##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031##
##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036##
##STR00037##
12. A pharmaceutical composition comprising a therapeutically
effective amount of the hexahydrodibenzo[a,g]quinoline compound,
the enantiomer, diastereoisomer, racemate, pharmaceutically
acceptable organic salt or inorganic salt, crystalline hydrate or
solvate thereof, or mixture thereof according to claim 1, and one
or more pharmaceutically acceptable carriers.
13. A method of treating a nervous system disease relating to
dopamine receptors and serotonin receptors in a subject in need
thereof, comprising administering to the subject the pharmaceutical
composition according to claim 12.
14. The method according to claim 13, wherein the nervous system
disease is Parkinson's disease, schizophrenia, drug addiction, or
migraine.
15. A preparation method of hexahydro-dibenzo[a,g]quinoline
compound according to claim 1, wherein the definitions of R1-R4 and
R8 are described above, when each of R5 and R6 is independently a
halogen-substituted or unsubstituted C1-C6 alkoxy, a substituted or
unsubstituted benzyloxy, and R7 is H; or when R5 is a
halogen-substituted or unsubstituted C1-C6 alkoxy, a substituted or
unsubstituted benzyloxy, R6 is a hydroxy, and R7 is H, the
compounds are prepared according to the second reaction route;
other compounds are prepared according to the first reaction route;
wherein, a substituent for substitution is a C1-C6 alkyl, a halogen
or a C1-C6 alkoxy: the first reaction route: ##STR00038##
##STR00039## reagents and reaction conditions: a) acetic acid,
nitromethane, ammonium acetate, 80.degree. C.; b) lithium aluminum
hydride, anhydrous tetrahydrofuran, reflux; c) ammonium formate,
anhydrous methanol, palladium carbon, hydrogen, room temperature;
d) 1-ethyl-3-(3-dimethylpropylamine) carbodiimide, anhydrous
dichloromethane, triethylamine, room temperature; e) nitrogen
protection, phosphorus oxychloride, acetonitrile, reflux; and f)
catalyst (Noyori), N, N-dimethylformamide, triethylamine/formic
acid or sodium borohydride; g) aldehyde, acid conditions; the
preparation of Compound 2a: a substrate is dissolved in an
appropriate amount of glacial acetic acid, to which 1.2-2.0
equivalent of ammonium acetate is added to form a mixture, 5-10
equivalent of nitromethane is added to the mixture at room
temperature and reacted in an oil bath, and then the reaction
system is cooled to room temperature and a large amount of solid is
precipitated, Compound 2a is obtained by suction filtration; the
preparation of Compound 3a: lithium aluminum hydride is suspended
in an appropriate amount of anhydrous tetrahydrofuran and placed in
an ice water bath; a solution of unsaturated nitro-compound 2a in
anhydrous tetrahydrofuran is slowly added dropwise; after the
addition is completed, the reaction solution is transferred into an
oil bath, refluxed, and then cooled to room temperature, then the
defined amount of water is added slowly and a clear solution is
obtained by filtration, after dried over anhydrous sodium sulfate
and evaporated to dryness, an oily Compound 3a is obtained; the
preparation of Compound 5a: a substrate 4a is dissolved in an
appropriate amount of anhydrous methanol, and 1.5-3.0 equivalent of
ammonium formate is added; 10% palladium carbon is added under
stirring and hydrogen is ventilated at the same time; the reaction
is carried out at room temperature overnight; after the palladium
carbon is removed by filtration, the solution is evaporated to
dryness to give an oily Compound 5a; the preparation of Compound
6a: at room temperature, the substrate 3a or 5a is condensed with
R5-, R6-, R7-, and R8-substituted phenylacetic acid in the presence
of 1-ethyl-3(3-dimethyl-propylamine) carbodiimide or triethylamine,
and anhydrous dichloromethane, then the product is purified by
column chromatography or recrystallized by using ethanol to give
Compound 6a; the preparation of Compound 7a: under N.sub.2, the
substrate 6a in acetonitrile used as solvent is refluxed under the
action of phosphorus oxychloride to obtain Compound 7a; the
preparation of Compound 8a: Compound 7a is reduced by sodium
borohydride to form racemic Compound 8a; or catalyst Noyori as the
chiral reducing reagent, N,N-dimethylformamide,
triethylamine/formic acid are used to carry out the asymmetric
reduction reaction, thereby obtaining Compound 8a with a single
configuration; the preparation of Compound 9a: the intermediate
Compound 8a is reacted with aldehyde under acidic condition to
obtain Compound 9a; the second reaction route: ##STR00040##
##STR00041## wherein R9' is a C1-C6 alkyl, R5' is a
halogen-substituted or unsubstituted C1-C6 alkyl, or a substituted
or unsubstituted benzyl, R6' is a halogen-substituted or
unsubstituted C1-C6 alkyl, or a substituted or unsubstituted
benzyl, wherein a substituent for substitution is a C1-C6 alkyl, a
halogen or a C1-C6 alkoxy; reaction reagents and conditions: a)
room temperature, acetic acid, liquid bromine; b) alkylating
reagent/benzylating reagent, solvent, organic alkali/inorganic
alkali; c) catalyst containing copper or copper ion, alkaline
condition, water, 90.degree. C. to 150.degree. C. of reaction
temperature, pH 1-3; d) phenylboronic acid, toluene,
paraformaldehyde and water; e) solvent, alkylating
reagent/benzylating reagent, organic alkali/inorganic alkali; f)
nitrating reagent; g) phenethylamine containing at least one
electron-donating substituent, ethanol, reflux; h) solvent,
acylating reagent, inorganic/organic alkali; i) solvent, condensing
agent; j) sodium borohydride, sodium cyanoborohydride or sodium
acetoxy borohydride/catalyst (Noyori), N, N-dimethylbenzamide,
triethylamine and formic acid; k) solvent, inorganic alkali; l)
solvent, halogenating reagent, organic/inorganic alkali; m) reflux,
concentrated hydrochloric acid, ethanol/BCl.sub.3, dichloromethane;
the preparation of Compound 10a: at room temperature, Compound 1b
is reacted with liquid bromine to obtain product Compound 10a; the
preparation of Compound 11a: under the action of organic/inorganic
alkali, Compound 10a is reacted with an alkylating reagent or a
benzylating reagent in solvent to obtain Compound 11a, wherein said
solvent can be selected from the following group: methanol,
ethanol, acetone, N, N-dimethylformamide, dimethyl sulfoxide,
tetrahydrofuran, dichloromethane, chloroform, dioxane; said
alkylating reagent is dimethyl sulfate, methyl iodide,
diazomethane, or trifluoro methyl sulfonic acid methyl ester; said
benzylating reagent is a alkoxy-, alkyl-, nitro- or
halogen-substituted benzyl chloride or benzyl bromide; said
inorganic alkali is selected from the following group: sodium
hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide,
potassium hydride, sodium hydride, sodium tert-butoxide, potassium
tert-butoxide, potassium carbonate, sodium carbonate and calcium
carbonate; and said organic alkali is selected from triethylamine,
diisopropylethylamine, pyridine, N, N-dimethylaniline, N,
N-dimethyl-pyridine; the preparation of Compound 12a: a catalyst
used in the reaction is one or two of the followings: copper
sulfate, copper oxide, copper powder, copper chloride, copper
bromide, copper iodide, copper carbonate, copper nitrate, copper
hydroxide and the like; the reaction is conducted in the presence
of alkali, such as sodium hydroxide, potassium hydroxide, cesium
hydroxide, calcium hydroxide, barium hydroxide or quaternary
ammonium hydroxide; the reaction can be, but not necessarily,
finished with the help of microwave, the reaction temperature is
between 90.degree. C. and 150.degree. C.; and Compound 12a can be
obtained by adjusting the pH value of reaction mixture to 1-3 after
the reaction is finished; the preparation of Compound 13a: 2.0-3.0
equivalent of phenylboronic acid is refluxed in toluene, and then
paraformaldehyde is added and reacted in toluene; the solvent is
evaporated and the reaction is conducted in water; the reaction
mixture is extracted with dichloromethane; then the extract liquid
is dried over sodium sulfate and the solvent is evaporated; after
stirred in diethyl ether, Compound 13a is obtained by filtration;
the preparation of Compound 14a: Compound 13a is reacted with an
alkylating reagent, an acylating reagent or a benzylating reagent
in a solvent under the action of organic/inorganic alkali to obtain
Compound 14a; said solvent is selected from the following group:
methanol, ethanol, acetone, N,N-dimethylformamide, dimethyl
sulfoxide, tetrahydrofuran, dichloromethane, chloroform, and
dioxane; said alkylating reagent is dimethyl sulfate, methyl
iodide, diazomethane, or methyl trifluoromethanesulfonate; said
acylating reagent is acetyl chloride, acetic anhydride, benzoyl
chloride, trifluoroacetic acid anhydride; said benzylating reagent
is alkoxy-, alkyl-, nitro-, or halogen-substituted benzyl chloride
or benzyl bromide; said inorganic alkali is selected from sodium
hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide,
potassium hydride, sodium hydride, sodium tert-butoxide, potassium
tert-butoxide, potassium carbonate, sodium carbonate or calcium
carbonate; and said organic alkali is selected from triethylamine,
diisopropylethylamine, pyridine, N,N-dimethylaniline, or N,
N-dimethyl-pyridine; the preparation of Compound 15a: under the
action of a nitrating reagent, Compound 15a, nitration product, is
obtained from Compound 14a; the reaction temperature is between
0.degree. C. and 25.degree. C., and the reaction time is 10 minutes
to 12 hours; said nitrating reagent is a mixture of concentrated
sulfuric acid and nitric acid, a mixture of nitric acid, sodium
nitrate and concentrated sulfuric acid, a mixture of concentrated
sulfuric acid and potassium nitrate, a mixture of concentrated
sulfuric acid and sodium nitrite, or a mixture of acetic acid and
concentrated nitric acid; the preparation of Compound 16a: Compound
15a with the same equivalent of phenylethylamine are added to an
appropriate amount of ethanol and refluxed overnight; ethanol is
evaporated and the crude product is recrystallized in a
recrystallization solvent; said recrystallization solvent is
selected from one or two of the followings: ethyl acetate,
n-hexane, benzene, toluene, petroleum ether, ethanol, isopropanol,
methanol, chloroform, and xylene; the preparation of Compound 17a:
Compound 16a is dissolved in solvent and organic/inorganic alkali
is added; an acylating agent is slowly added at 0.degree. C.; then
the reaction proceeded at room temperature and water is added; the
reaction mixture is extracted with dichloromethane and
dichloromethane layer is washed with saturated saline solution; the
extract liquid is dried over sodium sulfate and evaporated to
dryness, thereby obtaining Compound 17a; wherein said acylating
agent is acetic anhydride, acetyl chloride, trifluoroacetic
anhydride, trichloroacetic anhydride, methyl chloroformate, or
ethyl chloroformate; said organic alkali is triethylamine,
diisopropyl ethylamine, pyridine, N,N-dimethylaniline, or
N,N-dimethyl pyridine; and said inorganic alkali is potassium
carbonate, sodium carbonate, sodium bicarbonate, potassium
bicarbonate, sodium hydroxide, or potassium hydroxide; the
preparation of Compound 18a: Compound 17a is dissolved in a solvent
and heated to reflux; a condensing reagent is added to the reaction
solution; the reaction is monitored by TLC; most of solvent is
evaporated, and the reaction solution is neutralized with saturated
sodium bicarbonate, extracted for three times with dichloromethane,
dried over sodium sulfate and evaporated to dryness; and the
product is directly used in next reaction without further
purification; wherein said solvent is anhydrous acetonitrile,
anhydrous toluene, or benzene; and said condensing reagent is
phosphorus oxychloride, phosphorus oxybromide, or phosphorus
pentoxide; the preparation of Compound 19a: the imine Compound 18
obtained above is asymmetrically reduced by using Noyori catalyst
in anhydrous N,N-dimethylformamide in the presence of triethylamine
and formic acid to obtain chiral amine 19a; the reaction is carried
out at room temperature for 7 to 12 hours; after the reaction is
finished, the reaction solution is neutralized with saturated
aqueous sodium bicarbonate solution, extracted with ethyl acetate,
and dried over sodium sulfate; or the achirality reduction is
conducted by using sodium borohydride, sodium cyanoborohydride or
sodium acetoxy borohydride; the preparation of Compound 20a:
Compound 19a is dissolved in a solvent and an inorganic alkali is
added to above solution, then the reaction is conducted at room
temperature and solid precipitates, and the precipitate is filtered
and dried, thereby obtaining the target Compound 20a, wherein said
inorganic alkali is sodium hydroxide, potassium hydroxide, cesium
hydroxide or potassium carbonate; said solvent may be a mixture of
water and one of ethanol, methanol, N,N-dimethylformamide; the
preparation of Compound 21a: in a solvent, Compound 20a is
halogenated with a halogenating agent under alkaline condition, and
then product 21a is obtained through ring-closing reaction, wherein
said halogenating agent is thionyl chloride, thionyl bromide,
phosphorus trichloride, phosphorus tribromide, phosphorus
pentachloride, or phosphorus pentabromide; said solvent is
dichloromethane, tetrahydrofuran, diethyl ether, or chloroform;
said alkaline condition is an organic alkali or an inorganic
alkali, wherein the organic alkali is triethylamine, pyridine,
diisopropylethylamine, or the inorganic alkali is potassium
carbonate, sodium carbonate, sodium bicarbonate, potassium
bicarbonate, sodium hydroxide, potassium hydroxide, calcium
carbonate, or ammonia; the preparation of Compound 22a: Compound
21a is dissolved in ethanol and concentrated hydrochloric acid is
added to reflux or BCl.sub.3 and dichloromethane is added to reflux
at low temperature in order to remove R6' protective group to give
Compound 22a.
16. The preparation method according to claim 15, wherein, in the
second reaction route: for the preparation of Compound 11a, said
solvent is acetone, N, N-dimethylformamide, or tetrahydrofuran; and
said organic alkali is benzyl chloride, benzyl bromide, methyl
iodide, dimethyl sulfate or potassium carbonate; for the
preparation of Compound 12a, the catalyst is one or two of the
followings: copper sulfate, copper oxide, copper powder; and said
alkaline condition is sodium hydroxide, potassium hydroxide, or
cesium hydroxide; for the preparation of Compound 14a, the solvent
is acetone, tetrahydrofuran, or N,N-dimethylformamide; said
alkylating reagent is dimethyl sulfate, or methyl iodide; said
acylating reagent is acetyl chloride, or acetic anhydride; and said
inorganic alkali is potassium carbonate; for the preparation of
Compound 15a, said nitrating reagent is a mixture of acetic acid
and concentrated nitric acid; for the preparation of Compound 16a,
said solvent for recrystallization is toluene, ethanol, or xylene;
for the preparation of Compound 17a, said acylating agent is acetic
anhydride, or acetyl chloride; said organic alkali is
triethylamine, diisopropyl ethylamine, or pyridine; and said
solvent is dichloromethane, tetrahydrofuran, diethyl ether, or
toluene; for the preparation of Compound 18a, said condensing
reagent is phosphorus oxychloride, and said solvent is anhydrous
acetonitrile; for the preparation of Compound 20a, said inorganic
alkali is sodium hydroxide and said solvent is a mixture of water
and ethanol or methanol; and for the preparation of Compound 22a,
ethanol or concentrated hydrochloric acid is used to remove R6'
protective group.
17. A substantially optically pure hexahydrodibenzo[a,g]quinoline
compound of general formula (I): ##STR00042## an enantiomer,
diastereoisomer, pharmaceutically acceptable organic salt or
inorganic salt, crystalline hydrate or solvate thereof, or mixture
thereof, wherein R.sub.2 is a hydroxy, a hydroxy-substituted C1-C6
alkyl, a substituted or unsubstituted C1-C6 alkoxy, a halogen, a
substituted or unsubstituted C1-C6 alkyl, a substituted or
unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6
alkynyl, a substituted or unsubstituted C3-C6 cycloalkyl, a
substituted or unsubstituted C1-C6 alkanoyl, a substituted or
unsubstituted C6-C20 aryl, a substituted or unsubstituted benzyl,
an amino acid or N-protected amino acid, or --(CO) R.sub.9; when
R.sub.2 is a substituted or unsubstituted C1-C6 alkyl, a
substituted or unsubstituted C1-C6 alkoxy, a substituted or
unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6
alkynyl, or a substituted or unsubstituted C3-C6 cycloalkyl, a
substituent for substitution can be a halogen or COOR.sub.10; when
R.sub.2 is a substituted or unsubstituted C1-C6 alkanoyl, a
substituted or unsubstituted C6-C20 aryl, or a substituted or
unsubstituted benzyl, a substituent for substitution is selected
from the following group: C1-C6 alkyl, a halogen, C1-C6 alkoxy;
wherein R.sub.9 is a substituted or unsubstituted C1-C6 alkyl, a
substituted or unsubstituted C2-C6 alkenyl, a substituted or
unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C6-C20
aryl, or heteroaryl selected from thiazolyl, pyrazolyl, imidazolyl,
thienyl, furyl, pyrrolyl, or pyridyl; when R.sub.9 is a substituted
or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6
alkenyl, or a substituted or unsubstituted C2-C6 alkynyl, a
substituent for substitution is a carboxyl, a substituted or
unsubstituted C6-C20 aryl, or heteroaryl selected from thiazolyl,
pyrazolyl, imidazolyl, thienyl, furyl, pyrrolyl, or pyridy; when
R.sub.9 is a substituted or unsubstituted C6-C20 aryl, a
substituent for substitution is a C1-C6 alkyl, a halogen or a C1-C6
alkoxy; R.sub.10 is H, a C6-C20 alkyl substituted or unsubstituted
C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl; when R.sub.2 is
an amino acid or N-protected amino acid, the amino acid can be
D-amino acid, L-amino acid or racemate; each of R.sub.3, R.sub.4 is
independently H, a halogen substituted or unsubstituted C1-C6
alkyl, a halogen substituted or unsubstituted C1-C6 alkoxy, a C2-C6
alkenyl, a C2-C6 alkynyl, a halogen, COOR.sub.11, or
CONR.sub.12R.sub.13, wherein R.sub.11 is H, a substituted or
unsubstituted C1-C6 alkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a
substituted or unsubstituted C6-C20 aryl, or a substituted or
unsubstituted benzyl; when R.sub.11 is a substituted or
unsubstituted C6-C20 aryl, or a substituted or unsubstituted
benzyl, a substituent for substitution is a C1-C6 alkyl, a halogen
or a C1-C6 alkoxy; when R.sub.11 is a substituted or unsubstituted
C1-C6 alkyl, a substituent for substitution is a halogen; each of
R.sub.13, R.sub.12 is independently H, a substituted or
unsubstituted C1-C6 alkyl or they and nitrogen atom together form
azetidine, pyrrolidinyl, piperazinyl, or morpholinyl, when R.sub.13
or R.sub.12 is a substituted or unsubstituted C1-C6 alkyl, a
substituent for substitution is a halogen; each of R.sub.1,
R.sub.5, R.sub.6, R.sub.7, R.sub.8 is independently H, a hydroxy, a
hydroxy-substituted C1-C6 alkyl, a halogen-substituted or
unsubstituted C1-C6 alkyl, a halogen substituted or unsubstituted
C1-C6 alkoxy, a halogen, a C3-C6 cycloalkyl, a halogen substituted
or unsubstituted C2-C6 alkenyloxy, a halogen-substituted or
unsubstituted C3-C6 alkynyloxy, a substituted or unsubstituted
benzyloxy, a substituted or unsubstituted C6-C20 aryl,
R.sub.14COO--, R.sub.15R.sub.16N--; when R.sub.1, R.sub.5, R.sub.6,
R.sub.7, or R.sub.8 is a substituted or unsubstituted benzyloxy, or
a substituted or unsubstituted C6-C20 aryl, a substituent for
substitution is a C1-C6 alkyl, a halogen, or a C1-C6 alkoxy;
wherein R.sub.14 is H, a halogen-substituted or unsubstituted C1-C6
alkyl; each of R.sub.15 and R.sub.16 is independently selected from
H, a substituted or unsubstituted C1-C6 alkyl, a substituted or
unsubstituted C2-C6 alkenyl, or a substituted or unsubstituted
C2-C6 alkynyl or they and nitrogen atom together form azetidine,
pyrrolidinyl, piperazinyl, or morpholinyl, when R.sub.15 or
R.sub.16 is a substituted or unsubstituted C1-C6 alkyl, a
substituted or unsubstituted C2-C6 alkenyl, a substituted or
unsubstituted C2-C6 alkynyl, a substituent for substitution is a
C1-C6 alkyl, a halogen or a C1-C6 alkoxy; R.sub.1 and R.sub.2 can
together form a substituted or unsubstituted 5-7 membered
heterocycle, a substituent for substitution is a halogen, or a
halogen-substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, or
C2-C6 alkynyl; and the heterocycle contains 1-3 heteroatom(s)
selected from N, O or S; any two adjacent substituents of R.sub.5,
R.sub.6, R.sub.7 and R.sub.8 can together form a substituted or
unsubstituted 5-7 membered heterocycle, a substituent for
substitution is a halogen, or a halogen-substituted or
unsubstituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and the
heterocycle contains 1-3 heteroatom(s) selected from N, O or S; and
the configuration of chiral carbon atom in the compound of general
formula (I) is R or S configuration.
18. A pharmaceutical composition comprising a therapeutically
effective amount of the substantially optically pure
hexahydrodibenzo[a,g]quinoline compound, the enantiomer,
diastereoisomer, pharmaceutically acceptable organic salt or
inorganic salt, crystalline hydrate or solvate thereof, or mixture
thereof according to claim 17, and one or more pharmaceutically
acceptable carriers.
19. A method of treating a nervous system disease relating to
dopamine receptors and serotonin receptors in a subject in need
thereof, comprising administering to the subject the pharmaceutical
composition according to claim 18.
20. The method according to claim 19, wherein the nervous system
disease is Parkinson's disease, schizophrenia, drug addiction, or
migraine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation-In-Part application of
International Application No. PCT/CN2012/073661 filed Apr. 9, 2012,
which was published in the Chinese language on Dec. 6, 2012, under
International Publication No. WO 2012/163179 A1, the disclosure of
which is incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to the field of pharmaceutical
chemistry and chemotherapy. Specifically, the present invention
relates to a hexahydro-dibenzo[a,g]quinolizine compound (I) with
novel structure and derivatives, preparation method thereof,
pharmaceutical composition and use thereof for the preparation of
medicaments for treating neurological diseases relating to dopamine
receptor and serotonin receptor, in particular Parkinson's disease,
schizophrenia, drug addiction, migraine headaches and the like.
BACKGROUND ART
[0003] Nervous system disease is one of prevalent diseases in
contemporary society. However, many types of nervous system
diseases have not yet been effectively addressed in clinical
practice. In particular, the treatments for neurological diseases
such as schizophrenia, Parkinson's disease and the like are still
very far from achieving satisfactory results. In recent years,
studies have shown that schizophrenia is considered as the result
of D.sub.1 receptor dysfunction of medial prefrontal cortex (mPFC)
and thus enhancing the activity of D.sub.2 receptor of the ventral
tegmental area (VTA) and the nucleus accumbens region (NAc). By
carrying out working memory experiments for animals and patients,
short-term experiments reflecting the function of medial prefrontal
cortex and clinical trials, scientists have demonstrated that the
inactivation of D.sub.1 receptor is related to the negative
symptoms of schizophrenia and high activity of D.sub.2 receptor
generates the positive symptoms. Based on such hypothesis, if a
class of medicaments can effectively excite the activity of D.sub.1
receptor, and antagonize activity of D.sub.2 receptor in the
meantime, such medicaments should have good prospects for the
treatment of schizophrenia.
[0004] Parkinson's disease is a chronic progressive degenerative
diseases with brain dopaminergic neuron loss as main feature. For a
long time, L-Dopamine is a "gold standard" for the treatment of
Parkinson's disease. However, long-term administration of
L-Dopamine is often accompanied by high incidence of
treatment-related complications, such as dyskinesias, efficacy loss
and "on-off" phenomenon and the like, which are named as
"L-Dopamine long-term syndrome" and can not delay disease
progression.
[0005] DA receptor agonist is one of various substitutive therapies
for Parkinson's disease and mainly used with L-Dopamine in
Parkinson patients having dyskinesia. DA receptor agonist is
superior to L-Dopamine, the mechanism of which is that in the later
stages of Parkinson's disease, dopamine decarboxylase activity of
the nigrostriatal DA system is depleted, therefore, exogenous
L-Dopamine can not be transformed into DA through decarboxylation,
and at that time, even a large dose of L-Dopamine preparations is
ineffective; however, the function of DA receptor agonist is
irrelevant to DA synthesis and does not depend on the activity of
dopa decarboxylase, the molecular conformation thereof is similar
to that of DA, DA receptor agonist works by directly acting on
striatal synaptic DA receptor, primarily D.sub.1 receptor, in part
on D.sub.2 receptors; therefore, the combination of DA receptor
agonist can further improve motor symptoms of Parkinson's disease.
Based on such theory, if D.sub.1 receptor agonist with selectivity
can be developed, it is possible to provide a class of medicaments
with good effect for the treatment of Parkinson's disease.
Currently, some companies have developed various D.sub.1 receptor
selective agonists with selectivity, many of which have been
studied in clinical trail, but many medicament candidates have low
selectivity and obvious side effect. Therefore, the development of
D.sub.1 receptor selective agonist with high selectivity and little
side effect will undoubtedly have huge advantages for the treatment
of Parkinson's disease.
[0006] The hexahydrodibenzo[a,g]quinolizine compounds are a class
of alkaloids extracted from traditional Chinese medicine Corydalis
Tuber and Stephania genus plants, which have a common chemical
nucleus containing two-isoquinoline structure and having
--OCH.sub.3 in C.sub.2, C.sub.3, C.sub.9, and C.sub.10 or
substituted by --OH. Such alkaloids have various biological
activities, including anti-inflammatory effect, antibacterial
effect, anti-leukemia effect, anti-cancer effect and so on.
Academician Jin GuoZhang, et al. have systematically studied the
pharmacological effects of hexahydrodibenzo[a,g]quinolizine
compounds and demonstrated that levorotatory tetrahydropalmatine
has good analgesic effect accompanied by sedation, tranquillizing
effect and hypnotic effect, while dextrorotatory
tetrahydropalmatine has no significant analgesic effect. It is also
demonstrated that the target of levorotatory tetrahydropalmatine or
other hexahydrodibenzo[a,g]quinolizine alkaloids is dopamine
receptor. Jin Guozhang has also reported for the first time that
l-Stepholidine (l-SPD), one of hexahydrodibenzo[a,g]quinolizine
compounds (THPBs), is a lead compound with the dual role of D.sub.1
agonist and D.sub.2 antagonistic activity (Jin G Z. TIPS, 2002,
23-24). l-SPD, in clinical trials, has shown good therapeutic
effects on positive and negative symptoms and has non-classical
stabilizer features, and can be likely developed into a new class
of antipsychotic medicaments. Shen Jingshan, Yang Yushe et al.
disclosed a preparation method and use of l-SPD derivatives and
levorotatory Chloroscoulerine with antipsychotic effect, wherein
Scoulerine methanesulfonate has good water solubility and stability
(WO2008/014661, CN03151464, and CN1900076). However, the structures
of these compounds are not greatly modified, most of the compounds
have weak activity on D.sub.2 receptor, and many compounds have no
5-HT activity, poor solubility and low bioavailability. Meanwhile,
these compounds showed a certain degree of selectivity in D.sub.1
receptor vs D.sub.2 receptor. Therefore, it is significant to
continually modify hexahydrodibenzo[a,g]quinolizine compounds,
especially to develop compounds with better D.sub.2 activity or
develop D.sub.1 receptor agonists with better selectivity, thereby
providing beneficial help for treating Parkinson's disease.
[0007] The present invention provides the synthesis and use of a
class of hexahydro-dibenzo[a,g]quinoline compounds with novel
structures. Some compounds with such structures show good
selectivity in D.sub.1 vs D.sub.2 wherein many compounds also have
5-HT activity. Other compounds have dual pharmacological activities
of good D.sub.1 agonist and D.sub.2 antagonist and good solubility,
and can be used in the preparation of the medicaments for treating
neurological diseases, especially dopamine receptors and serotonin
receptor-associated neurological disease.
SUMMARY OF THE INVENTION
[0008] One object of the present invention is to provide a
hexahydrodibenzo[a,g]quinoline compound of general formula (I),
enantiomer, diastereoisomer, racemate and mixtures thereof, the
pharmaceutically acceptable organic salt or inorganic salt,
crystalline hydrate and solvate thereof.
[0009] Another object of the present invention is to provide a
preparation method for the compound of general formula (I).
[0010] Another object of the present invention is to provide a
pharmaceutical composition containing the compound of general
formula (I), enantiomer, diastereomer, racemate and mixtures
thereof, the pharmaceutically acceptable organic salt or inorganic
salt, crystalline hydrate and solvate thereof.
[0011] A further object of the present invention is to provide a
use of the compound of general formula (I) in the preparation of
medicaments for treating the diseases relating to dopamine
receptors and serotonin receptors.
[0012] Based on above objects, the invention relates to a
hexahydrodibenzo[a,g]quinoline compound of general formula (I),
enantiomer, diastereoisomer, racemate and mixtures thereof, the
pharmaceutically acceptable organic salt or inorganic salt,
crystalline hydrate and solvate thereof,
##STR00002##
[0013] wherein R.sub.2 is a hydroxy, a hydroxy-substituted C1-C6
alkyl, a substituted or unsubstituted C1-C6 alkoxy, a halogen, a
substituted or unsubstituted C1-C6 alkyl, a substituted or
unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6
alkynyl, a substituted or unsubstituted C3-C6 cycloalkyl, a
substituted or unsubstituted C1-C6 alkanoyl, a substituted or
unsubstituted C6-C20 aryl, a substituted or unsubstituted benzyl,
an amino acid or N-protected amino acid, or --(CO) R.sub.9;
[0014] when R.sub.2 is a substituted or unsubstituted C1-C6 alkyl,
a substituted or unsubstituted C1-C6 alkoxy, a substituted or
unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6
alkynyl, or a substituted or unsubstituted C3-C6 cycloalkyl, a
substituent for substitution can be a halogen or COOR.sub.10;
[0015] when R.sub.2 is a substituted or unsubstituted C1-C6
alkanoyl, a substituted or unsubstituted C6-C20 aryl, or a
substituted or unsubstituted benzyl, a substituent for substitution
can be selected from the following group: C1-C6 alkyl, a halogen,
and C1-C6 alkoxy;
[0016] wherein R.sub.9 is a substituted or unsubstituted C1-C6
alkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted
or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted
C6-C20 aryl, or heteroaryl selected from thiazolyl, pyrazolyl,
imidazolyl, thienyl, furyl, pyrrolyl, or pyridyl;
[0017] when R.sub.9 is a substituted or unsubstituted C1-C6 alkyl,
a substituted or unsubstituted C2-C6 alkenyl, or a substituted or
unsubstituted C2-C6 alkynyl, a substituent for substitution can be
a carboxyl, a substituted or unsubstituted C6-C20 aryl, or
heteroaryl selected from thiazolyl, pyrazolyl, imidazolyl, thienyl,
furyl, pyrrolyl, or pyridy;
[0018] when R.sub.9 is a substituted or unsubstituted C6-C20 aryl,
a substituent for substitution can be a C1-C6 alkyl, a halogen or a
C1-C6 alkoxy;
[0019] R.sub.10 is H, a C6-C20 alkyl substituted or unsubstituted
C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl;
[0020] when R.sub.2 is an amino acid or N-protected amino acid, the
amino acid can be D-amino acid, L-amino acid or racemate;
[0021] each of R.sub.3, R.sub.4 is independently H, a halogen
substituted or unsubstituted C1-C6 alkyl, a halogen substituted or
unsubstituted C1-C6 alkoxy, a C2-C6 alkenyl, a C2-C6 alkynyl, a
halogen, COOR.sub.11, or CONR.sub.12R.sub.13, wherein R.sub.11 is
H, a substituted or unsubstituted C1-C6 alkyl, a C2-C6 alkenyl, a
C2-C6 alkynyl, a substituted or unsubstituted C6-C20 aryl, or a
substituted or unsubstituted benzyl;
[0022] when R.sub.11 is a substituted or unsubstituted C6-C20 aryl,
or a substituted or unsubstituted benzyl, a substituent for
substitution can be a C1-C6 alkyl, a halogen or a C1-C6 alkoxy;
[0023] when R.sub.11 is a substituted or unsubstituted C1-C6 alkyl,
a substituent for substitution can be a halogen; each of R.sub.13,
R.sub.12 is independently selected from H, or a substituted or
unsubstituted C1-C6 alkyl, or they and nitrogen atom together form
azetidine, pyrrolidinyl, piperazinyl, or morpholinyl; when R.sub.13
or R.sub.12 is a substituted or unsubstituted C1-C6 alkyl, a
substituent for substitution can be a halogen;
[0024] each of R.sub.1, R.sub.5, R.sub.6, R.sub.7, R.sub.8 is
independently H, a hydroxy, a hydroxy-substituted C1-C6 alkyl, a
halogen-substituted or unsubstituted C1-C6 alkyl, a halogen
substituted or unsubstituted C1-C6 alkoxy, a halogen, a C3-C6
cycloalkyl, a halogen substituted or unsubstituted C2-C6
alkenyloxy, a halogen-substituted or unsubstituted C3-C6
alkynyloxy, a substituted or unsubstituted benzyloxy, a substituted
or unsubstituted C6-C20 aryl, R.sub.14COO--, R.sub.15R.sub.16N--;
when R.sub.1, R.sub.5, R.sub.6, R.sub.7, or R.sub.8 is a
substituted or unsubstituted benzyloxy, or a substituted or
unsubstituted C6-C20 aryl, a substituent for substitution can be a
C1-C6 alkyl, a halogen, or a C1-C6 alkoxy; wherein R.sub.14 is H, a
halogen-substituted or unsubstituted C1-C6 alkyl; each of R.sub.15
and R.sub.16 is independently selected from H, a substituted or
unsubstituted C1-C6 alkyl, a substituted or unsubstituted C2-C6
alkenyl, or a substituted or unsubstituted C2-C6 alkynyl, or they
and nitrogen atom together form azetidine, pyrrolidinyl,
piperazinyl, or morpholinyl; when R.sub.15 or R.sub.16 is a
substituted or unsubstituted C1-C6 alkyl, a substituted or
unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6
alkynyl, a substituent for substitution can be a C1-C6 alkyl, a
halogen or a C1-C6 alkoxy;
[0025] R.sub.1 and R.sub.2 can together form a substituted or
unsubstituted 5-7 membered heterocycle, wherein a substituent for
substitution can be a halogen, or a halogen-substituted or
unsubstituted C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and the
heterocycle contains 1-3 heteroatom(s) selected from N, O or S;
[0026] any two adjacent substituents of R.sub.5, R.sub.6, R.sub.7
and R.sub.8 can together form a substituted or unsubstituted 5-7
membered heterocycle, wherein a substituent for substitution can be
a halogen, or a halogen-substituted or unsubstituted C1-C6 alkyl,
C2-C6 alkenyl, or C2-C6 alkynyl; and the heterocycle contains 1-3
heteroatom(s) selected from N, O or S;
[0027] and the configuration of chiral carbon atom in the compound
of general formula (I) is R or S configuration.
[0028] Preferably, with the proviso that when the compound of
general formula (I) is racemate, the following conditions should be
fulfilled:
[0029] (a) when R.sub.2 is methoxyl, R.sub.3 is H, R.sub.4 is H or
methyl, and at least one of R.sub.5, R.sub.6, R.sub.7, and R.sub.8
is methoxyl or R.sub.6 and R.sub.7 together form
--O--CH.sub.2--O--, R.sub.1 can not be H, methoxyl or BnO;
[0030] (b) when R.sub.1 and R.sub.2 together form
--O--CH.sub.2--O--, and R.sub.7 or R.sub.8 is methoxyl, R.sub.5 can
not be methoxyl;
[0031] (c) when R.sub.6 and R.sub.7 together form
--O--CH.sub.2--O-- and R.sub.5 and R.sub.8 are H, R.sub.2 can not
be methoxyl and R.sub.1 and R.sub.2 can not together form
--O--CH.sub.2--O--; and
[0032] (d) the compound of general formula (I) is not DC037027,
##STR00003##
[0033] Preferably, in the compound, R.sub.1 is H, a
halogen-substituted or unsubstituted C1-C6 alkyl, a
halogen-substituted or unsubstituted C1-C6 alkoxy, a hydroxy, a
hydroxy-substituted C1-C6 alkyl or a halogen-substituted or
unsubstituted benzyloxy; R.sub.2 is a hydroxy, a
hydroxy-substituted C1-C6 alkyl, a halogen substituted or
unsubstituted C1-C6 alkyl, or a halogen substituted or
unsubstituted C1-C6 alkoxy, or a halogen; R.sub.3 is H, or a
halogen substituted or unsubstituted C1-C6 alkyl; R.sub.4 is H, a
halogen substituted or unsubstituted C1-C6 alkyl, or a halogen
substituted or unsubstituted C1-C6 alkoxy; R.sub.5 is H, a halogen
substituted or unsubstituted C1-C6 alkyl, a halogen substituted or
unsubstituted C1-C6 alkoxy or a halogen; R.sub.6 is H, a
halogen-substituted or unsubstituted C1-C6 alkyl, a
halogen-substituted or unsubstituted C1-C6 alkoxy, a hydroxy, or a
hydroxy-substituted C1-C6 alkyl; R.sub.7 is H, a
halogen-substituted or unsubstituted C1-C6 alkyl, a
halogen-substituted or unsubstituted C1-C6 alkoxy, a hydroxy, or a
hydroxy-substituted C1-C6 alkyl; R.sub.8 is H, a hydroxy, a
hydroxy-substituted C1-C6 alkyl, a halogen-substituted or
unsubstituted C1-C6 alkoxy, a halogen-substituted or unsubstituted
C1-C6 alkyl or a halogen;
[0034] or R.sub.1 and R.sub.2 can together form a C1-C6
alkyl-substituted or unsubstituted 5-7 membered heterocycle, and
the heterocycle contains 1-2 heteroatom(s) selected from N, O or
S;
[0035] R.sub.6 and R.sub.7 can together form a fluoro-, chloro- or
bromo-substituted 5-7 membered heterocycle, and the heterocycle
contains 1-2 heteroatom(s) selected from N, O or S.
[0036] More preferably, R.sub.1 is H, a C1-C6 alkyl, a C1-C6
alkoxy, a hydroxy, a hydroxy-substituted C1-C6 alkyl or benzyloxy;
R.sub.2 is a hydroxy, a hydroxy-substituted C1-C6 alkyl, a C1-C6
alkyl, a C1-C6 alkoxy or a halogen; R.sub.3 is H or a C1-C6 alkyl;
R.sub.4 is H, a C1-C6 alkyl, or a C1-C6 alkoxy; R.sub.5 is H, a
C1-C6 alkyl, a C1-C6 alkoxy or a halogen; R.sub.6 is H, a C1-C6
alkyl, a C1-C6 alkoxy, a hydroxy, or a hydroxy-substituted C1-C6
alkyl; R.sub.7 is H, a C1-C6 alkyl, a C1-C6 alkoxy, a hydroxy, or a
hydroxy-substituted C1-C6 alkyl; R.sub.8 is H, a hydroxy, a
hydroxy-substituted C1-C6 alkyl, a C1-C6 alkoxy, a C1-C6 alkyl or a
halogen; the halogen is F, Br or Cl;
[0037] R.sub.1 and R.sub.2 can together form a C1-C6
alkyl-substituted or unsubstituted 5- or 6-membered heterocycle,
and the heterocycle contains 1-2 heteroatom(s) selected from N, O
or S;
[0038] R.sub.6 and R.sub.7 can together form a fluoro-, chloro- or
bromo-substituted or unsubstituted 5- or 6-membered heterocycle,
and the heterocycle contains 1-2 heteroatom(s) selected from N, O
or S.
[0039] In another preferable embodiment, the configuration of
chiral C atom which is not linked with R.sub.3 or R.sub.4 in the
parent nucleus of compound of general formula (I) is S.
[0040] In another preferable embodiment, the configuration of
chiral C atom which is not linked with R.sub.3 or R.sub.4 in the
parent nucleus of compound of general formula (I) is R.
[0041] In another preferable embodiment, the compound of general
formula (I) is chiral compound.
[0042] In another preferable embodiment, R.sub.5 is methoxyl, and
R.sub.6 is hydroxyl.
[0043] In another preferable embodiment, R.sub.3 is a halogen
substituted or unsubstituted C1-C6 alkyl, a halogen substituted or
unsubstituted C1-C6 alkoxy, a C2-C6 alkenyl, a C2-C6 alkynyl, a
halogen, COOR.sub.11, or CONR.sub.12R.sub.13, i.e. R.sub.3 is not
H.
[0044] In another preferable embodiment, R.sub.8 is a
hydroxy-substituted C1-C6 alkyl, or a halogen.
[0045] In another preferable embodiment, one to four of R.sub.5,
R.sub.6, R.sub.7, and R.sub.8 is a hydroxy-substituted C1-C6 alkyl
or C1-C6 alkyl.
[0046] Most preferably, the hexahydrodibenzo[a,g]quinoline compound
according to the invention, enantiomer, diastereoisomer and
racemate thereof are selected from the following compounds:
##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##
##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013##
##STR00014## ##STR00015## ##STR00016## ##STR00017##
##STR00018##
[0047] The "pharmaceutically acceptable organic salt or inorganic
salt" is a slat formed from the reaction of the compound of general
formula (I) with inorganic acid, such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric
acid, nitric acid or phosphoric acid and the like, or with organic
acid, such as formic acid, acetic acid, propionic acid, oxalic
acid, malonic acid, maleic acid, tartaric acid, malic acid, fumaric
acid, methanesulfonic acid, citric acid, ethanesulfonic acid,
benzenesulfonic acid, citric acid, lactic acid, aspartic acid or
glutamic acid and the like, or a sodium, potassium, calcium or
ammonium salt which is formed from the reaction of the compound of
general formula (I) with alkali, such as sodium hydroxide,
potassium hydroxide, calcium hydroxide or ammonia.
[0048] The present invention also provides a preparation method for
the compound of general formula (I) and intermediates thereof. The
raw materials and reagents used in the present invention are
commercially available unless otherwise specified.
[0049] Wherein, R1-R4 and R8 are defined as above. When each of R5
and R6 is independently a halogen-substituted or unsubstituted
C1-C6 alkoxy, a substituted or unsubstituted benzyloxy (a
substituent for substitution is a C1-C6 alkyl, a halogen or a C1-C6
alkoxy), and R7 is H; or when R5 is a halogen-substituted or
unsubstituted C1-C6 alkoxy, a substituted or unsubstituted
benzyloxy (a substituent is a C1-C6 alkyl, a halogen or a C1-C6
alkoxy), R6 is a hydroxy, and R7 is H, the compounds of general
formula (I), including compounds DC037051, DC037052, DC037073,
DC037074, DC037081, DC037082 and DC037083, are prepared according
to the second reaction route; other compounds of general formula
(I) are prepared according to the first reaction route.
[0050] The first reaction route:
##STR00019## ##STR00020##
[0051] Reagents and reaction conditions: a) acetic acid,
nitromethane, ammonium acetate, 80.degree. C.; b) lithium aluminum
hydride, anhydrous tetrahydrofuran, reflux; c) ammonium formate,
anhydrous methanol, palladium carbon, hydrogen, room temperature;
d) 1-ethyl-3-(3-dimethylpropylamine) carbodiimide, anhydrous
dichloromethane, triethylamine, room temperature; e) nitrogen
protection, phosphorus oxychloride, acetonitrile, reflux; and f)
catalyst (Noyori), N, N-dimethylformamide, triethylamine/formic
acid or sodium borohydride; g) aldehyde, acid conditions.
[0052] The preparation method according to the first reaction route
is described in detail as follows.
[0053] The preparation of Compound 2a: 10 mmol of substrate (1a,
purchased from Alpha Aisha Company) is dissolved in an appropriate
amount of glacial acetic acid, to which 1.2-2.0 equivalent of
ammonium acetate is added to form a mixture. At room temperature,
5-10 equivalent of nitromethane is added to the mixture and reacted
in an 80.degree. C. oil bath for 10 hours. Then the reaction system
is cooled to room temperature and a large amount of solid is
precipitated. After filtered, Compound 2a is obtained.
[0054] The preparation of Compound 3a: 20 mmol of lithium aluminum
hydride is suspended in an appropriate amount of anhydrous
tetrahydrofuran and placed in an ice water bath. And a solution of
unsaturated nitro-compound (2a) in anhydrous tetrahydrofuran is
slowly added dropwise. After the addition is completed, the
reaction solution is transferred into an oil bath, refluxed for 3
hours, and then cooled to room temperature. The defined amount of
water is added slowly and a clear solution is obtained by
filtration. After dried over anhydrous sodium sulfate and
evaporated to dryness, an oily Compound 3a is obtained.
[0055] The preparation of Compound 5a: 10 mmol of substrate (4a,
purchased from Sigma-Aldrich Company) is dissolved in an
appropriate amount of anhydrous methanol, and 1.5-3.0 equivalent of
ammonium formate is added. 10% palladium carbon is added under
stirring and hydrogen is ventilated at the same time. The reaction
is carried out at room temperature overnight. After the palladium
carbon is removed by filtration, the solution is evaporated to
dryness to give an oily Compound 5a.
[0056] The preparation of Compound 6a: at room temperature,
substrate 3a or 5a is condensed with R5-, R6-, R7-, and
R8-substituted phenylacetic acid in the presence of
1-ethyl-3(3-dimethyl-propylamine) carbodiimide or triethylamine,
and anhydrous dichloromethane. The product is purified by column
chromatography or recrystallized by using ethanol to give Compound
6a with high yield.
[0057] The preparation of Compound 7a: under N.sub.2, substrate 6a
in acetonitrile used as solvent is refluxed under the action of
phosphorus oxychloride to obtain Compound 7a with high yield. For
compound 7a, further purification is not necessary, the operation
is simple and the reaction is quick.
[0058] The preparation of Compound 8a: Compound 7a can be reduced
by using sodium borohydride to form racemic Compound 8a, if
necessary. The chiral reducing reagent, such as catalyst (Noyori,
J. Am. Chem. Soc. 1996, 118, 4916-4917), N,N-dimethylformamide,
triethylamine/formic acid, can also be used to carry out the
asymmetric reduction reaction, thereby obtaining Compound 8a with a
single configuration.
[0059] The preparation of Compound 9a: the intermediate Compound 8a
is reacted with aldehyde under acidic condition to obtain Compound
9a with satisfactory yield and selectivity.
[0060] The second reaction route:
##STR00021## ##STR00022##
[0061] Wherein, R9' is a C1-C6 alkyl, R5' is a halogen-substituted
or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted
benzyl, R6' is a halogen-substituted or unsubstituted C1-C6 alkyl,
or a substituted or unsubstituted benzyl, wherein a substituent for
substitution can be a C1-C6 alkyl, a halogen or a C1-C6 alkoxy.
[0062] Reaction reagents and conditions: a) room temperature,
acetic acid, liquid bromine; b) alkylating reagent/benzylating
reagent, solvent, organic alkali/inorganic alkali; c) catalyst
containing copper or copper ion, alkaline condition, water,
90.degree. C. to 150.degree. C. of reaction temperature, pH 1-3; d)
phenylboronic acid, toluene, paraformaldehyde and water; e)
solvent, alkylating reagent/benzylating reagent, organic
alkali/inorganic alkali; f) nitrating reagent; g) phenethylamine
containing at least one electron-donating substituent, ethanol,
reflux; h) solvent, acylating reagent, inorganic/organic alkali; i)
solvent, condensing agent; j) sodium borohydride, sodium
cyanoborohydride or sodium acetoxy borohydride/catalyst (Noyori),
N, N-dimethylbenzamide, triethylamine and formic acid; k) solvent,
inorganic alkali; l) solvent, halogenating reagent,
organic/inorganic alkali; m) reflux, concentrated hydrochloric
acid, ethanol/BCl.sub.3, dichloromethane.
[0063] The preparation method according to the second reaction
route is described in detail as follows.
[0064] The preparation of Compound 10a: at room temperature,
Compound 1b (purchased from Accela ChemBio Co., Ltd.) is reacted
with liquid bromine. The reaction is finished in 1 to 2 hours. The
product is poorly dissolved in acetic acid. The post-processing is
simple so that pure product Compound 10a can be obtained
conveniently.
[0065] The preparation of Compound 11a: in an appropriate solvent,
Compound 10a is reacted with an alkylating reagent (such as
dimethyl sulfate, methyl iodide, diazomethane, methyl
trifluoromethanesulfonate or other alkylating reagent) or a
benzylating reagent (such as substituted benzyl chloride, benzyl
bromide or other benzylating reagent) under the action of
organic/inorganic alkali to obtain Compound 11a. Said solvent is
selected from the following group: methanol, ethanol, acetone, N,
N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,
dichloromethane, chloroform, dioxane, preferably, acetone,
tetrahydrofuran, and N, N-dimethyl formamide. Said inorganic alkali
is selected from the following group: sodium hydroxide, potassium
hydroxide, cesium hydroxide, barium hydroxide, potassium hydride,
sodium hydride, sodium tert-butoxide, potassium tert-butoxide,
potassium carbonate, sodium carbonate and calcium carbonate. Said
organic alkali is selected from triethylamine,
diisopropylethylamine, pyridine, N, N-dimethylaniline, N,
N-dimethyl-pyridine. The benzyl chloride, benzyl bromide, methyl
iodide, dimethyl sulfate and potassium carbonate are
preferable.
[0066] The preparation of Compound 12a: a catalyst used in the
reaction is relatively inexpensive and can be one or two of the
following: copper sulfate, copper oxide, copper powder, copper
chloride, copper bromide, copper iodide, copper carbonate, copper
nitrate, copper hydroxide and the like, preferably, one or the
combination of two of copper sulfate, copper oxide, and copper
powder. The reaction is conducted in the presence of alkali, such
as sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium
hydroxide, barium hydroxide or quaternary ammonium hydroxide,
preferably, sodium hydroxide, potassium hydroxide, or cesium
hydroxide. The reaction can be (but not necessarily) finished with
the help of microwave. The reaction temperature is between
90.degree. C. and 150.degree. C. The method is very effective for
preparing phenolic hydroxyl group. Relatively pure Compound 12a can
be obtained by adjusting the pH value of reaction mixture to 1-3
after the reaction is finished. If further purification is
necessary, recrystallization can be carried out by using one or
mixed solvent of two of the following solvents: ethyl acetate,
n-hexane, benzene, toluene, petroleum ether, ethanol, isopropyl
alcohol, methanol, chloroform, xylene, preferably, benzene,
toluene, xylene.
[0067] The preparation of Compound 13a: referring to Richard J.
Spangler, Brian G. Beckmann, Jong Ho Kim. J. org. chem., 1977, 42,
2989-2996. Mark Cushman, Frederick W. Dekow. J. org. chem., 1979,
44, 407-409. 2.0-3.0 equivalent of phenylboronic acid is refluxed
in toluene for 1 hour, and then paraformaldehyde is added and
reacted in toluene at the temperature of 100.degree. C. for 46
hours. The solvent is evaporated and the reaction is conducted in
water for 2 hours. Then the reaction mixture is extracted with
dichloromethane. Then the extract liquid is dried over sodium
sulfate and the solvent is evaporated. After stirred in diethyl
ether for 3 hours, Compound 13a is obtained by filtration.
[0068] The preparation of Compound 14a: in an appropriate solvent,
Compound 13a is reacted with an alkylating reagent (such as
dimethyl sulfate, methyl iodide, diazomethane, methyl
trifluoromethanesulfonate or other alkylating reagent), an
acylating reagent (acetyl chloride, acetic anhydride, benzoyl
chloride, trifluoroacetic acid anhydride) or a benzylating reagent
(such as substituted benzyl chloride, benzyl bromide or other
benzylating reagent) under the action of organic/inorganic alkali
to obtain Compound 14a. Said solvent is selected from the following
group: methanol, ethanol, acetone, N, N-dimethylformamide, dimethyl
sulfoxide, tetrahydrofuran, dichloromethane, chloroform, dioxane,
preferably, acetone, tetrahydrofuran, and N, N-dimethyl formamide.
Said inorganic alkali is selected from the following group: sodium
hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide,
potassium hydride, sodium hydride, sodium tert-butoxide, potassium
tert-butoxide, potassium carbonate, sodium carbonate and calcium
carbonate. Said organic alkali is selected from triethylamine,
diisopropylethylamine, pyridine, N,N-dimethylaniline,
N,N-dimethyl-pyridine. The benzyl chloride, benzyl bromide, methyl
iodide, dimethyl sulfate and potassium carbonate, acetyl chloride,
and acetic anhydride are preferable.
[0069] The preparation of Compound 15a: under the action of
conventional nitrating reagent, Compound 15a (nitration product) is
obtained from Compound 14a. The reaction temperature is between
0.degree. C. and 25.degree. C., and the reaction time is 10 minutes
to 12 hours. Said nitrating reagent can be a mixture of
concentrated sulfuric acid and nitric acid, a mixture of nitric
acid, concentrated sulfuric acid and sodium nitrate, a mixture of
concentrated sulfuric acid and potassium nitrate, a mixture of
concentrated sulfuric acid and sodium nitrite, a mixture of acetic
acid and concentrated nitric acid and the like, with the mixture of
acetic acid and concentrated nitric acid being preferred. The
mixing ratio is not particularly limited.
[0070] The preparation of Compound 16a: referring to Mark Cushman,
Frederick W. Dekow. J. org. chem., 1979, 44, 407-409. 10 mmol of
Compound 15a with the same equivalent of amine are added to an
appropriate amount of ethanol and refluxed overnight. The solvent
is evaporated, and the crude product is recrystallized by using a
suitable solvent. The solvent for recrystallization is selected
from one or two of the followings: ethyl acetate, n-hexane,
benzene, toluene, petroleum ether, ethanol, isopropanol, methanol,
chloroform, and xylene, preferably, toluene, xylene and
ethanol.
[0071] The preparation of Compound 17a: 6 mmol of Compound 16a is
dissolved in 20 mL of suitable solvent and 9 mmol of
organic/inorganic alkali is added. 9 mmol of acylating agent is
slowly added at 0.degree. C. Then the reaction is performed at room
temperature for one hour and appropriate amount of water is added.
The reaction mixture is extracted for three times with
dichloromethane and dichloromethane layer is washed with saturated
saline solution. The extract liquid is dried over sodium sulfate to
and evaporated to dryness, thereby obtaining Compound 17a. Compound
17a can be directly used in the next reaction without further
purification. Said acylating agent can be, such as acetic
anhydride, acetyl chloride, trifluoroacetic anhydride,
trichloroacetic anhydride, methyl chloroformate, ethyl
chloroformate, etc. Said organic alkali can be, such as
triethylamine, diisopropyl ethylamine, pyridine, N,
N-dimethylaniline, N, N-dimethyl pyridine, etc. And said inorganic
alkali can be, such as potassium carbonate, sodium carbonate,
sodium bicarbonate, potassium bicarbonate, sodium hydroxide and
potassium hydroxide etc. Preferably, said acylating agent is acetic
anhydride, acetyl chloride, said organic base is triethylamine,
pyridine, diisopropylethylamine, and said solvent is
dichloromethane, tetrahydrofuran, diethyl ether, toluene etc.
[0072] The preparation of Compound 18a: 5 mmol of Compound 17a is
dissolved in an appropriate amount of suitable solvent and heated
to reflux. 30 mmol of condensing reagent is added to the reaction
solution. The reaction is monitored by TLC. Most of solvent is
evaporated, and the reaction solution is neutralized with saturated
sodium bicarbonate, extracted for three times with dichloromethane,
dried over sodium sulfate and evaporated to dryness. The product is
directly used in the next reaction without further purification.
The suitable solvent can be anhydrous acetonitrile, anhydrous
toluene, benzene and the like, and the condensing reagent can be
phosphorus oxychloride, phosphorus oxybromide, phosphorus pentoxide
and the like, wherein said condensing reagent is preferably
phosphorus oxychloride, and said solvent is preferably anhydrous
acetonitrile.
[0073] The preparation of Compound 19a: The imine Compound 18a
obtained above is asymmetrically reduced by using Noyori catalyst
in anhydrous N,N-dimethylformamide in the presence of triethylamine
and formic acid to obtain chiral amine 19a. The reaction is carried
out at room temperature for 7 to 12 hours. After the reaction is
finished, the reaction solution is neutralized with saturated
aqueous sodium bicarbonate solution, extracted with ethyl acetate,
and dried over sodium sulfate. In addition, the achirality
reduction can also be conducted by using sodium borohydride, sodium
cyanoborohydride or sodium acetoxy borohydride.
[0074] The preparation of Compound 20a: 3 mmoL of Compound 19a is
dissolved in a suitable solvent and an appropriate amount of
inorganic alkali is added to the above solution. The reaction is
conducted at room temperature for 3 hours and solid precipitates.
The precipitate is filtered and dried, thereby obtaining the target
Compound 20a. Said inorganic alkali can be sodium hydroxide,
potassium hydroxide, cesium hydroxide or potassium carbonate, and
the like, preferably, sodium hydroxide. The solvent may be a
mixture of water and one of ethanol, methanol, N,
N-dimethylformamide, preferably, a mixture of water and ethanol or
methanol.
[0075] The preparation of Compound 21a: in a suitable solvent,
Compound 20a can be halogenated with a halogenating agent under
alkaline condition, and then the product 21a is obtained through
ring-closing reaction. Said halogenating agent is thionyl chloride,
thionyl bromide, phosphorus trichloride, phosphorus tribromide,
phosphorus pentachloride, phosphorus pentabromide, and the like.
The solvent is dichloromethane, tetrahydrofuran, diethyl ether,
chloroform and the like. Said alkali is an organic alkali or an
inorganic alkali, wherein the organic alkali is preferably
triethylamine, pyridine, diisopropylethylamine, and the inorganic
alkali is preferably potassium carbonate, sodium carbonate, sodium
bicarbonate, potassium bicarbonate, sodium hydroxide, potassium
hydroxide, calcium carbonate, ammonia, etc.
[0076] The preparation of Compound 22a: Compound 21a is dissolved
in ethanol and concentrated hydrochloric acid is added to reflux or
BCl.sub.3 and dichloromethane is added to reflux at low temperature
in order to remove R6' protective group for giving Compound 22a.
Preferably, ethanol or concentrated hydrochloric acid is used to
remove R6' protective group.
[0077] Further, the inventors have found that the compound of
general formula (I) has excellent D.sub.1 receptor selectivity and
5-HT receptor activity through experiments. The compounds of the
invention can be used for the preparation of medicament used in
experiment model relating to dopamine receptor and 5-HT receptor or
for the preparation of medicament for treating and preventing the
diseases relating to dopamine receptor and 5-HT receptor.
[0078] The invention also provides a pharmaceutical composition
which comprises a therapeutically effective amount of the compound
of general formula (I), enantiomer, diastereomer, racemate and
mixtures thereof, or a pharmaceutically acceptable salt thereof and
one or more pharmaceutically acceptable carriers. The
pharmaceutical composition may further include conventional
additives, such as odorant, flavoring agent and so on.
[0079] The pharmaceutical composition provided in the invention
contains preferably 1-99% of the compound of general formula (I) by
weight as active ingredient. Preferably, the compound of general
formula (I) as active ingredient is 65%.about.99% of pharmaceutical
composition based on the total weight of pharmaceutical
composition, and the remainders are the pharmaceutically acceptable
carriers and/or conventional additives.
[0080] The compound and pharmaceutical composition provided in the
invention can be various forms, such as tablet, capsule, powder,
syrup, solution, suspension, aerosol etc., and may be present in a
suitable solid or liquid carrier or diluent and suitable
disinfector for injection or instillation.
[0081] The various dosage forms of pharmaceutical composition of
the present invention can be prepared according to conventional
methods in pharmaceutical field. The unit dose of formulation
contains 0.05-200 mg of the compound of general formula (I),
preferably 0.1 mg-100 mg of the compound of general formula
(I).
[0082] The compound and pharmaceutical composition of the invention
can be used clinically in mammal including humans and animals, and
can be delivered through mouth, nose, skin, lung, or
gastrointestinal tract and other routes. The most preferable
administration route is oral. Most preferable daily dose is
0.01-200 mg/kg body weight for once administration, or 0.01-100
mg/kg body weight in divided doses. Regardless of administration
method, the optimal dose for individual should be established based
on specific therapeutic regime. Usually start from small dose and
gradually increase the dose until the most suitable dose is
found.
BRIEF DESCRIPTION OF DRAWINGS
[0083] FIG. 1 is a curve graph of functional assay of part of the
test compounds on D-.sub.2 receptor.
[0084] FIG. 2a-2c is a plasma concentration vs time curve after
DC037029 is intravenously and orally administered in rats.
DETAILED DESCRIPTION
[0085] The present invention will be further illustrated in the
following examples. These examples are intended to illustrate the
invention, but not limit the invention in any way. All parameters
of the examples as well as the rest of the description are
described based on the weight unless otherwise indicated.
Example 1
S-(-)-2-hydroxy-3,9,12-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]qui-
nolizine (DC037030) (prepared according to the first reaction
route)
1.1 Preparation of 3-methoxy-4-benzyloxy-.omega.-nitrostyrolene
(Compound 2)
[0086] The preparation was conducted with reference to org. Lett.,
2008, 8(8), 1525-1528. Firstly, the hydroxyl of vanillin (purchased
from Alfa Aesar company) was protected with benzyl. And then
protected vanillin and nitromethane were refluxed in ammonium
acetate and acetic acid to obtain the target product. Two-step
yield: 75%; melting point: 117-118.degree. C. .sup.1H NMR
(CDCl.sub.3): .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.95 (d,
J=13.2 Hz, 1H), 7.51 (d, J=13.2 Hz, 1H), 7.42-7.32 (m, 5H), 7.10
(dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.02 (d, J=1.8 Hz, 1H), 6.92 (d,
J=8.4 Hz, 1H), 5.22 (s, 2H), 3.92 (s, 3H); ESI-MS m/z 251
[M+H].sup.+.
1.2 Preparation of 3-methoxy-4-benzyloxyphenylethylamine (Compound
3)
[0087] Under N.sub.2, lithium aluminum hydride (6.0 g) was
suspended in anhydrous tetrahydrofuran (50 mL) Compound 2 (22.5 g)
was dissolved in 30 mL of anhydrous tetrahydrofuran and the
resulting solution was slowly added into above suspension dropwise.
Upon addition, the reaction solution was moved in an oil bath and
refluxed for 3 hours. After the reaction was finished, the reaction
solution was cooled to room temperature and then the same
equivalent of water as excessive lithium aluminum hydride was added
to quench the reaction. The precipitate was filtered off and then
the filtrate was evaporated to dryness. Yield: 85%. .sup.1H NMR
(CDCl.sub.3, 300 MHz): .delta. 8.20 (br, 2H), 7.46-7.33 (m, 5H),
6.99 (d, J=8.4, 1 H), 6.92 (d, J=1.5, 1 H), 6.75 (dd, J=8.4, J=1.5,
1H), 5.06 (s, 2H), 3.79 (s, 3H), 3.01 (t, 2H), 2.85 (m, 2H); ESI-MS
m/z 258 [M+H].sup.+.
1.3 Preparation of
N-(3'-methoxy-4'-benzyloxyphenylethyl)-2,5-dimethoxy
phenylacetamide (Compound 6)
[0088] 2,5-dimethoxyphenylacetic acid (392 mg, purchased from Sigma
Aldrich Company) was dissolved in anhydrous dichloromethane (10 mL)
Compound 3 (514 mg), EDCI (573 mg) and triethylamine (433 .mu.L)
was added, respectively. The reaction was conducted overnight under
N.sub.2. After completion of the reaction, the reaction solution
was washed with 1 N diluted hydrochloric acid, then the organic
phase was washed once with saturated sodium bicarbonate solution
and finally washed once with saturated salt solution. After dried
over sodium sulfate, the organic phase was evaporated and product 6
was obtained by column chromatography. .sup.1H NMR (CDCl.sub.3):
.delta. 7.46-7.26 (m, 5H), 6.80-6.51 (m, 5H), 6.49 (d, J=2.1, 1H),
5.83 (m, 1H), 5.14 (s, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.73 (s,
3H), 3.65 (s, 2H), 3.47-3.36 (m, 2H), 3.64-3.59 (m, 2H); ESI-MS m/z
436 [M+H].sup.+.
1.4 Preparation of
1-(2',5'-dimethoxy)benzyl-6-methoxy-7-benzyloxy-3,4-dihydro-isoquinoline
(Compound 7)
[0089] Under N.sub.2, Compound 6 (435 mg) was dissolved in 15 mL of
anhydrous acetonitrile and POCl.sub.3 (546 .mu.L) was added to
above solution. The reaction mixture was refluxed for 30 min and
then cooled. The reaction solution was concentrated to give oily
liquid. The oily liquid was dissolved in dichloromethane,
neutralized with saturated sodium bicarbonate, and extracted three
times. The organic phase was washed once with saturated saline
solution, dried and evaporated to dryness. .sup.1H NMR
(CDCl.sub.3): .delta. 7.48-7.32 (m, 5H), 7.00 (s, 1H), 6.80-6.68
(m, 4H), 6.6 (s, 1H), 3.99 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H),
3.70-3.60 (m, 5H), 2.65-2.60 (m, 2H); ESI-MS m/z 418
[M+H].sup.+.
1.5 Preparation of
1-(2',5'-dimethoxy)benzyl-6-methoxy-7-benzyloxy-1,2,3,4-tetrahydro-isoqui-
noline (Compound 8)
[0090] Compound 7 (418 mg) freshly prepared was dissolved in DMF (5
mL), 1% of (R,R)-Noyori catalyst, a mixed solution of triethylamine
and formic acid was added separately and the resulting solution was
stirred overnight at room temperature. After the completion of the
reaction, the reaction solution was neutralized with saturated
sodium bicarbonate, and extracted with ethyl acetate for three
times. The organic phase was washed once with saturated saline
solution, dried and concentrated. The product can be used in the
next reaction without further purification. ESI-MS m/z 420
[M+H].sup.+.
1.6
S-(-)-2-benzyloxy-3,9,12-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (Compound 9)
[0091] Compound 8 (419 mg) was mixed with aqueous formaldehyde and
formic acid and stirred to react at 90.degree. C. for 2 hours.
After the completion of the reaction, most of liquid was evaporated
and the remainder liquid was neutralized with saturated sodium
bicarbonate, and extracted with ethyl acetate for three times. The
organic phase was washed once with saturated saline solution, dried
and evaporated to dryness. And then the produce was purified by
column chromatography. .sup.1H NMR (CDCl.sub.3): .delta. 7.44-7.34
(m, 5H), 6.73 (s 1H), 6.70 (s, 1H), 6.66 (m, 2H), 5.14 (s, 2H),
4.19 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H), 3.52-3.30
(m, 3H), 3.21-3.12 (m, 2H), 2.66-2.50 (m, 3H); ESI-MS m/z 432
[M+H].sup.+.
Preparation of
S-(-)-2-hydroxy-3,9,12-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]qu-
inolizine (DC037030)
[0092] Compound 8 (300 mg) was dissolved in 5 mL of ethanol and 7
mL of concentrated hydrochloric acid was added with stirring. The
reaction was carried out at 90.degree. C. for 1.5 hours. After the
completion of the reaction, the reaction solution was cooled to
room temperature and most of liquid was evaporated. The remainder
liquid was neutralized with aqueous ammonia and the aqueous phase
was extracted with dichloromethane for many times until there is no
product in aqueous phase. The dichloromethane layer was washed with
saturated saline solution, dried and evaporated to dryness. And
then the product was purified by column chromatography. .sup.1H NMR
(CDCl.sub.3): .delta. 6.90 (s, 1H), 6.63 (s, 2H), 6.58 (s, 1H),
4.18-4.13 (m, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H),
3.49-3.34 (m, 3H), 3.19-3.07 (m, 2H), 2.67-2.49 (m, 3H); ESI-MS m/z
342 [M+H].sup.+.
Example 2
(.+-.)-2,3,10,11-tetramethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinoli-
zine (DC037001)
[0093] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.73 (s, 1H), 6.67 (s, 1H), 6.61 (s, 1H),
6.57 (s, 1H), 3.93 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.86 (s,
3H), 3.85 (s, 3H), 3.75-3.59 (m, 2H), 3.28-3.12 (m, 3H) 2.89-2.63
(m, 3H); ESI-MS m/z 356 [M+H].sup.+.
Example 3
(.+-.)-2,3,9,10,11-pentamethoxyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quin-
olizine (DC037002)
[0094] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.70 (s, 1H), 6.60 (s, 1H), 6.47 (s, 1H),
4.10 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.82 (s,
3H), 3.81 (s, 3H), 3.55-3.42 (m, 2H), 3.25-3.12 (m, 3H), 2.85-2.78
(m, 1H), 2.66-2.61 (m, 2H); ESI-MS m/z 386 [M+H].sup.+.
Example 4
[0095]
(.+-.)-2,3,9,12-tetramethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]q-
uinolizine (DC037003)
[0096] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.80 (s, 1H), 6.67 (s, 1H), 6.65 (s, 1H),
6.61 (s, 1H), 4.18 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.80 (s,
6H), 3.52-3.37 (m, 3H), 3.21-3.19 (m, 2H), 2.69-2.62 (m, 3H);
ESI-MS m/z 356 [M+H].sup.+.
Example 5
(8S,14S)-2,3,10,11-tetramethoxy-8-methyl-5,8,13,13a-tetrahydro-6H-dibenzo[-
a,g]quinolizine (DC037004)
[0097] Compound DC037004 was prepared according to Example 1 except
for reacting 686 mg of
1-(3,4-bimethoxy)benzyl-6,7-bimethoxy-1,2,3,4-bihydroisoquinoline,
acetaldehyde (10 mL) and formic acid (15 mL) at 90.degree. C. for 2
hours. .sup.1H NMR (CDCl.sub.3): .delta. 6.73 (s, 1H), 6.67 (s,
1H), 6.61 (s, 1H), 6.57 (s, 1H), 4.12-4.06 (m, 2H), 3.93 (s, 3H),
3.91 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.75-3.62 (m, 2H),
3.28-3.14 (m, 2H), 2.89-2.68 (m, 2H); ESI-MS m/z 370
[M+H].sup.+.
Example 6
(8R,14S)-2,3,10,11-tetramethoxy-8-methyl-5,8,13,13a-tetrahydro-6H-dibenzo[-
a,g]quinolizine (DC037005)
[0098] The preparation method was described in Example 5. .sup.1H
NMR (CDCl.sub.3): .delta. 6.73 (s, 1H), 6.67 (s, 1H), 6.61 (s, 1H),
6.57 (s, 1H), 4.12-4.06 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.89
(s, 3H), 3.87 (s, 3H), 3.75-3.62 (m, 2H), 3.28-3.14 (m, 2H),
2.89-2.68 (m, 2H); ESI-MS m/z 370 [M+H].sup.+.
Example 7
S-(-)-2,3,9,10,11-pentamethoxyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quino-
lizine (DC037006)
[0099] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.70 (s, 1H), 6.60 (s, 1H), 6.47 (s, 1H),
4.10 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.82 (s,
3H), 3.81 (s, 3H), 3.55-3.42 (m, 2H), 3.25-3.12 (m, 3H), 2.85-2.78
(m, 1H), 2.66-2.61 (m, 2H); ESI-MS m/z 386 [M+H].sup.+.
Example 8
(.+-.)-3,9,10,11-tetramethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinoli-
zine (DC037007)
[0100] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 7.16 (d, J=8.4, 1H), 6.79 (m, 1H), 6.67
(s, 2H), 6.58 (s, 1H), 3.95 (m, 1H), 3.83 (s, 6H), 3.80 (s, 3H),
3.64-3.56 (m, 2H), 3.32-3.13 (m, 3H), 2.85-2.63 (m, 3H); ESI-MS m/z
356 [M+H].sup.+.
Example 9
S-(-)-2,3,9,12-tetramethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizi-
ne (DC037008)
[0101] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 7.09 (d, J=8.4, 1H), 6.97 (s, 1H), 6.72
(d, J=8.4, 1H), 6.51 (s, 1H), 4.18 (m, 1H), 3.87 (s, 3H), 3.84 (s,
3H), 3.83 (s, 3H), 3.82 (s, 3H), 3.52-3.37 (m, 3H), 3.21-3.19 (m,
2H), 2.69-2.62 (m, 3H); ESI-MS m/z 356 [M+H].sup.+.
Example 10
(.+-.)-3,10,11-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine
(DC037009)
[0102] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 7.16 (d, J=8.4, 1H), 6.79 (m, 1H), 6.67
(s, 2H), 6.58 (s, 1H), 3.95 (m, 1H), 3.83 (s, 6H), 3.80 (s, 3H),
3.64-3.56 (m, 2H), 3.32-3.13 (m, 3H), 2.85-2.63 (m, 3H); ESI-MS m/z
326 [M+H].sup.+.
Example 11
S-(-)-3,10,11-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine
(DC037010)
[0103] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 7.18 (d, J=9.0, 1H), 6.78 (m, 1H), 6.66
(s, 2H), 6.57 (s, 1H), 3.94 (m, 1H), 3.83 (s, 6H), 3.80 (s, 3H),
3.65-3.58 (m, 2H), 3.30-3.12 (m, 3H), 2.86-2.62 (m, 3H); ESI-MS m/z
326 [M+H].sup.+.
Example 12
S-(-)-2,3-bimethoxy-10,11-methylenedioxy-5,8,13,13a-tetrahydro-6H-dibenzo[-
a,g]quinolizine (DC037011)
[0104] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.72 (s, 1H), 6.63 (m, 1H), 6.61 (s, 1H),
6.55 (s, 1H), 5.90 (s, 2H), 3.94 (m, 1H), 3.89 (s, 3H), 3.87 (s,
3H), 3.67-3.55 (m, 2H), 3.25-3.11 (m, 3H), 2.70-2.60 (m, 3H);
ESI-MS m/z 340 [M+H].sup.+.
Example 13
S-(-)-2,3,10,11-bimethylenedioxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quin-
olizine (DC037012)
[0105] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.72 (s, 1H), 6.60 (m, 1H), 6.58 (s, 2H),
6.53 (s, 1H), 5.91 (s, 2H), 5.90 (s, 2H), 3.92-3.87 (m, 1H),
3.65-3.51 (m, 2H), 3.19-3.10 (m, 3H), 2.83-2.59 (m, 3H); ESI-MS m/z
324 [M+H].sup.+.
Example 14
S-(-)-2,3-methylenedioxy-9,12-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (DC037013)
[0106] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.81 (s, 1H), 6.65 (s, 2H), 6.59 (s, 2H),
5.91 (s, 2H), 4.17 (m, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.51-3.32
(m, 3H), 3.20-3.13 (m, 2H), 2.68-2.50 (m, 3H); ESI-MS m/z 340
[M+H].sup.+.
Example 15
(.+-.)-2,3-bimethoxy-10,11-methylenedioxy-5,8,13,13a-tetrahydro-6H-dibenzo-
[a,g]quinolizine (DC037014)
[0107] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.73 (s, 1H), 6.63 (m, 1H), 6.58 (s, 1H),
6.56 (s, 1H), 5.91 (s, 2H), 3.92-3.89 (m, 1H), 3.84 (s, 3H), 3.83
(s, 3H), 3.63-3.51 (m, 2H), 3.20-3.09 (m, 3H), 2.82-2.76 (m, 1H),
2.66-2.57 (m, 2H); ESI-MS m/z 340 [M+H].sup.+.
Example 16
S-(-)-2,3-methylenedioxy-10,11-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[-
a,g]quinolizine (DC037015)
[0108] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.72 (s, 1H), 6.63 (m, 1H), 6.58 (s, 1H),
6.56 (s, 1H), 5.90 (s, 2H), 3.92 (m, 1H), 3.84 (s, 3H), 3.83 (s,
3H), 3.68-3.52 (m, 2H), 3.21-3.07 (m, 3H), 2.84-2.75 (m, 1H),
2.66-2.57 (m, 2H); ESI-MS m/z 340 [M+H].sup.+.
Example 17
S-(-)-2,3-methylenedioxy-9,10,11-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenz-
o[a,g]quinolizine (DC037016)
[0109] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.72 (s, 1H), 6.63 (m, 1H), 6.56 (s, 1H),
5.90 (s, 2H), 3.93-3.90 (m, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.83
(s, 3H), 3.68-3.58 (m, 2H), 3.24-3.07 (m, 3H), 2.85-2.77 (m, 1H),
2.66-2.54 (m, 2H); ESI-MS m/z 370 [M+H].sup.+.
Example 18
S-(-)-2,3-bimethoxy-9,11-dimethyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]qui-
nolizine (DC037017)
[0110] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 7.09 (s, 1H), 6.97 (s, 1H), 6.72 (s, 1H),
6.51 (s, 1H), 4.18-4.02 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H),
3.51-3.38 (m, 3H), 3.22-3.10 (m, 2H), 2.69-2.54 (m, 3H), 2.36 (s,
3H), 2.34 (s, 3H); ESI-MS m/z 308 [M+H].sup.+.
Example 19
(.+-.)-2,3-bimethoxy-9,11-dimethyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]qu-
inolizine (DC037018)
[0111] The preparation method was described in Example 5. .sup.1H
NMR (CDCl.sub.3): .delta. 7.09 (s, 1H), 6.97 (s, 1H), 6.72 (s, 1H),
6.51 (s, 1H), 4.18-4.02 (m, 1H), 3.87 (s, 3H), 3.85 (s, 3H),
3.51-3.38 (m, 3H), 3.22-3.10 (m, 2H), 2.69-2.54 (m, 3H), 2.36 (s,
3H), 2.34 (s, 3H); ESI-MS m/z 324 [M+H].sup.+.
Example 20
(8S,14S)-2,3,9,10,11-pentamethoxyl-8-methyl-5,8,13,13a-tetrahydro-6H-diben-
zo[a,g]quinolizine (DC037019)
[0112] The preparation method was described in Example 5. .sup.1H
NMR (CDCl.sub.3): .delta. 6.73 (s, 1H), 6.67 (s, 1H), 6.52 (s, 1H),
4.12-4.06 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.86
(s, 3H), 3.85 (s, 3H), 3.69-3.58 (m, 2H), 3.28-3.14 (m, 2H),
2.89-2.68 (m, 2H); ESI-MS m/z 400 [M+H].sup.+.
Example 21
(8S,14S)-2,3-bimethoxy-8-methyl-10,11-methylenedioxy-5,8,13,13a-tetrahydro-
-6H-dibenzo[a,g]quinolizine (DC037020)
[0113] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.66 (s, 1H), 6.61 (m, 1H), 6.56 (s, 1H),
6.55 (s, 1H), 5.91 (s, 2H), 4.37-4.24 (m, 1H), 3.87 (s, 3H), 3.85
(s, 3H), 3.15-2.79 (m, 7H), 1.45 (d, J=7.2, 3H); ESI-MS m/z 354
[M+H].sup.+.
Example 22
(.+-.)-2,3-methylenedioxy-10,11-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo-
[a,g]quinolizine (DC037021)
[0114] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.73 (s, 1H), 6.64 (m, 1H), 6.59 (s, 1H),
6.57 (s, 1H), 5.92 (s, 2H), 3.96-3.91 (m, 1H), 3.86 (s, 3H), 3.85
(s, 3H), 3.69-354 (m, 2H), 3.23-3.08 (m, 3H), 2.86-2.77 (m, 1H),
2.67-2.56 (m, 2H); ESI-MS m/z 340 [M+H].sup.+.
Example 23
(.+-.)-2,3-bimethoxy-10,11-bihydroxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]-
quinolizine (DC037022)
[0115] The preparation method was described in Example 5. .sup.1H
NMR (CDCl.sub.3): .delta. 6.70 (s, 1H), 6.69 (m, 1H), 6.53 (s, 1H),
6.44 (s, 1H), 5.92 (s, 2H), 4.24-4.20 (m, 1H), 3.84 (s, 3H), 3.82
(s, 3H), 3.40-337 (m, 1H), 3.16-3.10 (m, 1H), 3.01-2.70 (m, 1H),
2.67-2.56 (m, 2H); ESI-MS m/z 328 [M+H].sup.+.
Example 24
(.+-.)-2,3-bimethoxy-8-methyl-10,11-bihydroxy-5,8,13,13a-tetrahydro-6H-dib-
enzo[a,g]quinolizine (DC037023)
[0116] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.89 (s, 1H), 6.67 (s, 1H), 6.58 (s, 1H),
6.53 (s, 1H), 4.26-4.05 (m, 1H), 3.79 (s, 3H), 3.76 (s, 3H),
3.73-3.67 (m, 1H), 3.09-2.62 (m, 6H), 1.34 (d, J=6.6, 2H); ESI-MS
m/z 342 [M+H].sup.+.
Example 25
(.+-.)-2,3-bihydroxy-10,11-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]-
quinolizine (DC037024)
[0117] The preparation method was described in Example 5. .sup.1H
NMR (CDCl.sub.3): .delta. 7.04 (s, 1H), 6.95 (s, 1H), 6.76 (s, 1H),
6.53 (s, 1H), 4.18-4.06 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H),
3.51-3.36 (m, 3H), 3.21-3.19 (m, 2H), 2.69-2.62 (m, 3H); ESI-MS m/z
328 [M+H].sup.+.
Example 26
(8S,14S)-2,3-bihydroxy-8-methyl-10,11-bimethoxy-5,8,13,13a-tetrahydro-6H-d-
ibenzo[a,g]quinolizine (DC037025)
[0118] The preparation method was described in Example 5. .sup.1H
NMR (CDCl.sub.3): .delta. 6.55 (s, 1H), 6.53 (s, 1H), 6.48 (s, 1H),
6.44 (s, 1H), 4.55-4.48 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H),
3.30-3.05 (m, 4H), 2.93-2.86 (m, 2H), 1.62 (d, J=6.8, 2H); ESI-MS
m/z 342 [M+H].sup.+.
Example 27
(8R,14R)-2,3-bihydroxy-8-methyl-10,11-bimethoxy-5,8,13,13a-tetrahydro-6H-d-
ibenzo[a,g]quinolizine (DC037026)
[0119] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.55 (s, 1H), 6.53 (s, 1H), 6.48 (s, 1H),
6.44 (s, 1H), 4.55-4.48 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H),
3.30-3.05 (m, 4H), 2.93-2.86 (m, 2H), 1.62 (d, J=6.8, 2H); ESI-MS
m/z 342 [M+H].sup.+.
Example 28
(.+-.)-2,3-bihydroxy-9,10,11-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (DC037027)
[0120] The preparation method was described in Example 5. .sup.1H
NMR (CDCl.sub.3): .delta. 6.95 (s, 1H), 6.76 (d, J=8.4, 1H), 6.51
(s, 1H), 4.18-4.06 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.51-3.36
(m, 3H), 3.21-3.19 (m, 2H), 2.69-2.62 (m, 3H); ESI-MS m/z 328
[M+H].sup.+.
Example 29
(.+-.)-2,3-bihydroxy-8-methyl-9,10,11-trimethoxy-5,8,13,13a-tetrahydro-6H--
dibenzo[a,g]quinolizine (DC037028)
[0121] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.50 (s, 1H), 6.45 (s, 1H), 6.35 (s, 1H),
4.61-4.37 (m, 2H), 3.93 (s, 3H), 3.87 (s, 6H), 3.49-3.39 (m, 1H),
3.18-2.84 (m, 5H), 1.52 (d, J=6.0, 2H); ESI-MS m/z 342
[M+H].sup.+.
Example 30
S-(-)-2-hydroxy-3-methoxy-10,12-methylenedioxy-5,8,13,13a-tetrahydro-6H-di-
benzo[a,g]quinolizine (DC037029)
[0122] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.81 (s, 1H), 6.61 (s, 1H), 6.59 (s, 1H),
6.54 (s, 1H), 5.90 (s, 2H), 3.92-3.87 (m, 1H), 3.87 (s, 3H),
3.65-3.48 (m, 2H), 3.23-3.09 (m, 3H), 2.83-2.55 (m, 3H); ESI-MS m/z
326 [M+H].sup.+.
Example 31
S-(-)-2-hydroxy-3-methoxy-9,11-dimethyl-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (DC037031)
[0123] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.83 (s, 2H), 6.82 (s, 2H), 6.60 (s, 1H),
4.07-4.00 (m, 1H), 3.85 (s, 3H), 3.59-3.47 (m, 2H), 3.26-3.18 (m,
2H), 2.93-2.89 (m, 1H), 2.70-2.63 (m, 2H), 2.28 (s, 3H), 2.20 (s,
3H); ESI-MS m/z 310 [M+H].sup.+.
Example 32
2,3-bimethylenedioxy-9,12-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]q-
uinolizine (DC037032)
[0124] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.94 (s, 1H), 6.89 (s, 1H), 6.67 (d,
J=8.4, 1H), 6.65 (d, J=8.4, 1H), 5.92 (s, 2H), 4.12-4.06 (m, 1H),
3.88 (s, 3H), 3.84 (s, 3H), 3.54-3.47 (m, 2H), 3.31-3.20 (m, 3H),
2.86-2.78 (m, 1H), 2.65-2.56 (m, 2H); ESI-MS m/z 354
[M+H].sup.+.
Example 33
S-(-)-2,3-methylenedioxy-9,12-dimethyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,-
g]quinolizine (DC037033)
[0125] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.91 (d, J=8.4, 1H), 6.87 (d, J=8.4, 1H),
6.65 (s, 1H), 6.63 (s, 1H), 5.90 (s, 2H), 4.17-4.06 (m, 1H), 3.82
(s, 3H), 3.80 (s, 3H), 3.51-3.32 (m, 3H), 3.20-3.13 (m, 2H),
2.68-2.50 (m, 3H), 2.37 (s, 3H), 2.34 (s 3H); ESI-MS m/z 340
[M+H].sup.+.
Example 34
S-(-)-9,12-bimethoxy-2,3,5,8,13,13a-hexahydro-8H-benzo[3,2,a,g]furanquinol-
izine (DC037034)
[0126] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 7.11 (s, 1H), 7.01 (s, 1H), 6.65 (d,
J=8.1, 1H), 6.58 (d, J=8.1, 1H), 4.31 (m, 2H), 4.16-4.08 (m, 1H),
3.85 (s, 3H), 3.83 (s, 3H), 3.53-3.34 (m, 2H), 3.20-3.02 (m, 4H),
2.79-2.50 (m, 4H); ESI-MS m/z 338 [M+H].sup.+.
Example 35
S-(-)-2,3-bihydroxy-9,12-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]qu-
inolizine (DC037035)
[0127] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 7.04 (d, J=8.4, 1H), 6.95 (s, 1H), 6.76
(d, J=8.4, 1H), 6.53 (s, 1H), 4.18-4.06 (m, 1H), 3.85 (s, 3H), 3.84
(s, 3H), 3.51-3.36 (m, 3H), 3.21-3.19 (m, 2H), 2.69-2.62 (m, 3H);
ESI-MS m/z 328 [M+H].sup.+.
Example 36
S-(-)-2-bihydroxy-3,12-bimethoxy-10,11-methylenedioxy-5,8,13,13a-tetrahydr-
o-6H-dibenzo[a,g]quinolizine (DC037036)
[0128] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.92 (s, 1H), 6.86 (s, 1H), 6.61 (s, 1H),
5.81 (s, 2H), 4.13-4.08 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.84
(s, 3H), 3.54-3.48 (m, 2H), 3.32-3.23 (m, 3H), 2.83-2.77 (m, 1H),
2.63-2.54 (m, 2H); ESI-MS m/z 356 [M+H].sup.+.
Example 37
S-(-)-2-hydroxy-3-methoxy-(2',2'-bifluoro-10,11-methylenedioxy)-5,8,13,13a-
-tetrahydro-6H-dibenzo[a,g]quinolizine (DC037037)
[0129] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.91 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H),
6.63 (s, 1H), 4.12-4.09 (m, 1H), 3.87 (s, 3H), 3.56-3.48 (m, 2H),
3.34-3.24 (m, 3H), 2.82-2.76 (m, 1H), 2.64-2.55 (m, 2H); ESI-MS m/z
362 [M+H].sup.+.
Example 38
S-(-)-2-hydroxy-3-methoxyl-9-chloro-10,11-methylenedioxy-5,8,13,13a-tetrah-
ydro-6H-dibenzo[a,g]quinolizine (DC037038)
[0130] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.92 (s, 1H), 6.86 (s, 1H), 6.61 (s, 1H),
5.81 (s, 2H), 4.13-4.08 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.84
(s, 3H), 3.54-3.48 (m, 2H), 3.32-3.23 (m, 3H), 2.83-2.77 (m, 1H),
2.63-2.54 (m, 2H); ESI-MS m/z 3602 [M+H].sup.+.
Example 39
S-(-)-2-hydroxy-3-methoxyl-9-fluoro-10,11-methylenedioxy-5,8,13,13a-tetrah-
ydro-6H-dibenzo[a,g]quinolizine (DC037039)
[0131] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta. 6.98 (s, 1H), 6.83 (s, 1H), 6.63 (s, 1H),
5.84 (s, 2H), 4.12-4.09 (m, 1H), 3.86 (s, 3H), 3.55-3.49 (m, 2H),
3.34-3.22 (m, 3H), 2.84-2.77 (m, 1H), 2.63-2.52 (m, 2H); ESI-MS m/z
344 [M+H].sup.+.
Example 40
S-(-)-2-hydroxy-3-methoxyl-10,11-methylenedioxy-12-fluoro-5,8,13,13a-tetra-
hydro-6H-dibenzo[a,g]quinolizine (DC037040)
[0132] The preparation method was described in Example 1. ESI-MS
m/z 344 [M+H].sup.+.
Example 41
S-(-)-2-hydroxy-3-methoxyl-10,11-methylenedioxy-12-chloro-5,8,13,13a-tetra-
hydro-6H-dibenzo[a,g]quinolizine (DC037041)
[0133] The preparation method was described in Example 1. ESI-MS
m/z 360 [M+H].sup.+.
Example 42
S-(-)-2,3-methylenedioxy-10,11-methylenedioxy-12-fluoro-5,8,13,13a-tetrahy-
dro-6H-dibenzo[a,g]quinolizine (DC037042)
[0134] The preparation method was described in Example 1. ESI-MS
m/z 342 [M+H].sup.+.
Example 43
S-(-)-2,3-methylenedioxy-(2',2'-bifluoro-10,11-methylenedioxy)-5,8,13,13a--
tetrahydro-6H-dibenzo[a,g]quinolizine (DC037043)
[0135] The preparation method was described in Example 1. ESI-MS
m/z 360 [M+H].sup.+.
Example 44
S-(-)-2-hydroxy-3-fluoro-9,12-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (DC037044)
[0136] The preparation method was described in Example 1. ESI-MS
m/z 330 [M+H].sup.+.
Example 45
S-(-)-2-hydroxy-3-chloro-9,12-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (DC037045)
[0137] The preparation method was described in Example 1. ESI-MS
m/z 346 [M+H].sup.+.
Example 46
S-(-)-2-hydroxy-3-chloro-10,11-methylenedioxy-5,8,13,13a-tetrahydro-6H-dib-
enzo[a,g]quinolizine (DC037046)
[0138] The preparation method was described in Example 1. ESI-MS
m/z 330 [M+H].sup.+.
Example 47
S-(-)-2-hydroxy-3-fluoro-10,11-methylenedioxy-5,8,13,13a-tetrahydro-6H-dib-
enzo[a,g]quinolizine (DC037047)
[0139] The preparation method was described in Example 1. ESI-MS
m/z 314 [M+H].sup.+.
Example 48
S-(-)-2,3-methylenedioxy-10,11-methylenedioxy-12-chloro-5,8,13,13a-tetrahy-
dro-6H-dibenzo[a,g]quinolizine (DC037048)
[0140] The preparation method was described in Example 1. ESI-MS
m/z 358 [M+H].sup.+.
Example 49
(6R,14S)-3,9,10,11-tetramethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-dibenzo[-
a,g]quinolizine (DC037049)
[0141] Compound DC037049 was prepared according to the method
described in Example 1 except that 1.64 g of 3-methoxypropiophenone
was dissolved in 40 mL of anhydrous methanol, 0.924 mg of ammonium
acetate was added to above solution, and
3-methoxyphenyl-propanamine was obtained by hydrogenation under the
catalytic action of palladium carbon. .sup.1H NMR (CDCl.sub.3):
.delta. 7.13-7.15 (d, J=8.4, 1H), 6.74-6.77 (dd, J=8.4, J=2.4, 1H),
6.60-6.61 (d, J=2.4, 1H), 6.45 (s, 1H), 4.39-4.43 (d, J=15.2, 1H),
3.89 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.60-3.64
(m, 1H), 3.18-3.28 (m, 2H), 2.83-2.87 (m, 2H), 2.65-2.69 (m, 2H),
1.35-1.37 (d, J=6, 3H); ESI-MS m/z 370 [M+H].sup.+.
Example 50
(6S,14S)-3,9,10,11-tetramethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-dibenzo[-
a,g]quinolizine (DC037050)
[0142] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 7.15-7.17 (d, J=8.4, 1H), 6.76-6.78 (dd,
J=8.4, J=2.4, 1H), 6.62-6.63 (d, J=2.4, 1H), 6.47 (s, 1H),
4.41-4.45 (d, J=15.2, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.83 (s,
3H), 3.62-3.67 (m, 1H), 3.20-3.30 (m, 2H), 2.85-2.89 (m, 2H),
2.67-2.71 (m, 2H), 1.37-1.39 (d, J=6, 3H); ESI-MS m/z 370
[M+H].sup.+.
Example 51
(6R,14S)-2,3,9,10-tetramethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (DC037051) (prepared according to the second
reaction route)
[0143] Compound DC037051 was prepared according to the following
Example 81 except that 1.74 g of 2,3-bimethoxypropiophenone was
dissolved in 40 mL of anhydrous methanol, ammonium acetate was
added to above solution, and 2,3-bimethoxyphenyl-propanamine was
obtained by hydrogenation under the catalytic action of palladium
carbon. .sup.1H NMR (CDCl.sub.3): .delta. 6.86-6.89 (d, J=8.4, 1H),
6.77-6.80 (d, J=9, 1H), 6.72 (s, 1H), 6.58 (s, 1H), 4.52-4.57 (d,
J=15.9, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.85 (s,
3H), 3.59-3.64 (m, 1H), 3.24-3.33 (m, 2H) 2.79-2.95 (m, 2H),
2.61-2.65 (m, 2H), 1.38-1.40 (d, J=6.8, 3H); ESI-MS m/z 370
[M+H].sup.+.
Example 52
(6S,14S)-2,3,9,10-tetramethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (DC037052) (prepared according to the second
reaction route)
[0144] The preparation method was described in Example 81. .sup.1H
NMR (CDCl.sub.3): .delta. 6.85-6.88 (d, J=9, 1H), 6.77-6.80 (d,
J=8.4, 1H), 6.71 (s, 1H), 6.58 (s, 1H), 4.52-4.57 (d, J=15.9, 1H),
3.88 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.85 (s, 3H), 3.59-3.64
(m, 1H), 3.24-3.33 (m, 2H), 2.79-2.95 (m, 2H), 2.61-2.65 (m, 2H),
1.38-1.40 (d, J=6.8, 3H); ESI-MS m/z 370[M+H].sup.+.
Example 53
(6R,14S)-2,3,9,10,11-pentamethoxyl-6-methyl-5,8,13,13a-tetrahydro-6H-diben-
zo[a,g]quinolizine (DC037053)
[0145] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.71 (s, 1H), 6.58 (s, 1H), 6.48 (s, 1H),
6.58 (s, 1H), 4.41-4.46 (d, J=15, 1H), 3.89 (s, 3H), 3.88 (s, 3H),
3.86 (s, 3H), 3.84 (s, 3H), 3.84 (s, 3H), 3.62-3.65 (m, 1H),
3.20-3.29 (m, 2H), 2.79-2.90 (m, 2H), 2.61-2.66 (m, 2H), 1.37-1.39
(d, J=6, 3H); ESI-MS m/z 400 [M+H].sup.+.
Example 54
(6S,14S)-2,3,9,10,11-pentamethoxyl-6-methyl-5,8,13,13a-tetrahydro-6H-diben-
zo[a,g]quinolizine (DC037054)
[0146] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.71 (s, 1H), 6.59 (s, 1H), 6.48 (s, 1H),
6.58 (s, 1H), 4.41-4.46 (d, J=15, 1H), 3.90 (s, 3H), 3.88 (s, 3H),
3.86 (s, 3H), 3.84 (s, 3H), 3.84 (s, 3H), 3.62-3.64 (m, 1H),
3.19-3.27 (m, 2H), 2.79-2.91 (m, 2H), 2.61-2.66 (m, 2H), 1.37-1.39
(d, J=6, 3H); ESI-MS m/z 400 [M+H].sup.+.
Example 55
(6R,14S)-2,3,9,11-tetramethoxy-6-methyl-12-hydroxymethyl-5,8,13,13a-tetrah-
ydro-6H-dibenzo[a,g]quinolizine (DC037055)
[0147] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.91 (s, 1H), 6.63 (s, 1H), 6.49 (s, 1H),
4.58-4.70 (m, 2H), 4.32-4.37 (d, J=15, 1H), 3.87 (s, 3H), 3.84 (s,
3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.58-3.65 (m, 1H), 3.50-3.54 (m,
1H), 3.06-3.11 (m, 1H), 2.70-2.82 (m, 2H), 2.59-2.65 (m, 2H),
1.30-1.33 (d, J=6, 3H); ESI-MS m/z 400 [M+H].sup.+.
Example 56
(6S,14S)-2,3,9,11-tetramethoxy-6-methyl-12-hydroxymethyl-5,8,13,13a-tetrah-
ydro-6H-dibenzo[a,g]quinolizine (DC037056)
[0148] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.92 (s, 1H), 6.63 (s, 1H), 6.50 (s, 1H),
4.58-4.70 (m, 2H), 4.31-4.36 (d, J=15, 1H), 3.86 (s, 3H), 3.84 (s,
3H), 3.83 (s, 3H), 3.80 (s, 3H), 3.58-3.64 (m, 1H), 3.50-3.53 (m,
1H), 3.06-3.11 (m, 1H), 2.70-2.82 (m, 2H), 2.59-2.65 (m, 2H),
1.30-1.33 (d, J=6, 3H); ESI-MS m/z 400 [M+H].sup.+.
Example 57
(6R,14S)-3,9,11-trimethoxy-6-methyl-12-hydroxymethyl-5,8,13,13a-tetrahydro-
-6H-dibenzo[a,g]quinolizine (DC037057)
[0149] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 7.20-7.23 (d, J=8.7, 1H), 6.75-6.79 (dd,
J=8.7, J=2.4, 1H), 6.61-6.62 (d, J=2.4, 1H), 6.34 (s, 1H),
4.64-4.74 (m, 2H), 4.37-4.42 (d, J=15, 1H), 3.85 (s, 3H), 3.84 (s,
3H), 3.79 (s, 3H), 3.62-3.65 (m, 1H), 3.50-3.51 (m, 1H), 3.13-3.18
(m, 1H), 2.89-2.90 (m, 2H), 2.67-2.70 (m, 2H), 1.38-1.40 (d, J=6,
3H); ESI-MS m/z 370 [M+H].sup.+.
Example 58
(6S,14S)-3,9,11-trimethoxy-6-methyl-12-hydroxymethyl-5,8,13,13a-tetrahydro-
-6H-dibenzo[a,g]quinolizine (DC037058)
[0150] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 7.20-7.23 (d, J=8.7, 1H), 6.76-6.80 (dd,
J=8.7, J=2.4, 1H), 6.60 (d, J=2.4, 1H), 6.34 (s, 1H), 4.63-4.74 (m,
2H), 4.37-4.42 (d, J=15, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.80 (s,
3H), 3.62-3.65 (m, 1H), 3.50-3.51 (m, 1H), 3.13-3.18 (m, 1H),
2.89-2.90 (m, 2H), 2.66-2.70 (m, 2H), 1.38-1.40 (d, J=6, 3H);
ESI-MS m/z 370 [M+H].sup.+.
Example 59
(6R,14S)-2-hydroxy-3,9,10,11-tetramethoxy-6-methyl-5,8,13,13a-tetrahydro-6-
H-dibenzo[a,g]quinolizine (DC037059)
[0151] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.91 (s, 1H), 6.67 (s, 1H), 6.45 (s, 1H),
4.40-4.45 (d, J=15, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 3.82 (s, 6H),
3.61-3.63 (m, 1H), 3.18-3.23 (m, 2H), 2.82-2.91 (m, 2H), 2.66-2.70
(m, 2H), 1.37-1.39 (d, J=6, 3H); ESI-MS m/z 386 [M+H].sup.+.
Example 60
(6S,14S)-2-hydroxy-3,9,10,11-tetramethoxy-6-methyl-5,8,13,13a-tetrahydro-6-
H-dibenzo[a,g]quinolizine (DC037060)
[0152] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.90 (s, 1H), 6.67 (s, 1H), 6.46 (s, 1H),
4.40-4.45 (d, J=15, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s, 6H),
3.61-3.63 (m, 1H), 3.18-3.24 (m, 2H), 2.83-2.91 (m, 2H), 2.66-2.70
(m, 2H), 1.38-1.40 (d, J=6, 3H); ESI-MS m/z 386 [M+H].sup.+.
Example 61
(6R,14S)-2-hydroxy-3,9,11-trimethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-dib-
enzo[a,g]quinolizine (DC037061)
[0153] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.97 (s, 1H), 6.75 (s, 1H), 6.66 (s, 1H),
6.36 (s, 1H), 4.37-4.42 (d, J=15, 1H), 3.87 (s, 3H), 3.85 (s, 3H),
3.79 (s, 3H), 3.53-3.59 (m, 1H), 3.43-3.50 (m, 1H), 3.08-3.12 (m,
1H), 2.73-2.81 (m, 2H), 2.62-2.68 (m, 2H), 1.36-1.38 (d, J=6, 3H);
ESI-MS m/z 356 [M+H].sup.+.
Example 62
(6S,14S)-2-hydroxy-3,9,11-trimethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-dib-
enzo[a,g]quinolizine (DC037062)
[0154] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.98 (s, 1H), 6.77 (s, 1H), 6.65 (s, 1H),
6.36 (s, 1H), 4.39-4.44 (d, J=15, 1H), 3.87 (s, 3H), 3.85 (s, 3H),
3.79 (s, 3H), 3.53-3.58 (m, 1H), 3.42-3.48 (m, 1H), 3.06-3.11 (m,
1H), 2.73-2.80 (m, 2H), 2.62-2.68 (m, 2H), 1.36-1.38 (d, J=6, 3H);
ESI-MS m/z 356 [M+H].sup.+.
Example 63
(6R,14S)-2-hydroxy-3,9,11-trimethoxy-6-methyl-12-hydroxymethyl-5,8,13,13a--
tetrahydro-6H-dibenzo[a,g]quinolizine (DC037063)
[0155] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.97 (s, 1H), 6.66 (s, 1H), 6.36 (s, 1H),
4.57-4.76 (m, 2H), 4.37-4.42 (d, J=15, 1H), 3.86 (s, 3H), 3.85 (s,
3H), 3.81 (s, 3H), 3.57-3.64 (m, 1H), 3.42-3.49 (m, 1H), 3.10-3.15
(m, 1H), 2.77-2.88 (m, 2H), 2.64-2.71 (m, 2H), 1.35-1.37 (d, J=6,
3H); ESI-MS m/z 386 [M+H].sup.+.
Example 64
(6S,14S)-2-hydroxy-3,9,11-trimethoxy-6-methyl-12-hydroxymethyl-5,8,13,13a--
tetrahydro-6H-dibenzo[a,g]quinolizine (DC037064)
[0156] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.99 (s, 1H), 6.67 (s, 1H), 6.36 (s, 1H),
4.58-4.76 (m, 2H), 4.37-4.42 (d, J=15, 1H), 3.87 (s, 3H), 3.85 (s,
3H), 3.81 (s, 3H), 3.57-3.65 (m, 1H), 3.44-3.49 (m, 1H), 3.10-3.14
(m, 1H), 2.77-2.88 (m, 2H), 2.65-2.71 (m, 2H), 1.37-1.39 (d, J=6,
3H); ESI-MS m/z 386 [M+H].sup.+.
Example 65
(6R,14S)-2,3-bimethoxy-6,9,11-trimethyl-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (DC037065)
[0157] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.85 (s, 1H), 6.83 (s, 1H), 6.73 (s, 1H),
6.58 (s, 1H), 3.99-4.14 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H),
3.63-3.66 (m, 1H), 3.25-3.28 (m, 2H), 2.82-2.96 (m, 2H), 2.62-2.71
(m, 2H), 2.28 (s, 6H), 1.37-1.39 (d, J=6, 3H); ESI-MS m/z 340
[M+H].sup.+.
Example 66
(6S,14S)-2,3-bimethoxy-6,9,11-trimethyl-5,8,13,13a-tetrahydro-6H-dibenzo[a-
,g]quinolizine (DC037066)
[0158] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta. 6.84 (s, 1H), 6.83 (s, 1H), 6.72 (s, 1H),
6.58 (s, 1H), 4.01-4.15 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H),
3.63-3.65 (m, 1H), 3.24-3.28 (m, 2H), 2.82-2.95 (m, 2H), 2.61-2.70
(m, 2H), 2.27 (s, 6H), 1.37-1.39 (d, J=6, 3H); ESI-MS m/z 340
[M+H].sup.+.
Example 69
(S)-2,3,11-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine
(DC037067)
[0159] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta.6.99-7.02 (d, J=9, 1H), 6.75 (s, 2H), 6.72
(s, 1H), 6.62 (s, 1H), 4.01-4.13 (m, 1H), 3.91 (s, 3H), 3.88 (s,
3H), 3.79 (s, 3H), 3.56-3.68 (m, 2H), 3.28-3.35 (m, 1H), 3.12-3.19
(m, 2H), 2.80-2.94 (m, 1H), 2.62-2.70 (m, 2H); ESI-MS m/z 326
[M+H].sup.+.
Example 68
(S)-2-hydroxy-3,11-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinoliz-
ine (DC037068)
[0160] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta.6.97-7.00 (d, J=9, 1H), 6.85 (s, 1H),
6.69-6.74 (m, 2H), 6.60 (s, 1H), 4.00-4.12 (m, 1H), 3.87 (s, 3H),
3.78 (s, 3H), 3.57-3.69 (m, 2H), 3.26-3.32 (m, 1H), 3.10-3.16 (m,
2H), 2.84-2.93 (m, 1H), 2.63-2.69 (m, 2H); ESI-MS m/z 312
[M+H].sup.+.
Example 69
(S)-2-benzyloxy-3,11-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinol-
izine (DC037069)
[0161] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta.7.46-7.47 (m, 2H), 7.39-7.40 (m, 2H),
7.31-7.33 (m, 1H), 6.97-7.00 (d, J=9, 1H), 6.76 (s, 1H), 6.70-6.74
(m, 1H), 6.64-6.66 (m, 2H), 5.15 (s, 2H), 3.94-3.99 (m, 1H), 3.88
(s, 3H), 3.79 (s, 3H), 3.62-3.66 (m, 1H), 3.50-3.54 (m, 1H),
3.11-3.16 (m, 2H), 2.77-2.81 (m, 1H), 2.60-2.69 (m, 2H); ESI-MS m/z
402 [M+H].sup.+.
Example 70
(S)-2,3-methylenedioxy-11-methoxyl-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]qu-
inolizine (DC037070)
[0162] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta.6.98-7.01 (d, J=9, 1H), 6.69-6.74 (m, 3H),
6.59 (s, 1H), 5.92 (s, 2H), 3.94-3.99 (m, 1H), 3.79 (s, 3H),
3.56-3.68 (m, 2H), 3.22-3.29 (m, 1H), 3.09-3.16 (m, 2H), 2.83-2.92
(m, 1H), 2.60-2.67 (m, 2H); ESI-MS m/z 310 [M+H].sup.+.
Example 71
(6R,14S)-2-hydroxy-3,9,12-trimethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-dib-
enzo[a,g]quinolizine (DC037071)
[0163] The preparation method was described in Example 49. .sup.1H
NMR (CDCl.sub.3): .delta.6.89 (s, 1H), 6.64 (s, 2H), 6.55 (s, 1H),
4.44-4.48 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H),
3.52-3.60 (m, 1H), 3.38-3.42 (m, 1H), 3.14-3.22 (m, 1H), 2.78-2.86
(m, 1H), 2.58-2.66 (m, 3H), 1.36-1.38 (d, J=6, 3H); ESI-MS m/z
356[M+H].sup.+.
Example 72
(6S,14S)-2-hydroxy-3,9,12-trimethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-dib-
enzo[a,g]quinolizine (DC037072)
[0164] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta.6.88 (s, 1H), 6.64 (s, 2H), 6.54 (s, 1H),
4.43-4.47 (m, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H),
3.53-3.60 (m, 1H), 3.38-3.43 (m, 1H), 3.15-3.24 (m, 1H), 2.77-2.84
(m, 1H), 2.58-2.67 (m, 3H), 1.36-1.38 (d, J=6, 3H); ESI-MS m/z
356[M+H].sup.+.
Example 73
(6S,14R)-2,10-bihydroxy-3,9-bimethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-di-
benzo[a,g]quinolizine (DC037073) (prepared according to the second
reaction route)
[0165] Compound DC037073 was prepared according to the following
Example 81 except that 1.74 g of 2,3-bimethoxypropiophenone was
dissolved in 40 mL of anhydrous methanol, 0.96 mg of ammonium
acetate was added to above solution, and
2,3-bimethoxyphenyl-propanamine was obtained by hydrogenation under
the catalytic action of palladium carbon. .sup.1H NMR (CDCl.sub.3):
.delta.6.80-6.82 (m, 3H), 6.56 (s, 1H), 5.30-5.50 (m, 2H),
4.49-4.56 (m, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.58-3.62 (m, 1H),
3.24-3.35 (m, 2H), 3.15-3.24 (m, 1H), 2.77-2.88 (m, 2H), 2.60-2.66
(m, 2H), 1.36-1.38 (d, J=6, 3H); ESI-MS m/z 342[M+H].sup.+.
Example 74
(6S,14S)-2,10-bihydroxy-3,9-bimethoxy-6-methyl-5,8,13,13a-tetrahydro-6H-di-
benzo[a,g]quinolizine (DC037074) (prepared according to the second
reaction route)
[0166] The preparation method was described in Example 81. .sup.1H
NMR (CDCl.sub.3): .delta.6.80-6.82 (m, 3H), 6.56 (s, 1H), 5.28-5.49
(m, 2H), 4.50-4.56 (m, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.56-3.61
(m, 1H), 3.24-3.34 (m, 2H), 3.16-3.24 (m, 1H), 2.76-2.85 (m, 2H),
2.58-2.64 (m, 2H), 1.36-1.38 (d, J=6, 3H); ESI-MS m/z
342[M+H].sup.+.
Example 75
(S)-2,3,9,11-tetramethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine
(DC037075)
[0167] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta.6.72 (s, 1H), 6.60 (s, 1H), 6.30 (s, 2H),
4.07-4.12 (d, J=15, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.78 (s, 3H),
3.77 (s, 3H), 3.55-3.59 (m, 1H), 3.35-3.40 (m, 3H), 3.15-3.28 (m,
2H), 2.63-2.67 (m, 2H); ESI-MS m/z 356 [M+H].sup.+.
Example 76
(S)-2,3,9,11-tetramethoxy-12-hydroxymethyl-5,8,13,13a-tetrahydro-6H-dibenz-
o[a,g]quinolizine (DC037076)
[0168] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta.6.77 (s, 1H), 6.60 (s, 1H), 6.35 (s, 1H),
4.60-4.76 (m, 2H), 4.08-4.13 (d, J=15, 1H), 3.88 (s, 3H), 3.85 (s,
6H), 3.81 (s, 3H), 3.51-3.55 (m, 2H), 3.35-3.46 (m, 2H), 3.12-3.17
(m, 2H), 2.60-2.67 (m, 2H); ESI-MS m/z 386 [M+H].sup.+.
Example 77
(S)-2,3-methylenedioxy-9,11-bimethoxy-12-hydroxymethyl-5,8,13,13a-tetrahyd-
ro-6H-dibenzo[a,g]quinolizine (DC037077)
[0169] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta.6.78 (s, 1H), 6.58 (s, 1H), 6.35 (s, 1H),
5.88 (s, 2H), 4.60-4.76 (m, 2H), 4.09-4.14 (d, J=15, 1H), 3.87 (s,
3H), 3.84 (s, 3H), 3.47-3.55 (m, 2H), 3.35-3.43 (m, 2H), 3.11-3.18
(m, 2H), 2.58-2.67 (m, 2H); ESI-MS m/z 370 [M+H].sup.+.
Example 78
(S)-2,3-methylenedioxy-9,11-bimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g-
]quinolizine (DC037078)
[0170] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta.6.73 (s, 1H), 6.59 (s, 1H), 6.30 (s, 2H),
5.90 (s, 2H), 4.07-4.12 (d, J=15, 1H), 3.82 (s, 3H), 3.79 (s, 3H),
3.52-3.56 (m, 1H), 3.35-3.40 (m, 1H), 3.06-3.24 (m, 3H), 2.80-2.89
(m, 1H), 2.57-2.68 (m, 2H); ESI-MS m/z 340 [M+H].sup.+.
Example 79
(S)-2-hydroxy-3,9,11-trimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo-[a,g]quin-
olizine (DC037079)
[0171] The preparation method was described in Example 1. .sup.1H
NMR (CDCl.sub.3): .delta.6.81 (s, 1H), 6.59 (s, 1H), 6.29 (s, 2H),
4.07-4.12 (d, J=15, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H),
3.52-3.58 (m, 1H), 3.36-3.42 (m, 1H), 3.06-3.26 (m, 3H), 2.79-2.89
(m, 1H), 2.58-2.69 (m, 2H); ESI-MS m/z 342 [M+H].sup.+.
Example 80
(S)-2-hydroxy-3,9,11-trimethoxy-12-hydroxymethyl-5,8,13,13a-tetrahydro-6H--
dibenzo[a,g]quinolizine (DC037080)
[0172] The preparation method was described in Example 1.
Example 81
S-(-)-9-methoxyl-10-hydroxy-2,3,5,8,13,13a-hexahydro-8H-benzo[3,2,a,g]fura-
nquinolizine (DC037081) (prepared according to the second reaction
route)
2.1 Preparation of methyl 3-bromo-4-hydroxy-phenylacetate (Compound
10)
[0173] Methyl 3-hydroxy-phenylacetate (16.6 g, purchased from
Accela ChemBio Co., Ltd.) was dissolved in glacial acetic acid (100
mL) and liquid bromine solution in glacial acetic acid (16 g in 50
mL glacial acetic acid) was dropwise added to above solution. The
reaction was conducted for 2 hours and the product was obtained by
filtering.
[0174] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.39 (d, J=1.5
Hz, 1H), 7.11 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H),
3.70 (s, 3H), 3.54 (s, 2H).
2.2 Preparation of methyl 3-bromo-4-benzyloxy-phenylacetate
(Compound 11)
[0175] Compound 10 (12.3 g) was dissolved in 100 mL acetone and 7.6
g of potassium carbonate was added. 8.6 g of benzyl bromide was
added with stirring. The solid was removed by suction filtration
and the liquid was evaporated to product 11.
[0176] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.51-7.33 (m,
6H), 7.15 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H),
5.15 (s, 2H), 3.70 (s, 3H), 3.55 (s, 2H).
2.3 Preparation of 3-hydroxy-benzyloxyphenylacetic acid (Compound
12)
[0177] The substrate 11 (3.4 g), 6 mL of water, 1.5 g of KOH and
150 mg Cu powder were loaded into a microwave reaction tube and
stirred at room temperature for half an hour. The obtained mixture
was degassed by ultrasound. At 140.degree. C., the microwave
reaction proceeded for 50 minutes. The undissolved substance was
filtered off. The pH value of the solution was adjusted to 1-3 by
concentrated hydrochloric acid. The crude product was obtained by
filtration. The product was recrystallizated with toluene to obtain
Compound 12.
[0178] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.43-7.38 (m,
5H), 6.90 (s, 1H), 6.89 (dd, J=8.1 Hz, J=2.1 Hz, 1H), 6.74 (d,
J=8.1 Hz, 1H), 5.10 (s, 2H), 3.56 (s, 2H).
2.4 Preparation of Compound 13
[0179] The substrate 12 (3 g), phenylboronic acid (2.7 g) and 60 mL
of anhydrous toluene were added to the reaction bottle. The
reaction mixture was placed in 110.degree. C. oil bath for reacting
for 2 hours. The reaction mixture was poured into a sealed tube
while 3 g of paraformaldehyde and appropriate amount of molecular
sieves were added. The reaction proceeded at 100.degree. C. for 46
hours. After completion of the reaction, the molecular sieves were
filtered off while they were hot and toluene was evaporated to
obtain a slightly yellow solid. 50 mL of water was added and the
reaction proceeded in 100.degree. C. oil bath for 2 hours. After
cooled, the reaction mixture was extracted with dichloromethane
until there is no product in aqueous phase. The dichloromethane
phase was dried over anhydrous sodium sulfate and evaporated to
dryness to obtain a slightly yellow solid. An appropriate amount of
anhydrous ether was added, stirred for 3 hours at room temperature,
and then filtered to give a white solid, i.e. Compound 13.
[0180] The preparation was carried out with reference to Richard J.
Spangler, Brian G. Beckmann, Jong Ho Kim. J. org. chem., 1977, 42,
2989-2996. Mark Cushman, Frederick W. Dekow. J. org. chem., 1979,
44, 407-409.
2.5 Preparation of Compound 14
[0181] Compound 13 (2.7 g) was dissolved in acetone (50 mL)
Potassium carbonate (6.2 g) and iodomethane (15.5 g) were added.
The reaction mixture was refluxed for 2 hours. The insoluble
substances were filtered off and the solvent was evaporated.
Product 14 was obtained by column chromatography.
[0182] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.45-7.34 (m,
5H), 6.92 (d, J=8.2 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 5.40 (s, 2H),
5.12 (s, 2H), 3.91 (s, 3H), 3.62 (s, 2H).
2.6 Preparation of Compound 15
[0183] Compound 14 (2.84 g) was dissolved in glacial acetic acid
and a solution of concentrated nitric acid in glacial acetic acid
(630 mg in 6 mL of glacial acetic acid) was added slowly to above
solution. The reaction was conducted for 2 hours and product 15 was
obtained by column chromatography.
2.7 Preparation of Compound 16
[0184] Compound 15 (658 mg) and
2-[5-(2,3-dihydrobenzofuranyl)]-ethylamine (516 mg) were dissolved
in 7 mL of anhydrous ethanol. The reaction mixture was refluxed
overnight, and cooled to precipitate solid. Product 16 was obtained
by filtration.
[0185] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 7.48-7.32 (m,
5H), 6.93 (d, J=8.4, 1 H), 6.86 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.1
Hz, 1H), 6.65 (d, J=1.8, 1H), 6.54 (dd, J=8.1, 1.8 Hz, 1H), 6.10
(m, 1H), 5.07 (s, 2H), 4.61 (s, 2H), 4.26 (t, 2H), 3.84 (s, 3H),
3.51 (s, 2H), 3.46-3.40 (q, J=6.8 Hz, 2H), 2.97 (t, 2H), 2.67 (t,
J=6.8 Hz, 2H).
2.8 Preparation of Compound 17
[0186] Compound 16 (930 mg) was dissolved in anhydrous
dichloromethane (25 mL) while anhydrous pyridine (0.24 mL) and a
catalytic amount of DMAP were added. In an ice bath, a solution of
acetyl chloride in dichloromethane was slowly added. After
addition, the reaction was continued at room temperature for 1 hour
and an appropriate amount of water was added. The reaction mixture
was extracted with dichloromethane for three times. The
dichloromethane layer was washed with saturated saline solution,
dried over sodium sulfate and evaporated to dryness to give
Compound 17 which can be directly used in next reaction without
further purification.
[0187] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.44-7.32 (m,
5H), 6.92 (d, J=8.4, 1 H), 6.89 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.0
Hz, 1H), 6.61 (d, J=1.6, 1H), 6.53 (dd, J=8.0, 1.6 Hz, 1H), 5.40
(m, 1H), 5.08 (s, 2H), 5.02 (s, 2H), 4.26 (t, 2H), 3.83 (s, 3H),
3.82 (s, 2H), 3.44-3.39 (q, J=6.8 Hz, 2H), 2.96 (s, 2H), 2.67-2.63
(t, J=6.8 Hz, 2H), 1.92 (s 3H).
2.9 Preparation of Compound 18
[0188] Compound 17 (760 mg) was dissolved in anhydrous acetonitrile
(15 mL), to which phosphorus oxychloride (1.1 mL) was added. The
reaction solution was refluxed for 30 min and then cooled to room
temperature. Most of the solvent and the phosphorus oxychloride
were evaporated. The reaction solution was neutralized by using
saturated sodium bicarbonate solution and extracted with
dichloromethane for three times. Most of the solvent was
evaporated, and the reaction solution was neutralizated with
saturated sodium bicarbonate solution, extracted for three times
with dichloromethane. The extract phase was dried over sodium
sulfate and evaporated to dryness to give Compound 18 which can be
directly used in next reaction without further purification.
[0189] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.43-7.31 (m,
5H), 6.96 (s, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.77 (s, 1H), 6.73 (d,
J=8.4 Hz, 1H), 5.20 (s, 1H), 5.02 (s, 2H), 4.68 (s, 2H), 4.28 (t,
2H), 4.01-3.98 (t, J=7.6 Hz, 2H), 3.84 (s, 2H), 2.97 (t, 2H),
3.09-3.06 (t, J=7.6 Hz, 2H), 2.00 (s, 3H).
2.10 Preparation of Compound 19
[0190] Compound 18 (489 mg) and R type of Noyori catalyst (7 mg)
were dissolved in DMF (5 mL) A mixture of triethylamine and formic
acid (v/v=5:2) was added into the reaction mixture and the reaction
was conducted overnight at room temperature. The reaction solution
was neutralizated with saturated aqueous sodium bicarbonate
solution to alkalinity and the mixture was extracted with ethyl
acetate. The ester phase was washed once with saturated saline
solution, dried and evaporated to dryness to give product 19.
[0191] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.43-7.31 (m,
5H), 7.01 (d, J=8.4, 1 H), 6.92 (d, J=8.4 Hz, 1H), 6.66 (s, 1H),
6.59 (s, 1H), 5.30 (m, 2H), 5.02 (s, 2H), 4.26 (t, 2H), 4.02-3.99
(m, 1H), 3.90 (s, 3H), 3.22-3.16 (m, 2H), 2.95 (t, 2H), 2.90-2.80
(m, 2H), 2.74-2.71 (m, 2H), 2.01 (s, 3H).
2.11 Preparation of Compound 20
[0192] Compound 19 (491 mg) was dissolved in ethanol (4.5 mL), and
to the solution, water (1.5 mL) and sodium hydroxide (80 mg) were
added. The solution was reacted at room temperature for 3 hours and
solid precipitated. The target product 20 was obtained by
filtration.
2.12 Preparation of Compound 21
[0193] Compound 20 (447 mg) was dissolved in anhydrous
dichloromethane. Under N.sub.2, thionyl chloride (0.53 mL) was
added slowly to the solution cooled in ice-bath. After addition,
the reaction proceeded at room temperature for 2 hours. A saturated
sodium bicarbonate solution was added into the reaction solution to
alkalinity and the reaction proceeded at room temperature for 2
hours. The dichloromethane layer was separated and the aqueous
phase was extracted for three times with dichloromethane. The ester
phase was washed once with saturated sodium chloride solution,
dried over sodium sulfate and evaporated to dryness. And then
product 21 was obtained by column chromatography.
[0194] .sup.1H NMR (CDCl.sub.3, 400 MHz): .delta. 7.47-7.31 (m,
5H), 6.83 (d, J=8.1, 1 H), 6.78 (d, J=8.1 Hz, 1H), 6.75 (s, 1H),
6.64 (s, 1H), 5.14 (s, 2H), 4.27 (t, 2H), 4.25-4.19 (m, 1H), 3.87
(s, 3H), 3.54-3.45 (m, 2H), 3.21-3.06 (m, 3H), 2.76-2.59 (m,
5H).
2.13 Preparation of
S-(-)-9-methoxyl-10-hydroxy-2,3,5,8,13,13a-hexahydro-8H-benzo[3,2,a,g]fur-
anquinolizine
[0195] Compound 21 (431 mg) was dissolved in ethanol, and
concentrated hydrochloric acid was slowly added. The mixture was
refluxed for 1.5 hours and then cooled to room temperature. Most of
hydrochloric acid was evaporated and the residue was neutralized
with aqueous ammonia to alkalinity. The resulting mixture was
extracted with dichloromethane until no product remains in aqueous
phase. And then the product was obtained by column
chromatography.
[0196] .sup.1H NMR (CDCl.sub.3): .delta. 6.83 (m, 3H), 6.59 (s,
1H), 4.34-4.29 (m, 1H), 4.26 (t, 2H), 3.86 (s, 3H), 3.67-3.61 (m,
2H), 3.30-3.24 (m, 3H), 2.97 (t, 2H), 2.93-2.71 (m, 3H); ESI-MS m/z
324 [M+H].sup.+.
Example 82
S-(-)-2,3-bimethylenedioxy-9-methoxyl-10-hydroxy-5,8,13,13a-tetrahydro-6H--
dibenzo[a,g]quinolizine (DC037082)
[0197] The preparation method was described in Example 81.
[0198] .sup.1H NMR (CDCl.sub.3): .delta. 6.87 (m, 2H), 6.76 (s,
1H), 6.60 (s, 1H), 4.34-4.29 (m, 1H), 4.28 (m, 4H), 3.85 (s, 3H),
3.31-3.25 (m, 3H), 2.97 (t, 2H), 2.92-2.70 (m, 3H); ESI-MS m/z 340
[M+H].sup.+.
Example 83
S-(-)-2'-methyl-9-methoxyl-10-hydroxy-2,3,5,8,13,13a-hexahydro-8H-benzo[3,-
2,a, g]furanquinolizine (DC037083)
[0199] The preparation method was described in Example 81.
[0200] .sup.1H NMR (CDCl.sub.3): .delta. 6.82 (m, 3H), 6.61 (s,
1H), 4.33-4.28 (m, 1H), 4.24 (m, 1H), 3.87 (s, 3H), 3.64-3.57 (m,
2H), 3.30-3.24 (m, 3H), 2.97 (t, 2H), 2.93-2.71 (m, 3H); ESI-MS m/z
338 [M+H].sup.+.
Pharmacological Experiments
[0201] 1. In the present invention, the pharmacological experiments
were conducted to study the affinity of
hexahydrodibenzo[a,g]quinolizine compound of general formula I and
derivatives thereof on dopamine D.sub.1, dopamine D.sub.2,
5-HT.sub.1A, and 5-HT.sub.2A receptor. The experimental materials
required for pharmacological experiments were commercially
available unless otherwise specified.
[0202] (1). Determination of the affinity of
hexahydrodibenzo[a,g]quinolizine compound of general formula I and
derivatives thereof on dopamine D1, dopamine D2, 5-HT.sub.1A, and
5-HT.sub.2A receptor.
[0203] 1) The Experimental Method
[0204] Different concentrations (10.sup.-5 M-10.sup.-11 M) of the
compound of the invention and corresponding isotope receptor ligand
as well as receptor protein were loaded into the reaction tube and
incubated in 30.degree. C. water bath for 60 minutes. The reaction
was terminated in a refrigerator. The reaction mixture was put in a
Millipore filter (millipore) cell sample collector, filtered
through suction filtration using GF/C glass fiber filter paper, and
dried. The resulting sample was placed into 0.5 mL tube. 500 .mu.L
liquid scintillation fluid was added and intensity of radioactivity
was determined by counting.
[0205] 2) The Experimental Materials
[0206] {circle around (1)} Construction of receptor and materials
for cell culture: Escherichia coli. DH5.alpha. strain; insect virus
transfer vector pVL1393 plasmid; BaculoGold linear Chinese
baculovirus DNA, purchased from ParMingen company; mkD1RcDNA; rD2R
cDNA; various restriction endonucleases, TaqDNA polymerase, T4
ligase, etc., LB medium; insect cell culture TNM-FH.
[0207] {circle around (2)} The Experimental Materials for Receptor
Binding
[0208] For dopamine D1 receptor: isotope receptor ligands [3H]
SCH23390 (85.0 Ci/mmol) (D1-selective, purchased from Amersham
Corporation), D1 receptor protein expressed in HEK-293 cells;
[0209] For D2 dopamine receptor: isotope receptor ligands [3H]
Spiperone (77.0 Ci/mmol) (D2-selective, purchased from Amersham
Corporation); D2 receptor protein expressed in HEK-293 cells;
[0210] For 5-HT1A receptor: isotope receptor ligands [3H]
8-OH-DPAT; 5-HT1A receptor protein expressed in HEK-293 cells;
[0211] For 5-HT2A receptor: isotope receptor ligands
[3H]-Ketanserin; 5-HT2A receptor protein expressed in HEK-293
cells;
[0212] Firstly, the above receptor proteins are dissolved in DMSO
and then diluted with double distilled water to the appropriate
concentration (10.sup.-5 M-10.sup.-11 M).
[0213] (+) Butaclamo purchased from RBI company, GF/C glass fiber
filter paper purchased from Whatman Co., scintillation fluid
(dopamine D1, D2 receptors)/liposoluble scintillation fluid
(5-HT1A, 5-HT2A receptor), Beckman LS-6500 multi-function liquid
scintillation counter.
[0214] 3) The experimental results are showed in table 1 and 3.
[0215] 2. Determination of the inhibition property of
hexahydrodibenzo[a,g]quinolizine compound of general formula I and
derivatives thereof on dopamine D.sub.2 receptor.
[0216] (1) The Experimental Method
[0217] Each medicament was dissolved in serum-free F12 culture
medium containing 100 .mu.M of IBMX. CHO cells which can stably
express D2 receptor were pre-incubated at 37.degree. C. for 10 min,
and then 10 .mu.M Forskoline and 10 .mu.M Dopanie were added at the
same time to react for 10 min 100 .mu.L of pre-cooled 1 M of
HClO.sub.4 was added and the reaction was terminated at 4.degree.
C. for 1 hour. 20 .mu.L of 2 M K.sub.2CO.sub.3 was added to
neutralize the reaction. The resulting mixture was centrifugated at
3000 rpm for 15 min, and the precipitate KClO.sub.4 was discarded.
A certain amount of the supernatant was taken for cAMP detection.
Spiperone and Quinpirole were used as positive control.
[0218] (2) The experimental materials
[0219] (3) The experimental results are showed in table 2 and FIG.
1.
TABLE-US-00001 TABLE 1 Determination results of the affinity of
some representative compounds on dopamine D1, and D2 receptors Com-
D.sub.1 receptor D.sub.2 receptor pound inhibition IC.sub.50
inhibition IC.sub.50 No. ratio (%) Ki (nM) (nM) ratio (%) Ki (nM)
(nM) DC037001 58.95 ND ND 14.7 ND ND DC037002 77.95 ND ND 27.05 ND
ND DC037003 98.0 246.86 370.30 75.75 ND ND DC037006 91.75 320.11
648.23 48.0 ND ND DC037007 87.65 1003.72 2032.50 49.05 ND ND
DC037008 101.0 50.07 101.39 92.8 334.38 1727.60 DC037009 -13.6 ND
ND 0.35 ND ND DC037010 66.8 ND ND 51.5 ND ND DC037011 59.3 ND ND
41.7 ND ND DC037012 95.8 147.91 299.52 89.3 239.90 1239.4 DC037013
103.4 23.65 47.90 85.6 485.43 2508.05 DC037014 58.2 ND ND 25.8 ND
ND DC037015 59.2 ND ND 59.3 ND ND DC037016 95.5 376.83 763.07 66.2
ND ND DC037017 94.5 337.78 684.01 97.4 223.61 1155.30 DC037018 82.5
1440.62 2917.20 77.4 ND ND DC037019 10.3 ND ND 65.3 ND ND DC037020
47.3 ND ND 57.1 ND ND DC037021 56.5 ND ND 44.5 ND ND DC037022 89.0
497.87 1008.16 10.6 ND ND DC037024 91.3 740.67 1499.85 76.2 ND ND
DC037027 92.0 522.03 1057.10 64.7 ND ND DC037029 99.63 4.20 8.19
100.08 32.16 91.11 DC037030 99.89 3.70 7.22 74.27 ND ND DC037031
98.99 28.91 56.37 90.10 160.99 456.13 DC037032 99.21 25.25 49.23
28.67 ND ND DC037033 91.94 208.21 416.4 13.75 ND ND DC037034 95.30
248.04 483.67 17.36 ND ND DC037035 99.68 6.72 13.27 84.30 ND ND
DC037081 22.60 ND ND 73.07 ND ND DC037082 99.32 7.51 14.65 63.94 ND
ND DC037075 97.88 64.12 113.81 39.50 ND ND DC037077 97.33 182.41
323.79 41.75 ND ND DC037078 97.79 74.50 141.58 1.02 ND ND DC037079
99.99 5.18 9.85 76.21 ND ND SCH- 100 1.24 2.52 ND ND ND 23390
Spiperone ND ND ND 100 0.50 2.56 ND: the test was not
conducted.
TABLE-US-00002 TABLE 2 Determination results of the inhibition of
some representative compounds on dopamine D2 receptor D.sub.2
receptor Compound No. Antagonist IC50 agonist IC50 DC037003 3.30
.mu.M -- DC037008 4.03 .mu.M -- DC037013 9.74 .mu.M -- DC037017
16.19 .mu.M -- DC037018 15.61 .mu.M -- DC037024 0.591 .mu.M --
Spiperone 0.0014 .mu.M -- Quinpirole -- 0.462 .mu.M --: no agonist
activity
TABLE-US-00003 TABLE 3 Determination results of the affinity of
some representative compounds on hydroxyptamine 5-HT.sub.1A and
5-HT.sub.2A receptor 5-HT.sub.1A receptor 5-HT.sub.2A receptor
Compound inhibition inhibition No. ratio (%) Ki (nM) IC.sub.50 (nM)
ratio (%) Ki (nM) IC.sub.50 (nM) DC037013 86.93 ND ND 41.32% ND ND
DC037029 60.97 ND ND 49.91 ND ND DC037030 80.41 493.48 626.40 39.99
ND ND DC037034 83.77 497.43 631.40 26.46 ND ND DC037032 95.36 40.59
51.53 37.75 ND ND DC037075 90.77 730.02 922.44 54.04% ND ND
DC0370077 88.63 599.89 758.03 45.63% ND ND 5-HT 100 0.62 0.79 ND ND
ND Spiperone ND ND ND 100 2.94 5.67 ND: the test was not
conducted.
[0220] It can be seen from the tables that the tested compounds,
for example Compound DC037029, DC037030, DC037031, DC037032,
DC037035, DC037079, and DC037082, have strong affinity on dopamine
D1, D2 receptors. Further, some compounds of the present invention
exhibit a certain affinity on 5-HT1A.
[0221] 2. Results of In Vivo Pharmacokinetic Experiment of Rats
[0222] Pharmacokinetic properties of Compound DC037029 in rats were
preliminarily studied in this experiment. After the tested compound
was delivered to rats by intravenous administration and
intragastric administration, respectively, the whole blood samples
were collected at different time point and the plasma was
separated. The concentration of compound in plasma was determined
by liquid chromatography-tandem mass spectrometry.
[0223] (1) Administration Regimen
[0224] Six healthy male SD rats with the weight of 200-220 g were
randomly divided into 2 groups, each of which has three rats. The
rats in each group were administrated with the tested compound by
gavage or intravenous injection, respectively. Details are shown in
table 4.
TABLE-US-00004 TABLE 4 administration regimen Number Adminis-
Adminis- of tration Administration tration Group animals Compound
route dose volume 1 3 DC037029 gavage 20 10 2 3 DC037029 vein 10
5.0
[0225] The compound was dissolved in 10% DMSO/10% Tween/10% normal
saline.
[0226] The rats are fasted for 12 h and can drink water ad libitum
before test. 2 h after dosing, the rats ate all together. The time
point for collecting blood samples and the sample processing are
listed as follows.
[0227] Intragastric administration time: 0.25, 0.5, 1.0, 2.0, 3.0,
5.0, 7.0, 9.0 and 24 h after administration.
[0228] Intravenous administration time: 5 min, 0.25, 0.5, 1.0, 2.0,
3.0, 5.0, 7.0, 9.0 and 24 h after administration. At above time
point, 0.3 ml venous blood was taken from retrobulbar venous plexus
of the rat and loaded into heparinization tube. After centrifuged
at 1000 rpm for 5 min, the plasma was separated and frozen at
-20.degree. C. in a refrigerator.
[0229] (2) Pharmacokinetic Results
[0230] After the rats were administrated with DC037029 by gavage or
intravenous injection, respectively, the concentrations of the
medicament in plasma were showed in table 5 and 6, the
corresponding pharmacokinetic parameters were showed in table 7 and
8, and the curves of plasma concentration vs time were showed in
FIG. 2a-2c.
[0231] After 20 mg/kg of DC037029 was administered through gavage,
the time T.sub.max for the plasma concentration in rats reaching
the peak concentration is 0.67.+-.0.29 h, the peak concentration
C.sub.max is 453.+-.147 ng/ml, the area AUC.sub.0-t below the curve
of plasma concentration vs time is 2867.+-.798 ngh/ml, and the
elimination half-life t.sub.1/2 is 3.26.+-.0.82 h.
[0232] After 10 mg/kg DC037029 was administered through intravenous
injection, AUC.sub.0-t is 4196.+-.141 ngh/ml, t.sub.1/2 is
5.44.+-.0.85 h, plasma clearance rate CL is 2.38.+-.0.08 L/h/kg,
steady state distribution volume Vss is 3.49.+-.0.24 L/kg;
[0233] After 20 mg/kg of DC037029 was administered through gavage
in rat, absolute bioavailability is lavage 34.2%.
TABLE-US-00005 TABLE 5 Plasma concentration (ng/mL) of rats after
20 mg/kg of DC037029 was administered through gavage the number
time (h) of the animal 0.0 0.25 0.5 1.0 2.0 3.0 5.0 7.0 9.0 24.0 1
BLQ 416 494 455 326 207 236 80.3 41.3 1.26 2 BLQ 493 553 575 492
431 330 118 113 1.90 3 BLQ 268 289 230 218 231 233 169 91.9 9.67
average 392 445 420 345 289 266 122 82.2 4.28 standard 114 139 175
138 123 55 44 37.1 4.68 deviation
TABLE-US-00006 TABLE 6 Plasma concentration (ng/mL) of rats after
10 mg/kg of DC037029 was administered through intravenous injection
the number time (h) of the animal 0.083 0.25 0.5 1.0 2.0 3.0 5.0
7.0 9.0 24.0 4 4169 2766 1788 1047 527 294 83.7 21.1 9.26 1.61 5
3837 2874 1984 1365 596 243 77.2 21.7 7.41 1.41 6 4576 3010 2055
1211 590 228 65.0 19.2 7.31 2.26 average 4194 2883 1942 1207 571
255 75.3 20.7 8.00 1.76 standard 170 122 138 159 38 34 9.5 1.3 1.10
0.45 deviation
TABLE-US-00007 TABLE 7 Pharmacokinetic parameters of rats after 20
mg/kg of DC037029 was administered through gavage the number
C.sub.max AUC.sub.0-t of the T.sub.max (ng/ (n g/ AUC.sub.0-.infin.
MRT t.sub.1/2 F animal (h) mL) mL) (ng h/mL) (h) (h) (%) 1 0.50 494
2260 2265 4.00 2.89 2 1.00 575 3771 3779 4.67 2.70 3 0.50 289 2570
2629 6.45 4.20 average 0.67 453 2867 2891 5.04 3.26 34.2 standard
0.29 147 798 790 1.27 0.82 deviation CV (%) 43.3 32.6 27.8 27.3
25.1 25.1
TABLE-US-00008 TABLE 8 Pharmacokinetic parameters of rats after 10
mg/kg of DC037029 was administered through intravenous injection
the number AUC.sub.0-t of the (ng h/ ALC.sub.0-.infin. MRT
t.sub.1/2 CLz Vss animal mL) (ng h/mL) (h) (h) (L/h/kg) (L/kg) 4
4034 4046 1.53 5.01 2.47 3.78 5 4262 4272 1.42 4.88 2.34 3.33 6
4292 4313 1.46 6.42 2.32 3.38 average 4196 4210 1.47 5.44 2.38 3.49
standard 141 144 0.05 0.85 0.08 0.24 deviation CV (%) 3.4 3.4 3.6
15.7 3.5 7.0
[0234] The above results for pharmaceutical experiments indicate
that the compounds of the invention have better metabolic
properties than l-SPD, especially higher bioavailability and action
time, thereby overcoming the defects of l-SPD, such as difficulties
in oral absorption, low bioavailability and the like. Especially,
oral bioavailability of the compounds of the invention is improved
nearly five times compared with that of prodrug thereof (according
to CN101037436, the oral bioavailability of l-SPD is 6.83%), which
facilitates the preparation of compounds with better drug
properties.
Radioligand Binding Assays
[0235] The affinity of compounds to D.sub.1 and D.sub.2 dopamine
receptors were determined by competition binding assays. Membrane
homogenates of HEK293T cells were stably transfected with D.sub.1,
or D.sub.2 receptors. Duplicated tubes were incubated at 30.degree.
C. for 50 mins (for D.sub.1, and D.sub.2) with increasing
concentrations of respective compound and with [.sup.3H]SCH23390
(for D.sub.1 dopamine receptors), or [.sup.3H]Spiperone (for
dopamine D.sub.2 receptor) in a final volume of 200 .mu.L binding
buffer containing 50 mM Tris, 4 mM MgCl.sub.2, pH 7.4. Nonspecific
binding was determined by parallel incubations with either 10 .mu.M
SCH23390 for D.sub.1, or Spiperone for D.sub.2 receptors
respectively. The reaction was started by addition of membranes (15
ng/tube) and stopped by rapid filtration through Whatman GF/B
glassfiber filter and subsequently washed with cold buffer (50 mM
Tris, 5 mM EDTA, pH 7.4) using a Brandel 24-well cell harvester.
Scintillation cocktail was added and the radioactivity was
determined in a MicroBeta liquid scintillation counter. The
IC.sub.50 and Ki values were calculated by nonlinear regression
(PRISM, Graphpad, San Diego, Calif.) using a sigmoidal function.
The inhibition and Ki values of tested compounds are listed in
Table 9.
TABLE-US-00009 TABLE 9 The Ki values of tested compounds Compound
D.sub.1 D.sub.2 Inhibition No. configuration Inhibition (%) or
K.sub.i (nM) (%) or K.sub.i (nM) DC037078 S 64.12 .+-. 4.43 39.50%
DC037076 S 74.51 .+-. 3.85 1.02% DC037079 S 2.53 .+-. 0.16 83.31%
DC037081 S 17.29 .+-. 0.54 146.9 .+-. 10.2 DC037031 S 28.91 .+-.
2.73 160.9 .+-. 21.1 DC037013 S 23.65 .+-. 1.18 85.6% DC037030 S
3.70 .+-. 0.26 74.27% DC037035 S 6.72 .+-. 0.34 84.30%
[.sup.35S]GTP.gamma.S Binding Assays
[0236] For detecting the agonism action of the compounds, the
[.sup.35S]GTP.gamma.S binding assay was performed at 30.degree. C.
for 40 mins in reaction buffer containing 50 mM Tris, pH 7.5, 5 mM
MgCl.sub.2, 1 mM EDTA, 100 mM NaCl and 1 mM (DL)-dithiothreitol
(DTT). The assay mixture (200 .mu.L) contained 30 .mu.g of membrane
protein, 0.1 nM [.sup.35S]GTP.gamma.S, and 40 .mu.M guanosine
triphosphate (GDP) with various concentration of the compound. The
D.sub.1 receptor agonist SKF38393 and antagonist SCH23390 were used
for reference. Non specific binding was measured in the presence of
100 .mu.M 50-guanylimidodiphosphate (Gpp(NH)p). The reaction was
terminated by adding 3 mL of ice-cold washing buffer (50 mM Tris,
pH 7.5, 5 mM MgCl.sub.2, 1 mM EDTA, and 100 mM NaCl) and was
rapidly filtered with GF/C glass fiber filters (Whatman) and rinsed
for three times. Filters were dried and radioactivity was
determined by liquid scintillation counting. The results are
summarized in Table 10. The results show that DC037030 and DC037079
have good D.sub.1 receptor selectivity and D.sub.1 receptor
antagonistic activity.
TABLE-US-00010 TABLE 10 [.sup.35S]GTP.gamma.S binding assays of
DC037030 and DC037079 for D.sub.1 receptor D1 agonist D1 antagonist
Compound No. EC.sub.50 (nM) Emax % IC.sub.50 (.mu.M) Imax %
DC037030 -- -- 1.9 .+-. 0.4 86.8 .+-. 1.6 DC037079 -- -- 1.4 .+-.
0.2 94.2 .+-. 1.5 SKF38393 247.5 .+-. 26.1 100 -- -- SCH23390 -- --
0.74 .+-. 0.05 81.0 .+-. 2.7
INDUSTRIAL APPLICABILITY
[0237] Hexahydrodibenzo[a,g]quinolizine compounds of the invention
have relatively low toxicity and good solubility.
[0238] The preparation method for hexahydrodibenzo[a,g]quinolizine
compounds of the invention has many advantages, such as mild
reaction condition, abundant and readily-available raw materials
that can be easily found, simple operation and post-processing,
good selectivity, etc.
[0239] Hexahydrodibenzo[a,g]quinolizine compounds of the invention
have excellent selectivity among different subtypes of serotonin
receptors and dopamine receptors.
[0240] Therefore, the compounds of the invention can be used in
preparing medicaments for treating the diseases relating to nervous
system, especially to the dopamine receptors D.sub.1 and D.sub.2 as
well as serotonin receptors 5-HT.sub.1A and 5-HT.sub.2A.
* * * * *