Note: Descriptions are shown in the official language in which they were submitted.
-1- A}~P-8165
DIOXY OCTAHYDROBENZOCYCLOHEPTAPYRIDOISOQUINOLINE DERIYATIVES
Background of the Invention
This invention relates to dioxy derivatives of octahydrobenzocyclo-
heptapyridoisoquinolines, having two adjacent oxy substituents on the aromatic
portion thereof, to processes for preparing the derivatives, to pharmaceutical
compositions therefor, and to methods of using the derivatives.
S The dioxy derivutives of this invention possess valuable pharmaco-
logic properties. For example, the compounds exhibit useful antipsychotic
activity. More specifically, the dioxy derivatives are central nervous system
depressant agents and, thus, are usef~ as neurolep~c drugs. In addition, the
dioxy derivatives possess a low order OI toxicity. This combination of attributes
10 renders the dioxy derivatives useful and desirable as therapeutic agents for
treating schizophrenia
U.S. Patent 3,852,452, issued December 3,1974 and V.S. Patent
3,985,751, issued October 12,1976 disclose octahydrobenzocycloheptapyrido-
isoquinolines, which lack substituents on the aromatic portion thereof.
U.S. Patent 3,896,130, issued July 22,1975, discloses octahydro-
benzocycloheptapyridoisoquinoline derivatives with a variety of substituents
on the aromatic portion thereof; however, none of the substituents are adjacent
to another.
U.S. Patent 4,346,090, issued August 24,1982, discloses chloro
2 o substituted octahydrobenzocycloheptapyridinoisoquinolines.
The dioxy octahydrobenzocycloheptapyridoisoquinoline derivatives
of the present invention differ from the previously described octahydrobenzo-
cycloheptapyridoisoquinolines by having two adjacent oxy substituents on two
adjacent carbon atoms of the aromatic portion thereof.
Summary of the Invention
The dioxy octahydrobenzocycloheptapyridoisoquinoline derivatives
Of the present invention are represented by formula I
-2- AHP-8165
R3
Rl (I)
~ 41
M
in which L is hydroxy and M is l~drogen or lower alkyl, or L and M are both
10 hydrogen; Rl and R are independently lower aL~coxy or nydroxy and each of
R3, R4 and R is hydrogen with the proviso that when R2 is hydroxy then Rl
is hydroxy, or each of Rl, R4 and R5 is hydrogen and R2 and R3 are independentlylower alkoxy or hydroxy with the proviso that when R is hydroxy then R3
is hydroxy; or each of R, R and R is hydrogen and R and R5 are both lower
15 alkoxy or both hydroxy; or a therapeuffcally acceptable acid addition salt there-
of.
Preferred compounds of formula I are represented b~ formula I
in which L is hydroxy and M is hydrogen or lower aIkyl, or L and M are both
hydrogen; Rl and R2 are independently lower aL'coxy or hydroxy and each of
20 R3, R4 and R5 is hydrogen with the proviso that when R2 is hydroxy then Rl
is hydroxy; or each of R, R and R5 is hydrogen and R2 and R3 are independently
lower alkoxy or hydroxy with the proviso that when R is hydroxy then R
is hydroxy; or a therapeutically accepta~le acid addition salt thereof.
More preferred compounds of formula I are represented by formula
25 la
~ ~ R
r~ r ~l $r~
-3- AH P-816 5
in which L is a hydroxyl, which is trans to the hydrogen at position 13b and
M is lower alkyl, which is cis to the hydrogen at position 13b, or L is a hydroxyl,
which is cis to the hydrogen at position 13b and M is a hydrogen, which is transto the hydrogen at position 13b; or L and M are both hydrogen, and Rl and R2
are independently lower alkoxy or hydroxy with the proviso that when R2 is
5 hydroxy then Rl is hydroxy; or a therapeutically acceptable acid addition salt thereof.
The most preferred compounds of formula I are represented by
formula Ia in which L is a hydroxyl, which is trans to the hydrogen at position
13b and M is a lower alkyl, which is cis to the hydrogen at position 13b, and
10 Rl and R2 are independently lower alkoxy or hydroxy with the proviso that
when R2 is hydroxy then Rl is hydroxy; or a therapeuticalIy acceptable acid
addition salt thereof.
Included within the scope of this invention are the stereochemical
isomers of the compounds of formula I which result from asymmetric centers,
15 contained therein. These isomeric forms are purified readily by crystalliz-
ation or chromatography.
Individual optical isomers of the compounds of formula I, which
might be separated by fractional crystallization of the diastereoisomeric salts
formed thereof, for instance, with ~ or l-tartaric acid or D~+~c~-brom~
20 camphor sulfonic acid, are also included.
Another aspect of this invention involves a method of producing
neurolepffc effects in a mammal which comprises administering to said mammal
an effective neuroleptic amount of a compound of formtda I, or a therapeu-
tically acceptable acid addition salt thereof.
2~ Still an~ther aspect of this invention involves a pharmaceutical
composition comprising a compound of formula I, or a therapeutically acceptable
acid addition salt thereof, and a pharrnaceutically acceptable carrier.
Details of the Invention
Subsequent to the filing of the above-noted ~.S. Patent 3,852,452,
30 the stereochemistry of the compounds described therein as isomer A and isomerB have been assigned on the basis of mechanistic, spectral and X-ray crystal-
1 -~ f~ ?~
-4- AH P-816 5
lography considerations. Accordingly, in the present application a compound
of formula la of the present invention, in which the hydrogen at position 4a
is shown as '!a", corresponds in respect to configuration to the isomer A dis-
closed in the patent. Isomer B has simiIar stereochemistry except that the
hydrogen at p~sition 4a is "~".
Note that in U.S. Patent 3,852,482, and the other U.S. patents
recited in the introductory portion of this patent application, the nomenclatureused therein describes the pentacyclic ring system of the final products as
being a 1,4,5,6,6a,10,11,15b-octahydr~5H-benzo~6,7] cyclohepta[l,2,3-de~ pyri~
~2,1-a3 isoquinoli~e ring system, whereas in this patent application the identical
10 pentacyclic ring system is described in the currently more acceptable nomen-
clature as being a 2,3,4,4a,8,9,13b,14~ctahydro-lH-benzo~6,7] cycIohepta[1,~,3-
de] pyrido[2,1-a~ isoquinoline ring system.
The dioxy oct~hydrobenzocycloheptapyridoisoquinoline derivatives
of this invention are capable of forming acid addition salts with theraeputically
15 aceeptable acids. An acid addition salt can be prepared by reacting the base
forrn of a derivative with either one equivalent or preferably an excess of
an appropriate acid in an organic solvent, e.g. diethyl ether or an ethanol~iethyl
ether mixture. Such salts may advantageously be used for the purpose of iso-
lating and/or purifying the compounds of this invention and, if not therapeu-
20 tically acceptable acid addition salts, may be transformed in a manner knowninto the corresponding salts with therapeu~cally acceptable acids. The thera-
peutically acceptable acid addition salts, when administered to mammals,
exhibit the same pharmacologic actiYities as the corresponding bases. For
many purposes it is preferable to administer the salts rather than the base
25 compounds. Among the acid addition salts suitable for administration are
salts such as the sulfate, phosphate, lactate, tartrate, maleate, citrate Qnd
hydrochloride. Both the base compounds and the therapeutically acceptable
acid addition salts have the distinct advantage of possessing a relatively low
order of toxicity.
The term 'lower alkylL" as used herein means straight chain alkyl
radicals containing from one to six carbon atoms and branched chain aL~cyl
.
-5- AHP-8165
radical containing up to four carbon atoms and includes methyl, ethyl, propyl,
l-methylethyl, butyl, 2-methylpropyl and l,l-dimethylethyl. Preferred lower
alkyl radicals contain one to three carbon atoms.
The term 'qower aLkoxy" as used herein means a straight chain
alkoxy radical containing from one to six carbon atoms, preferably one to
5 three carbon atoms, or a branched chain alkoxy radical containing three or
four carbon atoms, and includes methoxy, ethoxy, l-methylethoxy, butoxy
and hexanoxy.
The term "complex borohydride" as used herein means the metal
borohydrides, including sodium borohydride, sodium cy~no~orohydride, potflssium
10 borohydride, lithium borohydride, lithium triethylborohydride, zinc borohydride
and the like, and metal trihydrocarbylborohydrides including lithium 9-aL~yl-
9-borobicyclo[3,3,1] nonylhydride, in which the aLcyl contains one to seven
carbon atoms, preferably lithium 9-tert-butyl-9-borobicyclo[3,3,1] nonylhydride. The term "reducible organosulfonate" as used herein means an
15 organosulfonate of an alcohol which can be reduced with a complex borohydride whereby the organosulfonyloxy group is replaced by a hydrogen atom.
The term"halo" as used herein means the halo radical selected
from bromo, chloro and iodo.
The term '~ydrohalic acid" as used herein means a commercially
20 available, concentrated solution of hydrogen chloride, hydrogen bromide or
hydrogen chloride in water.
The term '~ower alkanol" as used herein means both straight and
branched chain alkanols containing from one to four carbon atoms and includes
methanol, ethanol, l-methyleth~nol and butanol.
The useful neuroleptic activity of the dioxy derivatives of formulae
I and Ia and their acid addition salts with therapeutically acceptable acids
may be demonstrated in standard pharmacologic tests, such as, for example,
the tests commonly used for detecting neuroleptic activity described by A.
Randrup and L. Mwlkvad in "Amphetamines and Related Compounds", E. Costa
30 and S. Garattini, Eds., Raven Press, New York, N.Y., 1970, pages 695-713.
For example, in the test "d-Amphetamine-Induced Stereotyped
Behavior in Rats", a test described by K. Voith and F. Herr in Pharmacologia
-6- AHP-816 5
42,11(1375) for evaluating neurolepffc activity, the following dioxy derivPtiveswere effective in abolishing the amphetamine-induced sniffling, licking and
gnawing. The minimum effective dose (i.p.) expressed in mg/kg of body weight
is indicated in parentheses: (+)5,6-dimethoxy-(4a,13b-trans)-(3-hydroxy, 13b-
trans)-3-(1-methylethyl)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cyclohepta-~,2,3-de] pyrido~2,1-a] isoquinolin-3-ol hydrochloride (5.0 mg/kg), described
in example 8; (+)5,6-dimethoxy-(4a,13~trans)-(3-hydroxy,13~cis~2,3,4,4a,8,9,-
13b,14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-
3-ol hydrochloride (30 mg/kg), described in example 7; (+)6,7-dim~thoxy-(4a,13b-cis)-(3-hydroxy,13b-trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cyclohepta-
~,2,3-de] pyridoE2,1-a] isoquinolin-3-ol hydrochloride (20 mg/kg), described
in example 7; (+)6,7-dimethoxy-(4a,13b-trans)-(3-hydroxy,13~cis)-2,3,4,4a,8,9,-
13b,14-octahydro-lH-benzo[6,7] cyclohepta~,2,3-de] pyrido[2,1-a] isoquinolin-
3-ol hydrochloride (20 mg/kg~, described in example 7; (+)5,6-dimethoxy-(4a,13
trans)-2,3,4,4a,8,9,13b,14-octahydr~lH-benzo[6,7~ cyclohepta[l,2,3-de] pyrido-
[2,1-a] isoquinoline (20 mg/kg), described in example 8; (+)(4a,13b-trans)-(3-
hydroxy,l3b-trans)-3-(1-methylethyl~2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] -
cyclohepta~,2,3-de] pyrido[2,1-a] isoquinoline-3,5,6-triol hydrobromide (5.0
mg/kg), described in example 10; (+)(4a,13b-cis)-2,3,4,4a,8,9,13b,14-oct~Lhydro-lH-benzo[6,7] cyclohepta~,2,3-de] pyrido[2,1-a] isoquinoline-5,6-diol hydrochloride
20 (30 mg/kg), described in example 10; (+)6-methoxy-(4a,13~trans~(3-hvdroxy,13b-
trans)-3-(1-methylethyl~2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cyclohepta-
~,2,3-de] pyrido[2,1-a] isoquinoline-3,5-diol hydrochloride (0.16 mg/kg), described
in example 12; (+)6-metho~y~4a,13~trans~(3-hydroxy913b~is)-2,3,4,4a,8,9,13b,14-
octahydro-lH-benzo[6,7] cyclohepta~,2,3-de] pyrido[2,1-a~ isoquinoline-3,7-diol
25 hydrochloride (20 mg/kg), described in example 12; (+)6-methoxy-(4a,13b-trans~
(3-hydroxy,13b-cis~2,3,4,4a,8,9,13b,14-octahydro-lH-benzo~6,7] cycloheph-
~,2,3-de] pyrido[2,1-a] isoquinoline-3,5-diol (2.5 mg/kg), described in example
13; and (+)(4a,13b-trans~2,3,4,4a,8,9,13b,14-octahydro-lH-ben~o[6,7] cyclohepta-~,2,3-de] pyrido[2,1-a~ isoquinoline-5,6-diol hydrobromide (2.5 mg/kg), described
30 in example 14.
When the dioxy derivatives of this invention are used as neuroleptic
agents in mammals, e.g. rats and mice, they are used alone or in combination
~7~ AH P-816 5
with pharmacologically acceptable carriers, the proportion of which is àetermined
by the solubility and chemical nature of the compound, chosen route of adminis-
tration and standard biological practice. For example, they may be administered
orally, or parenterally by injection.
For administration to a mammal by parenteral injection, it is pre-
5 ferred to use the compounds of formula I in solution in a ste~ile aqueous vehiclewhich may also contain other solutes such as buffers or preservatives, as well
as sufficient quantities of pharmaceutically acceptable salts or of glucose
to make the solution isotonic.
When the compounds of this invention are employed orally as neuro-
10 leptic agents in mammals, orally effective, neurolepffc amounts of the compoundsare administered to the mammal, either alone or combined with pharmaceutically
acceptable excipients in a dosage form, i.e. capsule or tQblet, or the compoundsare administered orally in the form of solutions or suspensions.
The tablet compositions contain the active ingredient in admixture
15 with non-toxic pharmaceutical excipients known to be suitable in the manu-
facture of tablets. Suitable pharmaceutical excipients are, for example, starch,milk, sugar, certain types of clay and so forth. The tablets may be uncoated
or they may be coated by known techniques so as to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a sustained action
20 over a longer period.
The aqueous suspensions of the invention contain the active ingred-
ie~t in admixture with one or more nontoxic pharmaceutical excipients known
to be suitable in the manufacture of aqueous suspensions. Suitable excipients
are, for example, methylcellulose, sodium alginate, gum acacia~ lecithin and
25 so forth. The aqueous suspensions may slso contain one or more preservatives,one or more coloring agents, one or more flavoring agents and one or more
sweetening agents.
Non-aqueous suspensions may be formulated by suspending the
active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame
30 oil, or coconut oil, or in a mineral oil, for example liquid paraffin, and the
suspension may contain a thickening agent, for example beeswax, hard paraffin
r~
-8- AHP-8165
or cetyl alcohol. These compositions may also contain a sweetening agent,
a flavoring agent and an anti-oxidant.
The dosage of the present therapeutic agents will vary with the
form of administration and the particular compound chosen. Furthermore,
it will vary with the particular host under treatment. Genera~ly, treatment
5 is initiated with small dosages substantially less than the optimum dose of
the compound. Thereafter, the dosage is increased by smaLI increments until
the optimum effect under the circumstances is reached. In general9 the com-
pounds of this invention are most desirably administered for neuroleptic pu~
poses at a concentration level- that will generally afford effective results without
10 causing sny harmful or deIeterious side effects, for example, catalepsy, and
preferably at a level that is in a range of from about 0.01 mg to about lO0 mg
per kilogram of body weight per day, although as aforementioned variations
will occur. However, a dosage level that is in the range of from about 0.1
mg to about lO mg per kilogram of body weight per day is most desirably employed15 in order to achieve effective results.
Process
A starting materi~l for preparing the dioxy derivatives of this in-
vention is the aminoketone of formula II
R3
20 R4 ~ ~ ~, R ~II)
O
in which two of the R groups (appropriately selected from Rl to RS, inclusively)represent two adjacent lower aL~coxy groups at positions S and 6, at positions
6 and 7, or at positions 11 and 12 of the compound's pentacyclic nucleus, and
30 each of the remaining three R groups is hydrogen. In other words, Rl and R2
are both lower alkoxy and each of R3, R4 and R5 is hydrogen, or each of Rl,
-9- AHP-8165
R4 and R5 is hydrogen and R2 and R3 are bo~h lower alkoxy, or each of Rl,
R2 and R3 is hydrogen and R4 and R5 are both iower aLkoxy. Using appro-
pr.ately substituted di(lower)alkoxydibenzo[a,d] cyclohepten-5-one derivatives,
the process described for the preparation of 2,3,4,4a,8,9,13b,14-octahydro-lH-
benzo-lH-benzo[6,7~ cycloheptaLl,2,3-de] pyrido[2,1-a] isoquinolin-3-one (i.e.
the compound which is represented by formula II in which Rl to R5, inclusively,
are hydrogen), described by F.T. Bruderlein and L.G. Humber, U.S. Patent
3,985,7519 issued October 12,1976, can be used to prepare the arninoketones
of formula II having two adjacent lower allcoxy groups at positions 5 ~d 6,
or at positions 6 and 7. This process gives fl mixture of cis and trans isomers,resulting from the two possible configurations of the hydrogen atom at position
4a; namely, the hydrogen atom at position 4a may be either cis or trans to
the hydrogen atom at position 13b. The two isomers can be separated by chroma-
tography.
The aminoketones of formula II having two adjacent lower aLkoxy
groups at positions 11 and 12 (R and R = lower alkoxy) can be prepared by
using a modification of the Bruderlein and Humber process. In this instance~
a 10,11-di(lower)alkoxy-9,12-dichloro-1,7,8,13b-tetrahydroben~o[6,7] cyclohepta-[1,2,3-del isoquinoline is condensed with 1-buten-3-one to obtain a 11,12-di(lower)-
alkoxy-10,13-dichloro-(4a,13b-trans)-2,3,4,4a,8,9,13,14-octahydro-lH-benzo[6,7] -
cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-3-one. (~ote: The trans isomer
is the preponderant product formed.) The two chlorine atoms of the latter
compound do not lend themselves to facile elimination to give directly the
corresponding aminoketone of formula II in which R4 and R5 are lower alkoxy;
however, by reducing the said latter compound (i.e. 11,12-di(lower)alkoxy-10,13-25 dichloro-(4a,13~trans)-2,3,4,4a,8,9 ,13,14-octahydro-lH-benzo[6,7] cyclohepta-
[1,2,3-de] pyrido[2,1-a] isoquinolin-3-one) with sodium borohydride, the corres-ponding dichloropentacyclic alcohol is obtained. Transformation of the latter
compound according to the reactions illustrated in scheme 1, below, yields
the desired aminoketone of formula II in which both of R4 and R5 are lower
30 alkoxy and each of Rl, R2 and R3 is hydrogen.
-10- AHP-~165
SC H lEM E 1
R~ R ~
OH OH
'H
III~1 IV=I~wherein Rl,R2 and R3- H)
\ ~ '~" ~
II (4a,13b-cis) II C4a,13b-trans)
More specifically, with reference to scheme 1, the dichloro penta-
cyclic alcohol of formula III is subjected to the action of sodium in liquid ammonia
whereby the two chlorine atoms are removed and, surprisingly, the 4a,13~trans
ring system of pentacyclic alcohol lII is transformed (epimerized) to give the
25 4a,13~cis pentacyclic alcohol IV. This alcohol is a compound of formula I
of the invention. Oxidation of the latter alcohol gives the corresponding amino-ketone of formula II in which R4 and R5 are both lower alkoxy of the 4a,13b-
cis series. Treatment of the latter compound with a strong mineral acid, for
example hydrochloric acid, effects the epimerization of the latter compound
30 into the corresponding aminoketone of formul~ II of the 4a,13b-trans series.
The aminoketone of formula II in which the R groups are as defined
above can be converted to the compounds of formula I by:
AHP-8165
(a) reacting the aminoketone of formula II with a reagent of
formula M-X in which M is lower alkyl and X is Mg-(halo) or Li to obtain the
corresponding compound of formula I in which L is hydroxy, M is lower f~lkyl
and Rl to R5, inclusively, represents two adjacent lower a~oxys and three
hydrogens as defined hereinabove; or
(b) reducing the aminoketone of formula II with Q complex boro-
hydride to obtain the corresponding compound of formula I in which L is hydroxy
and M is hydrogen, and Rl to R5, inclusively, represent two adjacent lower
alkoxys and three hydrogens as defined hereinabove; or
(c) transforming the aminoketone of formula II to a compound
of formula I in which L and M are both hydrogen and Rl to R5, inclusively,
represent two adjacent lower aL'coxys and three hydrogens as defined hereinaboveby subjecffng the compound of formula II to the Wolff-Kishner reduction; or
by forming a corresponding reducible organosulfonate of the hydroxyl of the
compound of formula Iin which L is hydroxy, M is hydrogen and R1 to R5,
inclusively, represent two adjacent lower alkoxy groups and three hydrogens
as defined herein, and reducing the resulting organosulfonyl derivative with
lithium triethylborohydride or lithium aluminum hydride; or
(d) reacffng the compound of formula I in which L is hydroxy
and M is hydrogen or lower aLkyl, or L and M are both hydrogen, and Rl to
20 R, inclusively, represent two adjacent lower aLkoxys and three hydrogens
as defined hereinabove, with boron tribromide or a hydrohalic acid to obtain
the corresponding compound of formula I in which L is hydroxy and M is hydrogen
or lower alkyl, or 1. and M are both hydrogen, and two of the R groups, appro-
priately selected from Rl to R5, inclusively, represent two ad~acent hydroxys
25 at positions 5 and 6, at positions 6 or 7, or at positions 11 and 12 of the compound's
pentacylic nucleus and each of the remaining three R groups is hydrogen; or
(e) selectively deaLkylating the compound of formula I in which
L is hydroxy and M is hydrogen or lower alkyl, or L and M are both hydrogen;
Rl and R2 ere both lower alkoxy and each of R3, R4 and R5 is hydrogen, or
30 each of Rl, R4 ~nd R5 is hydrogen and R2 and R3 are both lower alkoxy, with
concentrated hydriodic acid at 0 to 30 C, with concentrated hydrochloric
acid at 90 to 109 C, or with methanesulfonic acid in the presence of methionine,
-12- AHP-8165
to obtain the corresponding compound of formula I in which L is hydrox~T and
M is hydrogen or lower alkyl, or L and M are both hydrogen; and Rl is hydroxy,
R2 is lower alkoxy and each of R3, R4 and R5 is hydrogen, or each of Rl, R4
and R5 is hydrogen, R2 is lower aLkoxy and R3 is hydroxy.
.~ preferred starting material for the processes described in the
above sections (a), (b) and (c), followed optionally by the processes described
in section (d) or (e) is the aminoketone of formula Ila
~ IIa)
N ~H
~0
in which Rl and R2 are independently lower alkoxy.
More specifically, with reference to section (a) of the above process
for preparing the compound of formula I, the compounds of formula I in which
L is hydroxy, M is lower alkyl and Rl to R represent two adjacent lower al`koxysand three hydrogens as defined herein, are obtained by reacting the aminoketone
of formula Il with an appropriate Grignard reagent of formula M-X in which
20 M is lower alkyl and X is Mg-(halo) in an inert solvent, for example, diethylether or tetrahydrofuran, according to the conditions of the Grignard reaction.
In this manner, the corresponding compound of formula I in which L is hydroxy
and M is lower all<yl is obtained. Suitable reaction times and temperatures
range from 15 minutes to twenty four hours and from -40 to 90 C., respectively.
Alternatively, the aminoketone of formula Il is reacted with an
appropriate organolithium reagent of M-X in which M is lower alkyl and X
is Li under the same conditions as described for the Grignard reaction.
With reference to section (b), the compounds of formula I in which
L is hydroxy, M is hydrogen, and R to R represent two adjacent lower alkoxys
30 and three hydrogens as defined herein, are obtained by reducing the amino-
-13- AHP-8165
ketone of formula II with a molar excess of a complex borohydride, for example
sodium borohydride or cyanoborohydride, in an inert solvent. Suitable inert
solvents include tetrahydrQfuran, or lower alkanols, preferably methanol, ethanol
or 2-propanol. An inert solvent consisting of a mixture of methanol or ethanol
with a small amount of added chloroform (0.5 to 5%, V/V)7 to increase the
5 solubility characteristics of the solvent, has been found to be practical and
advantageous for performing the reduction. The reduction usually is performed
at temperatures ran~ing from 0 C to the boiling point of the reaction mixture
for 30 minutes to three hours. When sodium cyanoborohydride is used, the
reduction is preferably performed at or near a pH of 4, for example in the
10 presence of acetic acid. The preferred complex borohydride is sodium boro-
hydride. This reduction affords mair.ly the corresponding compound of formula
I wherein the hydroxyl at position 3 is cis to the hydrogen at position 13b.
With reference to section (c), the compounds of formula I in which
L and M are both hydrogen, and Rl to R5 represent two adjacent lower alkoxys
15 and three hydrogens as defined herein, can be ob ained by subjecting the a~
propriate aminoketone of formula II to the Wolff-Kishner reduction. A modi-
fication of the Wolff-Kishner process has been found to be very effective and
convenient. In this instance, the aminoketone was reacted with ~toluene-
sulfonylhydrazide in acidic dimethylformamide-sulfolane (1:1, v/v) and the
20 ~esulting hydrazone was reduced with sodium cyanoborohydride, see R.O. Hutchins
et al., J. Amer. Chem. Soc., 93,1793 (1971). Note, however, when the (4a,13b-
trans) isomer of the aminoketone of formula II was used in this modification,
partial epimerization took place during the reduction giving a mixture of 4a,13b-
cis) and (4a,13b-trans) products. Such an epimerization was not noted for the
2 5 (4a,13b-cis) isomer.
Alternatively, the arninoketone of formula II is transformed to
desired compounds of formula I in which L and M are both hydrogen by a two
step process involving a reducible organosulfonate. More explicitly, the amino-
ketone first is reduced with a complex borohydride, see above; the resulting
30 corresponding alcohol ta compound of formula I in which L is hydroxy) is con-verted into a reducible organosulfonyl derivative, preferably the corresponding
-14- AH P-816 5
mesylate or tosylate, which is reduced with lithium triethylborohydride or
lithium aluminum hydride to give the desired compound of formula I. Methsne-
sulfonyl chloride and p-toluenesulfonyl chloride9 in the presence of triethylamine,
are convenient reagents for preparing the mesyl and tosyl derivatives, res-
pectively; and lithium triethylborohydride is the preferred reagent for reducing5 the derivatives.
With reference to section (d), the compounds of formula I in which
L is hydroxy and M is hydrogen or lower aLkyl, or L and M are both hydrogen,
and the R groups, Rl to R5 inclusi~ely, represent two adjacent hydroxys at
positions 5 and 6, at positions 6 and 7, or at positions ll and 12 of the compounds
lO pentacylic nucleus for twc of the R groups and the remaining R groups are
hydrogen, are obtained by deal~cylating the correspond;ng dialkoxy cornpounds
of formula I. The dealkylation can be performed in a concentrated hydrohalic
acid, preferably concentrated hydrochloric acid (33 to 38% by weight/volume
of hydrogen chloride in water), concentrated hydrobromic acid (40 to 50%
15 by weight/volume of hydrogen bromide in water) or preferably by concentrated
hydriodic acid (47 to 57% by weight/volume of hydrogen iodide in water).
The time and temperature ranges for this reaction are variable and depend
on the nature of the starting material and the hydrohalic acid employed. The
reaction is usually performed at 80 C to the boiling point of the reaction
20 mixture and the course of the reacffon is monitored by subjecting aliquots
of the reaction mixture to thin layer chromatography to determine the required
reaction time for completion of the reaction. Under such circumstances, for
example, a reacffon time of one to three hours generslly is required to effect
dealkylation when 47-5796 (w/v) hydriodic acid is employed at reaction temper-
25 atures ranging from 110 to 127 C. Preferably, the dealkylation is done by re-
acting the corresponding diaLcoxy compound of formula I with an effective
amount of boron tribromide, usually two to ten molar equivalents, at -20 to
20 C for 30 minutes to three hours in an inert solvent, for example, chloroformor methylene dichloride. Thereafter, the reaction mixture is cooled to about
-40 C to 0 C and excess boron tribromide E; decomposed and the orthobroic
ester of the product is hydrolyzed with 8 iowér alkanol, preferably methanol
or ethanol. The desired compound of formula I can be isolated thereafter
~ i~ f .~ r~
-lS- AH P-816 5
by precipitating the compound from solution with a non-polar solvent, for
instance diethyl ether or hexane.
~ Vith reference to section (e), the compounds of formula I in which
L is hydroxy and M is hydrogen or lower allcyl, or L and M are both hydrogen7
and Rl is hydroxy, R is lower aLkoxy and each o R3, R4 and R5 is hydrogen~
5 or each of Rl, R4 flnd R5 is hydrogen, R2 is lower alkoxy and R3 is hydroxy,
are obtained by selectively dealkylating the corresponding dialkoxy compound
of formula I in which L is hy~roxy and M is lower alkyl or L and M are both
hydrogen, and Rl and R2 are both lower alko~y and each of R3, R4 and R5
is hydrogen, or each of Rl, R4 and R5 is hydrogen and R2 and R3 are both
10 lower alkoxy. This selective dealkylation generally can be performed by reacting
the diaL~07y compound of formula I with concentrated hydriodic acid at 0
to 30 C for one t~ three weeks, or with concentrated hydrochloric acid at
gO to 109 C for about 10 to 24 hours. In such instances, the course of the re-
action is followed by tl.in layer chromatography techniques and is stopped
lS when only a trace of starting material remains in the reaction mixture and
a small amount of the corresponding completely dealkylated derivative begins
to form. The preferential dealkylation, however, can be performed best by
subjecting the dialkoxy compound of formula I to the action of the methane-
sulfonic acid in the presence of methionine according to the method described
20 by F. Nobutaka, I. Hiroshi and Y. Haruaki, J. Chem. Soc., Perkin 1, 2288 (1977).
This latter reaction is best performed at 20 to 25 C for one to three days
using an excess of methanesulfonic acid as the solvent.
Finally, an alternative preparation of compound of formula IR in
which L and M are both hydrogen, Rl and R2 are both hydroxy and each of
25 R3, R4 and R is hydrogen, or each of Rl, R4 and R5 is hydrogen and R2 and
R are both hydroxy, is realized in a multistep process using the appropriate
4,5- or 5,6-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7~ cyclohepta~l,2,3-de] iso-
quinoline as the starting materi~l according to the process depicted in scheme
2.
-16- AHP-8165
~SC EIEM E 2
~{OCH3
1) ~CH2Br H
N ~ 2) ~-0- (CH2j 4-~lgBr ~ H pdlC
~-0
(VI)
l)BBI;~OH
N ~ 2) EtOH N
/ H
~~ Br
(YI I~
Ia (L and M-H, R1 and R2=OH and R3, R4 and R5-H or
R, R and R5-H and R2 and R3-oH)
More explicitly, the starting material of formula Y is reacted with
benzyl bromide and the resulting isoquinolinium salt is reacted with phenoxy-
25 butyl magnesium bromide in the usu~l way to afford the phenoxybutyl derivativeof formula VI. Upon catalytic hydrogenation with palladium on charcoal, the
protecting benzyl group on the nitrogen of the latter compound is removed
and the secondary amine of formula VII is obtained. Subsequent treatment
of the secondary amine of formula VII with boron tribromide in the usual manner
30 effected, in a single step, the cleavage of the three ether bonds present in
the molecule, i.e. the cleavage of the methoxy groups and the cleavage of
-17- AHP-8165
the phenoxy blocking group, to give the hydrobromide of formula YIlI. Fin~lly,
heating of the hydrobromide in 2-ethoxyethanol at 130 C or diglyme at 140 C
giv~s the desired compound of formula I.
The following examples illustrate further this invention.
EXAMPLE 1
1,4-Dichloro-2,3-dimethoxy-10,1l-dihydro-5H-diben~o[a,d] cyclohepten-5-one
A solution of 2,3-dimethoxy-10,11-dihydro-5H-clibenzo[a,d} cyclohepten-
5-one (491 g, 1.85 mol), described by S.O. Winthrop et al., J. Org. Chem., 27,
230 (1962), and N-chlorosuccinimide (550 g, 4.1 mol) in acetic acid (3.5L) was
heated at reflux for 3.5 hr and then cooled to 55C. Water (3.5L) was added
dropwise and the mixture was stirred at 20-22 C ~room temperature) for 20
hr. The resulting precipitate was collected, washed with acetic acid-water
(1:1, v/v) and then water, and dried at 50 C for 48 hr to give a yellow-brown
solid (542 g). The solid was dissolved in chloroform. The solution was treated
with charcoal, filtered and concentrated whereupon a solid precipitate resulted.The precipitate was collected and crystallized from chloroform and then from
hexane to give the title compound as a pale yellow solid, mp 158-156 C. An
additional 119 g of the title compound was obtained by concentrating the mother
liquors to dryness, clissolving the resldue in benzene, passing the benzene solution
of the residue through silica gel, concentrating the eluate to dryness, triturating
the res~ting solid with hexane, and collecting the solid by filtration.
EXAMPLE 2
N-Formyl-(2,3~dimethoxy-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-yl)methyl-
amine
A 250 mL thre~necked flask was charged under nitrogen with
magnesium (9.6 g~ 0.4 mol), mercuric chloride (0.4 g) and dry tetrahydrofur~n
(70 mL). The mixture was cooled to -10 C to -20 C and a solution of freshly
distilled chloromethyl ethyl ether (37.6 ml, 0.4 mol) in dry tetrahydrofuran
(70 mL) was added dropwise within 0.5 hr at -15 C. The mixture was stirred
at that temperature for 5 hr, and then cooled to -40 C. The cooled solution
was removed by a syringe and added to a stirred suspension of 2,3-dirnethoxy-
10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-one (53.6 g, 0.2 mol) in tetrahydro-furan (300 mL) at -10 C. The reaction mixture was stirred at that temperature
eS ~
-18- AHP-8165
for one hour during which the suspension turned into a clear green~sh solution.
The solution was allowed to warm up to 20-2~ C over 18 hr and then poured
onto ice and water containing ammonium chloride (22 g). The solution was
saturated with sodium chloride and extracted with diethyl ether. The organic
layer was washed with sodium chloride solution, dr;ed, and evaporated to give
5 a yellow oil. Crystallization of the oil from pentane gave 5-(ethoxymethyl)-
2,3-dimethoxy-10,11-dihydro-5H-dibenzo[a,d] cyciohepten-5-ol as a pale yellow
solid (59 g) of sufficient purity for the next step. A pure sample of the lattercompound, prepared by two additional crystallizations of the pale yellow solid
from chloroform-hexane, had mp 98-100 C and I~ (CHC13) 3520, 2840, 1255,
l O 1110 c m~l.
The latter compound (58 g9 018 mol) was dissolved in formic acid
(110 mL, 98%). The solution was kept at 20-22 C for 2.5 hr and then heated
at steam bath temperature for 3 hr. The solution was then poured into ice
water. The resulting precipitate was collected, washed with water and dried
15 to give 2,3-dimethoxy-10,11-dihydro-5~-dibenzo[a,d] cycloheptene-5-carbox-
aldehyde, as an off-white solid (36 g) of sufficient purity for the next step.
A pure sample of the latter compound prepared by crystallization from chloro-
form and hexane, had mp 130-132 C and IR ~CHC13) 2830,1718,1255,1112 cm 1.
The latter compound (35 g, 0.125 mol) was suspended in a mixture
20 of hydroxylamine hydrochloride (15.8 g, 0.22 mol) in ethanol (170 mL) and water
(50 mL). The suspension was cooled in an ice bath. Powdered sodium hydroxide
(31.6 g, 0.8 mol) was added to the suspension. Thereafter, the suspension was
stirred vigorously at 20-22 C for 3 hr. Water (500 mL) was added and the
mixture was stirred for an additional 18 hr. The mixture was concentrated
25 to one-half its volume. The resulting precipitate was collected, dissolved
in water and the solution rendered acidic by the dropwise addition of acetic
acid (60 ml). The precipitate was collected to give 2,3-dimethoxy-10,11-di-
hydro-5~I-dibenzo[a,d] cyclohepten-5-aldoxime as a pale yellow solid (33.4
g) of sufficient purity for the next step. A pure sample of the latter compound,30 prepared by two additional recrystallizations from chloroform-hexane (with
charcoal treatment), had mp 176-177 C and IR (CHC13) 3570, 3310, 2830, 1265,
1118 cm .
~ ,r~ b? ~
-l9- AH P-816 5
Raney nickel alloy (42 g) was added in one portion to a well-stirred
mixture of the latter oxime (28 g, 0.094 mol) in ethanol (560 mL) and 2N aqueoussodium ~ydroxide (560 mL~. The mixture was filtered after 2 hr. The filtrate
was evaporated under reduced pressure and the residue was diluted with water.
The aqueous mixture was extracted with diethyl ether. The organic extract
5 was washed with water, dried (MgSO4) and filtered. A saturated solution of
hydrogen chloride in diethyl ether was added dropwise to the filtrate. The
precipitate was collected, washed with diethyl ether and dried to give (2,3-
dimethoxy-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-yl)methylamine hydr~
chloride (27.5 g). A pure sample of the hydrochloride, prepared by recrystal-
1() lization from methanol-diethyl ether, had mp 272-275 C and IR (white mineral
oil) 2900,1250,1100 cm~l.
The hydrochloride was converted quantitatively to its free base
by mixing the hydrochloride with 5% aqueous sodium hydroxide, extracting
the mixture with diethyl ether and concentrating the extract. The free base
15 had mp 82-85 C and, because it formed a carbonate saIt when exposed to
the atmosphere, it was kept under nitrogen.
Formic anhydride was prepared by heating formic acid (98%,1.13 mL)
with acetic anyhdride (2.9 mL) at 50-60~ C for 2 hr. The reaction mixture,
containing formic anhydride, was cooled to 20-22 C and a solution of the
20 above designated free base (4.42 g, 0.0155 mol) in dry tetrahydrofuran (30 mL)
was added dropwise to the reaction mixture while maintaining the temperature
below 40 C. Stirring was continued for 2 hr. The mixture was poured into
ice-water. The precipitate was collected and washed with water to give the
title compound (4.5 g). A pure sample of the title compound, obtained by two
25 crystallizations from chloroform-hexane, had mp 118-119 C and IR (CHC13)
3440, 3350,1685 cm~l.
By following the procedure of this example but replacing 2,3-di-
methoxy-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-one with an equivalent
amount of 1,4-dichlor~293-dimethoxy-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-
30 5-one, described in example 1, N-formyl-(1,4-dichloro-2~3-dimethoxy-10,11-di-hydro-5H-dibenzo~a,d] cyclohepten-5-yl)methylamine, mp 115-118 C and IR
(CHC13) 3430,1678 cm 1, was obtained.
;t ~.t~ r'~
-20- AHP-8165
EXAMPLE 3
4,5-Dimethoxy-1~7,8,12b-tetrahydrobenzo~6,7~ cyclohepta[l,2,3-de] isoquinoline
and 5,6-dimethoxy-1,7,8~12b-tetrahydrobenzo~6,7] cyclohepta[1,2,3-de] isoquin-
oline
A mixture of N-formyl-(2,3-dimethoxy-10,11-dihydro-5H-dibenzo-
[a,d] cyclohepten-5-yi)methylamine (23 g), described in example 2, and poly-
5 phosphate ester (459 g), prepared by the procedure described by L.F. Fieser
and M. Fieser in '~eagents for Organic Synthesis, John Wiley and Sons, Inc.,
New York, N.Y., ll.S.A. 1967~ p 892, in chloroform (225 mL) was stirred under
nitrogen at 20-22 C for 48 hr. The reaction mixture was poured onto ice.
The resulting mixture was rendered acidic with 10% aqueous hydrochloric acid,
lO washed with ethyl acetate, rendered basic with cooled concentrated ammonium
hydroxide and extracted with ethyl acetate. The latter extract was washed
with water, dried (MgS04) and evaporated to dryness to give a yellow oil (18.5 g).
The oil was subjected to chromatography on silica gel. Elution with acetone-
benzene (1:9, v/v) first gave 5,6-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7] cyclo-
15 hepta[l,2,3-de] isoquinoline (1.2 g), mp 166-167 C (after recrystallization from
a mixture of ethyl acetate, benzene and hexane ), and NMR (CDC13) ~ 3.8S
and 3.83 (2s, 6H), 6.85 (s, lH), 7.0-7.5 (m, 4H), 8.58 (s, lH). Continued elution
with the same eluant gave 4,5-dimethoxy-1,7,8,12~tetrahydrobenzo[6,7] cycl~
hepta[l,2,3-de] lsoquinollne (8.8 g), mp 131-132 C (after recrystallization from
20 a mixture of ethyl acetate, benzene and hexane), NMR (CDC13) ~ 3.82 (s,
6H), 6.70 (s, lH), 7.0-7.5 (m, 4H), 813 (s, lH), and IR (CHC13~ 1640 cm 1.
By following the procedure of this example but replacing N-formyl-
(2,3-dimethoxy-10,11-dihydro-SH-dibenzo[a,d] cyclohepten-5-yl)methylamine
with an equivalent amount of N-formyl~ 4-dichloro-2~3-dimethoxy-lo~ll-di
25 hydro-5H-dibenzo[a,d] cyclohepten-5-yl)methylamine, and using chloroform
as the eluant, 9,12-dichloro-10,11-dimethoxy-1,7,8,12~tetrahydrobenzo[6,7]-
cycloheptal,2,3-de] isoquinoline, mp 149-151 C (after recrystallization from
diethyl ether-hexane), NMR (CDC13) ~ 3.85 (s, 6H), 4.90 (doublet of doublets,
J - 5Hz and 14 cps, lH), 7.12 (s, 3H), 8.35 (s, lH), and IR (CHC13) 1625 cm 1,
30 was obtained. The hydrochloride of the latter compound has mp 230~ C.
-21- AHP-8165
EXAMPLE 4
(+)5,6-Dimethoxy-(4a,13~cis)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cyclo-
hepta[l,2,3-de3 pyrido[2,1-a] isoquinolin-3-one and
(+)5,6-Dimetho~y-(4a,13b-trans)-2,3,4,4a, 8,9,13b,14-octahydro-lH-benzo[6,7] -
cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-3-one
Freshly distilled l-buten-3-one (4.8 g, 0.69 mol, stablized with hydro-
quinone) was added to a suspension of the Schiff base, 4,5-dimethoxy-1,7,8,12b-
tetrahydrobenzo[6,7] cyclohepta[l,2,3-de] isoquinoline in the form of its
hydrochloride salt, in toluene (140 mL) and dry dimethylformamide (40 mL).
(The hydrochloride salt was prepared in situ by adding a saturated solution
of hydrogen chloride in diethyl ether to 12.0 g, 0.004 mole of the Schiff bsse,
10 described in ex~mple 3, and removing the excess solution of hydrochloride
by flash evaporation.) The mixture was heated at 105 C for 1.5 hr. The re-
sulting solid was collected and partitioned between chloroform and 5% aqueous
sodium bicarbonate solution. The aqueous phase was separated and was extracted
twice more with chloroform. The organic extracts were combined, dried and
15 concentrated. The second mentioned title compound (7.3 g) crystallized upon
the addition of diethyl ether. The mother liquors were subjected to chromato-
graphy on silica gel, using acetone-chloroform (1:19, v/v) as the eluant, to afford
serially the less polar, first mentioned title compound (0.27 g, after recrystal-
lization from chloroform-diethyl ether) and an additional amount (3.2 g) of
20 the second mentioned title compound.
The first mentioned title compound had mp 158-159 C, NMR (CDCl )
3.75 (s, 3H), 4.53(d, lH), 6.5 (s, lH), 7.1-7.8 (m, 4H), and lR (CHC13) 1715 cm ~.
The second mentioned title compound had mp 196-199 C, NMR
(CDC13) ~; 3.75 ~ 3.77 (2s, 6H), 4.8 (t, lH), 6.48 (s, lM), ~ .7 (m, 4H).
By following the procedure of this example, but using 5,6-dimethoxy-
1,7,8,12b-tetrahydrobenzo[6,7] cyclohepta[l,2,3-de] isoquinolin~, described in
example 3, as the Schiff base, (+)6,7-dimethoxy-(4a,13b-cis)-2,3,4,4a,8,9,13b,14-
octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-3-one;
mp 195-198~ C (recrystallized from chloroform-diethyl ether), NMR (CDC13)
~ 2.1-3.6(m, 12H), 3.62 (s, 6H), 4.3 (m, 2H), 6.4 (s, H), 6.85 (m, 3H), 7.3 (m,
-22- AHP-8165
lH); and (+~6,7-dimethoxy-(4a,13b-trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo-[6,7] cyclohepta[l92,3-de] pyrido~2,1-a] isoquinolin-3-one; mp 134-136 C (recry-
stallized from chloroform-hexare); NMR (CDC13) ~ 2.0-3.85 (m, 13H), 3.65
(s, 6H), 4.3 (t, J = 3.5Hz, lH), 6.45 ~s, H~, 6.85 (m, 3H), 7.35 (m, lH~, were obtained.
By following the procedure of this example, but using 9,12-dichloro-
10,11-dimethoxy-1,7,8,12~tetrahydrobenzo[6,7] cyclohepta[l,2,3-de~ isoquinoline,described in example 3, as the Schiff base, (+)10,13-dichloro-11,12-dimethoxy-
(4a,13b-trans)-2,3,4,4a,8,9,13,14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de] -pyrido[2,1-a] isoquinolin-3-one; mp 162-165 C (recrystallized from diethyl ether-
hexane); NMR (CDC13) ~ 3.84 (s, 6H), 4.91 (t, J = 9Hz, lH), 6.98 (M, 3H), was
obtained.
EXAMPLE_5
( ~ )11,12-Dim ethoxy-(4a,13b-trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] -
cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-3-one
Sodium borohydride (2.5 g, 0.06 mol) was added portionwise over
a period of 0.5 hr to a solution of (+)10,13-dichloro-11,12-dimethoxy-(4a,13~trans)-
2,3,4,4a,8,9,13b,]4-octahydro-lH-benzo[6,7] cyclohepta~l,2,3-de] pyrido[2,1-a] -isoquinolin-3-one ~3.0 g, 0.07 mol, described in example 4) in chloroform (3 mL)and methanol (50 mL) at 0 C. After the addition, the reaction mixture was
stirred at 0 C for 1.5 hr. Water (200 mL) was added. The precipitate was
collected, washed with water, and dissolved in chloroform. The chloroform
solution was dried (MgSO4) and then evaporated to dryness to afford (+)10,13-
dichloro-11,12-dimethoxy-(4a,13b-trans)-(3-hydroxy,13b-cis)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-3-ol as
a white solid (2.85 g) of sufficient purity for the next step. A sample of the
25 latter compound, crystallized from benzene-hexane, had mp 182-184 C and
NMR (Cr)C13) ~ 3.78 (s, 6H), 4.85 (doublet of doublet, lH), 6.9 (m, 3H).
A solution of the latter compound (2.85 g, 6.5 mmol) in dry tetra-
hydrofuran (30 mL) was added dropwise to boiling liquid ammonia over a period
of 10 min. To the resulting suspension, sodium metal (1.5 g, 0.065 mol~ was
30 added over a period of 20 min. The reaction mixture was stirred for 30 min.
The ammonia was evaporated under nitrogen. Water was added to the residue.
23- AHP-8165
The precipitate was collected, washed with water, dried and dissolved in chloro-form. The chloroform solution was filtered through a column of silica gel.
Evaporation of the eluate gave (+)11,12-dimethoxy-(4a,13b-cis)-(3-hydroxy,13b-
trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo~6,73 cyclohepta[l,2,3 de] pyrido-
[2,1-a] isoquinolin-3-ol as a pale yellow compound (1.85 g), mp 212-215 C, and
NMR (CDC13) ~ 3.65 and 3.70 (2s, 6H), 4.3 (d, lH), 6.32 (s, lH), 6.75 (m, 3H),
7.0 (s, lH). The hydrochloride of the latter free base had mp 264 C (dec) aftercrystallization from methanol.
A solution of triethylamine-sulfur trioxide complex (1.0 g) in di-
methyl sulfoxide (5 mL) was added dropwise to a cooled (150 C) solution of
10 the latter free base (0.41 g, 1.1 mmol) in dimethyl sulfoxide (5 mL) and triethyl-
amine (1.6 mL). The reaction mixture is stirred vigorously for 1.5 hr. The
addition of cold water to the reaction mixture gave a precipitate. The pre-
cipitate was collected, washed with water, dried~ and then subjected to puri-
fication by chromatography on silica gel using benzene as the eluant. The
15 appropriate fractions were combined to give the 4a,13b-cis isomer of the title
compound, i.e. (+)11,12-dimethoxy-(4a,13~cis)-2,3,4,4a,8,9,13b,14-octahydro-
lH-benzo~6,7] cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-3-one, mp 157-159 C
(after recrystallization from chloroform-diethyl ether-hexane), NMR (CDC13)~
2.4-3.75 (m, 13H), 3.85 (s, 3H), 3.91 (s, 3H), 4.6 (d, J = 4Hz, lH), 6.60 (s, lH),
20 7-1 (m, 3H), 7.35 (s, lH).
The latter compound was epimerized to the title compound as fol-
lows: A solution of the latter compound (2.2 g, 6.1 mmol) in lN HCl (60 mL)
was stirred at 75 C for 4 hr. Thereafter, the solution is cooled to 20-22 C
and diluted with water (60 mL) and rendered basic with concentrated ammonium
25 hydroxide. The resulting precipitate was collected, washed with water and
dried to give a pal~ yellow solid (2.0 g) which is a 3:1 (by weight) mixture of
the title compound and the 4a,13b-cis isomer of the title compound. The two
isomers were separated by chromatography on silica gel. Elution with pure
benzene, then benzene-ethyl acetate (19:1, v/v) and benzene-ethyl acetate
30 (9:1, vtV) gave first the above noted 4a,13b-cis isomer (0.66 g), followed bythe title compound (1.3 g), mp 196-198 C and NMR (CDC13) ~ 2.0-4.5 (m, 13H),
3.81~ 3.83 (2s, 6H), 4.70 (t, J = 5Hz, lH), 6.62 (s, lH), 7.00 (s + m, 4H).
-24- AHP-8165
EXAMPLE 6
. . _ . _
(+)5,6-Dim ethoxy-(4a,13b-trans)-(3-hydroxy,13~trans)-3-(1-methylethyl)-2,3,4,4a,-
8,9,13b,14-octahydro-lE-I-benzo[6,7] cyclohepta[l,2,3-de] pyrido[2,1-a~ isoquinolin-
3-ol (I; L = OH, M = CH(CEI3)2, Rl and R2 _ OCH3 and R3, R and R5 = H)
A solution of l-methylethyl chloride (3.14 g, 0.04 mol) in diethyl
ether (10 mL) was added to magnesium turnings (0.97 g, 0.04 mol), activated
5 with 0.1 mL of l-methylethyl iodide, in diethyl ether (2 mL) at a rate that main-
tained the reaction mixture at a gentle reflux. The reaction mixture was then
stirred for 30 min at 20-22 C, room temperature, diluted with diethyl ether
~10 mL)s cooled to -2 C and added to the starting material, (+)5,6-dimethoxy-
(4a,13~trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de~-
pyrido[2,1-a] isoquinolin-3-one (3.6 g, 0.01 mole, described in example 4) suspended
in diethyl ether (80 mL) at -40 C under nitrogen. After stirring 18 hr, tetra-hydrofuran (20 mL) was added to the reaction mixture and the resulting mixture
was partitioned between water and ethyl acetate. The layers were separated
and the aqueous phase was extracted twice more with ethyl acetate. The
combined organic extracts were washed with brine, dried (MgSO4) and eveporated
to dryness. The residue was subjected to chromatography ~n silica gel using
ethyl acetat~benz~le (3:7, v/v) as the eluant. Some starting material 10.25 g)
was first eluted. Further elution gave the title compound, NMR (CDC13)
1.0 ~d, J = 6Hz, 6H), 3.68 ~ 3.75 (2s, 6H), 4.8 (m, lH), 6.6 (s, lH), 7.1-7.4 (m,
4H).
The corresponding hydrochloride of the title compound had mp
~250 C; lR (white mineral oil) 3340, 2550,1270,1190 cm 1; Anal Calcd for
C26H33NO3.HCl: C, 70.33% H, 7.72% N, 3.16%; Found: C, 70.10% H, 7.84% r
N, 2.87%.
By following the procedure of example 6, but replacing the starting
material with (+~11,12-dimethoxy-(4a,13b-trans)-2,3,4,4a,8,9,13b,14-octahydro- ~
lH-benzo[6,7] cycloheptaCl,2,3-de~ pyrido[2,1-a] isoquinolin-3-one, described L
in example 5, (+)11,12-dimethoxy-(4a,13~trans)-(3-hydroxy-13b-trans)-3-(1-methyl-
ethyl~2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cycloheptarl,2,3-de] pyrido-
30 [2,1-a] isoquinolin-3-ol, NMR (CDC13) ~ 1.0 (d, 6H), 3.80 (s, 6H), 4.8 (broad,
-"5- AHP-8165
lH), 6.65 (s, H), fi.90 ~m, 4H), was obtained. The corresponding hydrochloride
of the latter compound had mp 204-208 C (dec); Anal Calcd for C26H33NO3.
HC~.H20; C, 67.59~6 H, 7.85% N, 3.03%; Found: C, 67.64% H, 7.7496 N, 2.97%.
EXAMPLE 7
(+~5,6-Dimethoxy-(4a,13b-trans)-(3-hydroxy,13~cis)-2,3,4,4a,8,9,13b,14-octahydro-
lH-benzo[6,7] cyclohepta[l,2,3-de3 pyrido[2,1-a] isoquinolin-3-ol (I; L = OH, M
= H, Rl and R2 = OCH3 and R3, R4 and R5 = H)
Sodium borohydride 10.60 g, 0.16 mol) was added portionwise to
a solution of the pentacyclic ketone, (+)5,6-dimetho~-(4a,13b-trans)-2,3,4,4a,-
8,9,13b~14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-
3-one (2.0 g, 5.5 mmol, described in example 4)? in methanol (50 mL) containing
a few mL of chloroform. The mixture was heated at reflux for one hr and
then concentrated under reduced pressure. The residue was partitioned between
ethyl acetate and water. The organic layer was separated, washed with brine,
dried (MgSO4) and concentrated to dryness. The residue was purified on silica
gel (60 g) using methanol-chloroform (1:49, v/v) as the eluant. The sppropriate
fractions were combined to yield the title compound (1.9 g), I~ (CHC13) 3600,
3450 cm .
The corresponding hydrochloride salt had mp 250 C ~after crystal-
lization from methanol-isopropanol-diethyl ether), NMR (DMS~d6) ~ 3.86
(s, 3H), 3.8 (s, 3H), 4.6 ~d, J = llHz, lH), 5.35 (t, J = 7Hz, lH), 6.9 (s, lH), 7.3
(m, 4H); IR (white mineral oil) 3230, 2560 cm ; Anal Calcd for C23H27N03.-
HCl: C, 68.73% H, 7.02% N, 3.49% Found: C, 68.42% H, 7.1796 N, 3.43%.
By following the procedure of example 7 but using an equivalent
amount of (+)6,7-dimethoxy-(4a,13b-cis)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo-
25 [6,7] cycloheptall,2,3-de] pyrido[2,1-al isoquinolin-3-one, described in example
4, as the pentacyclic ketone, a reaction temperature of 4 C and a reaction
time of 1.5 hr, (+)6,7-dimethoxy-(4a,13b-cis)-(3-hydroxy,13b-trans)-2,3,4,4a,8,9,-
13b,14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-
3-ol; mp 208-209~C and NMR (CDC13) ~ 3.6 (s, 6H), 4.0 - 4.5 (m, 2H, 6.3
30 s, lH), 6.9 (m, 3H), 7.3 (m, lH), was obtained. The corresponding hydrochloride
of the latter compound had mp C 270 C (after recrystallization from methanol-
diethyl ether); Anal Calcd for C2~ H27N03.HCl: C, 68.73% H, 7.02% 3.49%;
Found: C, 68.53% H, 7.21% N, 3.60%.
~ t ~ ? Ç ~ ¢~!~
-26- AHP-B165
Similarly, the use of (~)6,7-dimethoxy-(4a~13b-trans)-2,3,4,4a,8,9,-
13b,14-octahydro-lH-benzoi6,7] cyclohepta[l,2,3-de] pyrido[2,1-a3 isoquinolin-
3-one, described in example 4, as the pentacyclic ketone, a reaction temper-
ature of 4 G and a reaction time of 1.5 hr, (+)6,7-dimethoxy-(4a,13b-trans)-
(3-hydroxy,13~cis)-2,3,4,4a,8,g,13b,14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-5 de] pyrido[2,1-a] isoquinolin-3-ol; NMR (CDC13) ~ 3.83 (s, 6H), 4.46 (t, J =
3.8Hz, lH), 7.5 (m, 5H). The corresponding hydrochloride of the latter compound
had mp ~ 250~ C; Anal Calcd for C23H27NO3.HCl: C, 68.73% H, 7.02% ~,
3.49%; Found: C, 68.58~6 H, 7.17% N, 3.40%.
Similarly, the use of (+)11,12-dimethoxy-~4a,13~trans)-2,3,4,4a,8,g,-
13b,14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de] pyrido~2,1-a] isoquinolin-
3-one, described in example 5, as the pentacyclic ketone, a reaction t~mperatureof 20 to 22 C and a reaction time of one hr gave (+)11~12-dimethoxy-(4a,13b-
trans)-(3-hydroxy,13b-cis)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzol6,7] cyclo-
hepta~,2,3-de] pyrido[2,1-a] isoquinolin-3-ol; mp 114-116 C (recrystallized from
methanol-diethyl ether); NMR (CDC13) ~ 1.85 ~m, 4H), 2.5-4.5 (m, 10H), 4.85
(t, J = 6Hz, lH), 6.64 (s, lH), 6.95 (s, lH), 6.95 (m, 3H); Anal Calcd for C23H27-
NO3.1.5CH30H: C, 71.16% H, 8.04% N, 3.38%; Found: C, 71.05% H, 7.8096 N,
3.53%.
EXAMPLE 8
(+)5,6-Dim ethoxy-~4a,13b-cis)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cyclo-
hepta[l,2,3-de] pyrido[2,1-a] isoquinoline (I; L and M = H, Rl and R2 = OCH
and R3, R4 and R5 = H) 3
Over Q period of 10 min, a soluffon of sodium cyanoborohydride
(1.25 g, 20 mmol) in cyclohexane (10 mL) was added to a warm solution (100 C)
of (+)5,6-dimethoxy-(4a,13~cis)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7]-
cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-3-one (1.05 g, 3.0 mmol, described
in example 4) and p-toluenesulfonylhydrazide (0.75 g, 4.0 mmol), in a 1:1 (v/v)
mixture of dimethylformamide-sulfolane (5 mL) containing p-toluenesulfonic
acid (70 mg). The mixture was heated at 100-105 C for one hr. The reacffon
mixture was diluted with water (5 mL), cooled and extracted with benzene.
The residue was purified by chromatography on silica gel (60 g) using ethyl
-27- AHP-8165
acetate-benzene (1:9, v/v) ~s the eluant. Pooling of the appropriate fractions
afforded the title compound which was crystallized from methanol to give
two crops (275 mg and 158 mg). The pure title compound had mp 144-145 C;
NMR(CDC13) ~ 3.~5 & 3.80 (2s, 6H), 4.4 (m, lH), 6.65 (s, lH), 7.1 (m, 3H),
7.7 (m, lH); Anal Caicd for C23H27Nt:)2: C, 79.05% H, 7.79% N, 4.01%; Found:
C, 79.61% H, 7.8196 N, 4.01%.
EXAMPLE 9
(+)5,6-Dimethoxy-(4a,13b-trans)-2,3,4,4a,8,9,13b,14-octahydr~lH-benzo[6,7] -
cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinoline (I; L and M = H, R and R = OCH3
and R3, R4 and ~5 = H)
(+)5,6-Dimethoxy-(4a,13b-trans)-(3-hydroxy,13b-cis)-2,3,4,4a,8,9,13b-
14,-octahydro-lH-benzo~6,7] cyclohepta~,2,3-de] pyrido[2,1-a] isoquinolin-3-
ol (270 mg, 0.74 mmol, described in example ~ was dissolved in dichloromethane
(4 mL). The solution was cooled to about 4 C in a nitrogen atmosphere. Tri-
ethylamine (0.155 mL, 1.11 mmole) was added followed by dropwise addition
of methanesulfonyl chloride. The reaction mixture was stirred at 0 C for
2 hr and then evaporated to dryness. The residue taken up in ethyl acetate
and washed twice with water. The organic phase was dried (MgSO4) and eva-
porated to give a solid (0.266 mg). The solid was crystallized from dichloro-
methane and diethyl ether to give (+)5,6-dimethoxy-~4a,13b-trans)-(3 hydroxy,l3b-
cis)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,~3 cyclohepta[l,2,3-de] pyrido[2,1-
a] isoquinolin-3-ol mesylate, mp 122-12S C.
The preceding mesylate (9.0 g, 0.02 mol) was dissolved in dry tetra-
hydrofuran (90 mL). The solution was cooled to about 4 C, and under a nitrogen
atmosphere lithium triethylborohydride (~2 mL, 1 molar in tetrahydrofuran)
25 was added dropwise over 30 min. The reaction mixture was stirred at 20-22 C
for 3.5 hr, cooled and poured into ice-water (500 mL) containing concentrated
hydrochloric acid (20 mL). The mixture was made basic with concentrated
ammonium hydroxide (30 mL), saturated with sodium chloride and extracted
with ethyl acetate. The organic phase was washed with brine, dried (MgSO4)
30 and evaporated to dryness to give a brown oily liquid (7 g). The oil was passed
through 8 column of silica gel (350 g) using benzene and then acetone-benzene
?~ r-~r~
-28- AHP-8165
(1:19, v/v) as the eluants. (+)2-(3-butenyl-4,5-dimethoxy-1,2,3,7,8,12b-hexa-
hydrobenzo~6,7] cyclohepta[l,2,3-de] isoquinoline (3.0 g), mp 88-90 C, NMR
(GDC13) ~ 3.70 ~ 3.75 (2s, lH), 4.5 (m, lH), 5.1 (m,2H), 5.9 (m, lH), 6.4 (s, lH),
7.3 (m, 4H), was eluted first, followed by the title compound (0.60 g); mp 148-
14g C, NMR (CDC13) ~ 1.8 (m, 6H), 3.15 (m, 9H), 3.70 ~c 3.77 (2s, 6H), 4.80
(t, J - 7.5 Hz, lH), 6.55 (s, lH), 7.15 (m, 4H); Anal Calcd for C23H27N02: C,
79.0596 H, 7.79% N, 4.0196; Found: C, 79.25% H, 7,90~6 N, 4.02%.
EXAMPLE 10
(+)(4a,13b-trans)-(3-hydroxv,13~trans)-3-(1-Methylethyl~2,3,4,4a,8,9,13b,14-
octahydro-lH-benzoE6,7] cyclohepta~,2,3-de] pyrido[2,1-a] isoquinoline-3,5,6-
triol hydrobromide (the hydrogen bromide addition salt of I; L = OH, M = CH(CH3)2,
Rl and R2 = OH and R3, R4 and R5 = H)
The starting material, 5,6-dimethoxy-(4a,13b-trans)-(3-hydroxy,13
trans)-3-(1-methylethyl)-2,3,4,4a,8,9,13b,14~ctahydro-lH-benzo[6,7] cyclohepta
[1,2,3-de] pyrido[2,1-a] isoquinolin-3-ol (312 mg, 0.767 mmol, described in ex-
ample 6), was dissolved in chloroform (4 mL) under nitrogen. The solution
was cooled with an acetone/dry-ice bath to -20 C and a solution of boron
tribromide (0.5 mL) in 1 mL of chloroform was added dropwise to the cooled
solution. The gummy mixture was stirred for one hr at -20 C and then cooled
to -40 C. The addition of ethanol (6 mL) at -40 C gave a clear solution.
The solution was evaporated to dryness under reduced pressure at a maximum
temperature of 40 C. The resulting oil was dissolved in ethanol (0.5 mL).
Dilution of the ethanol solution with diethyl ether afforded a pale yellow powder.
The powder was collected, washed with diethyl ether and dried to give the
title compound, mp 283 C(dec), NMR (CD30D) ~ 1.0 (d, 6H), 5.1 (bro~d, lH),
6.6 (d, lH), 7.2 (m, 4H).
By following the procedure of example 10 but replacing the starting
material with an equivalent amount of (+)11,12-dimethoxy-(4a,13b-trans)-(3-
hydroxy-13b-trans)-3-(1-methylethyl~2,3,4,4a,8~9,13b,14-octahydro-lH-benzo-
[6,7] cyclohepta~,2,3-de] pyrido~2,1-a~ isoquinolin-3-ol, described in example
6, ~+)(4a,13b-trans)-(3-hydroxy,13b-trans)-3-(1 methylethyl~2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de] pyrido~2,1-a~ isoquinoline-3,11,12-
-29- AHP-8165
triol hydrobromide; mp 210 C; NMR (CD30D) ~ 1.0 (d, GH), 5.2 (m, lH), 6.5-
6.8 (m, 2H), 6.8-7.4 (m, 3H); Anal Calcd for C24H2gN03.HBr: C, 62-61% H,
6.5,~ N, 3.04,o; Found: C, 61.28%, H, 6.23% N, 3.09%, was obtained.
Similarly, using (+)11,12-dimethoxy-(4a,13b-trans)-(3-hydroxy,13b-
cis)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7~ cyclohepta[1,2,3-de~ pyrido[2,1-
a] isoquinolin-3-ol, described in example 7, as the starting material gave (+)(4a,-
13b-trans)-(3-hydroxy, 13b-cis)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,~] cyclo-
hepta[l,2,3-de] pyrido[2,1-a] isoquinoline-3,1l,12-triol hydrobromide; mp 257 C(dec, recrystallized from methanol-diethyl ether); Anal Calcd for C21H23N03.-
H~r: C, 60.29% H, 5.~8% N, 3.35~6; Found: C, 59.06% H, 6.03% N, 3.24%.
lQ The correspor~ding free base had NMR (CD30D) ~ 1.7 (m, 4H), 6.6 (s, lH), 6.75 (s, lH), 7.0 (m, 3H).
Similarly, using (+)5,6-dimethoxy-(4a,13b-cis)-2,3,4,4a,8,9,13b,14-
octahydro-lH-benzol6,~] cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinoline, described
in example 8, as the starting material gave (+)(4a,13b-cis)-2,3,4,4a,8,9,13b,14-15 octahydro-lH-benzo[6,~] cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinoline-5,6-diol
hydrobromide; mp 275 C (dec), NMR (DMS~d6) ~ 1.85 (m, 6H), 2.6-4.0 (m,
4H~, 4.3 (m, lH), 5.0 (m, lH), 6.6 (d, lH), ~.25 (m, 3H), 7.5 (m, lH), 8.95 (broad,
2H). The corresponding free base of the latter hydrobromide salt had NMR
(CDC13) ~ 1.0-4.0 (m, 15H), 4.4 (d, lH), 6.45 (s, lH), 7.1 (M, 3H), 7.55 (m, lH).
EXAMPLE 11
(+)(4a,13~trans)-(3-hydroxy,13b-cis)-2,3,4,4a,8,9,13b,14-Octahydro-lH-benz~
[6,7] cyclohepta~,2,3-de] pyrido[2,1-a] isoquinoline-3,5,6-triol hydrochloride
(the hydrogen chloride addition salt of I; L = OH, M = H, Rl and R2 = OH and
R3, R4 and R5 = H)
A mixture of (+)5,6-Dimethoxy-(4a,13b-trans~~(3-hydroxy,13b-cis)-
2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,~] cyclohepta[l,2,3-de] pyrido[2,1-a] -isoquinolin-3-ol (0.60 g, described in example 7) and 55% (v/w) hydriodic acid
(25 mL) was heated at reflux for 3 hr. The reaction mixture was cooled and
diluted with water. The precipitate (the hydriodide of the title compound)
30 was collected and mixed with concentrated hydrochloric acid. The mixture
was heated at reflux for 10 min. The solid was collected washed with water
and recrystallized from methanol diethyl ether to give the title compound
-30- AHP-8165
(0.6 g); mp ~ 250 C; NMR (DMSO-d6, free base) ~ 1.7 (m, 4H), 3.4 (m, 10H),
4.75 (m, lH), 6.5 (s, lH), 7.15 (m, 4H), 8.4 (broad, 3H); IR (white mineral oil)3500, 3420, 3390, 3170, 2fi70 cm 1; Anal Calcd for C21H23N03.HCl- C, 67.46%
H, 6.47% N, 3.75%; Found: C, 67.5096 H, 6.57% N, 3.75%.
By following the pro~edure of example 11 but using (+)11,12 dimethoxy-
(4a,13b-cis)-(3-h~7droxy, 13b-trans)-2~3,4,4a,8,9,13b,14-octahydro lH-benzo[6,7]-
cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-3-ol, described in example 5, as
the starting material, (+)(4a,13~cis)-(3-hydroxy,13b-trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo~6,7] cyciohepta[l,2,3-de3 pyrido~2,1-a3 isoquinoline-3,11,12-triol hydrochloride, mp 234 C (dec, after recrystallization from methanol
and diethyl ether); Anal Calcd for C21H23NQ3.HCl.CH3OH: C, 6S.09% H,
6.95% N, 3.45%; Found: C, 65.07% H, 6.5596 N, 3.47%, was obtained. The
corresponding free base of the latter salt had NMR ~CD3OD) ~ 2.0 (s, 2H),
6.6 (s, lH), 6.75 (s, lH), 7.2 (m~ 3H).
EXAMPLE 12
(+)6-Methoxy-(4a,13b-trans)-(3-hydroxy,13b-trans)-3-(1-methylethyl)-2,3,4,4a,8,9,-
13b,14-octahydro-lH~benzo[6,7] cyclohepta~,2,3-de] pyrido[2,1-a] isoquinoline-
3,5-diol (I; L = OH, M = CH(CH3)2, Rl = OH, R = OCH3 and R3, R4 and R5
= H)
A suspension of the starting material, (+)5,6-dimethoxy-(4a,13b-
20 trans)-(3-hydroxy,13~trans)-3-(1-methylethyl~2,3,4,4a,8,9,13b,14-octahydro-
lH-benzd6,7~ cyclohepta~l,2,3-de] pyrido[2,1-a~ isoquinolin-3-ol (0.50 g, 1.1 mmol,
described in example 6) in 55% (v/w) of hydriodic acid (25 mL) was stirred
at 20-22 C for 2 weeks in a closed vessel. The reaction mixture was diluted
with water. The precipitate was collected and suspended in dilute aqueous
25 sodium bicarbonate. The mixture was extracted with ethyl acetate. The extractwas dried (MgSO4) and evaporated to give the title compound in a 70% yield
as a foam, NMR (DMS~d6)~ 0.90 (d, J = 6Hz, 6H), 3.70 (s, 3H), 4.5 (brcad,
lH), 5.15 (broad, lH), 6.6 (s, lH), 7.1 (s, 4H).
The corresponding hydrochloride of the latter compound had mp
30 250 C (after crystallization from methanol-diethyl ether), Anal Calcd for
C25H31NO3.HCl: C, 69.83% H, 7.50%, N, 3026%; Found: C, 68.73% H, 7.82%
N, 3.24%.
-31- A~I P-816 5
By fo~lowing the procedure of example 12 but using (+)6,7-dimethoxy-
(4a,13~cis~-(3~hydroxy,13b-trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7~ -
cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinolin-3-ol, described in example 7, as
the starting material, (+) 6-methoxy-~4a,13b-cis)-(3-hydroxy,13~trans)-2,3,4,-
4a,9,9,13b,14-octahydro-lH-benzo[6,7] cyclohepta[l,2,3-de] wrido[2,1-a] isoquino-
line-3,7-diol, NMR (CDC13) ~- 3.78 (s, 3H), 6.48 (s, lH), 7.3 (m, 4H), was obtained.
The corresponding hydrochloride salt had mp 218 C (dec); Anal Calcd for C22H25-N03.HCl.2CH30H: C, 63.77% H, 7.58% N, 3.10%; Found: C, 63.98% H, 7.52%
N, 3.05%.
Similarly, the use of (+)6,7-dimethoxy-(4a,13b-trans)-(3-hydroxy,13
10 cis)-2,3,4,4a,8,9,13b,14-octahydro-111-benzo[6,7] cyclohepta[l,2,3-de] pyrido-
[2,1-a] isoquinolin-3-ol, described in example 7, as the starting material gave
(1) 6-methoxy-(4a,13b-trans)-(3-hydroxy,13b-cis)-2,3,4,4a,8,9,13b,14-octahydro-
lH-benzo[6,7] cycloheptaCl,2,3-de] pyrido[2,1-a] isoquinoline-3,7-diol, NMR (CDC13)
3.8 (s, 3H), 4.4 (broad, lH), 6.5 (s, lH), 7.2 (m, 4H~. The corresponding hydro-15 chloride salt of the latter compound had mp 254-256 C; Anal Calcd for C22H25-
N03.HCl.1.5CH30H: C, 64.74% H, 7.40% N, 3.21%; Found: C, 64.80% H, 7.03%
N, 3.21%.
EXAMPLE 13
(+)6-Methoxy-(4a,13b-trans~(3-hydroxy,13b-cis)-2,3,4,4a,8,9,13b,14-octahydro-
-
20 lH-benzo[6,7] cyclohepta[l,2,3-de] pyrido[2,1-a] isoquinoline-3,5-diol (I; L =
OH, M = H, Rl = OH, R2 = OCH3 and R3, R4 and R5 = H)
A mixture of (+)5,6-dimethoxy-(4a,13b-trans)-2,3,4,4a,8,9,13b,14-
octahydro-lH-benzo[6,7] cycloheptan,2,3-de] pyrido[2,1-a] isoquinolin-3-ol hydro-
chloride (1.4 g, described in example 7) and concentrated hydrochloric acid
25 (50 mL) was heated at reflux for 24 hr (oil bath temperature = 150 C). Aftercooling, water (50 mL) was added to the mixture. The white precipitate was
collected and partitioned between 1% (w/v) aqueous sodium hydroxide solution
and ethyl acetate. The organic layer was separated, dried (MgS04) and filtered
through charcoal. The filtrate was concentrated. The residue was recrystallized
30 from methanol to give the title compound (first crop, 0.49 g; second crop,
0.15 g). The pure title compound had mp 218-220 C; NMR (DMSO-d6) ~ 3.7
-32- AHP-8165
(s, 3H), 4.6 (s, lH~, 4.65 (rn, lH), 7.1 (m, 5H), 81 (s, lH); Anal Calcd For C22-
H25N03: C, 75.18% H, 7.17% N, 3.99%; Found: C, 75.3896 H, 7.31% N, 4.06%.
The corresponding hydrochloride had mp C 250 C (after recry-
stallization from methanol-diethyl ether); Anal Calcd for C22H25NO3.HCl:
C, 68.12% H, 6.76% N, 3.61%; Found: C, 67.45% H, 6.95% N, 3.52%.
EX AM PLE 14
(~) (4a,13b-trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo~6,7] cyclohepta[l,2,3-de] pyrido[2,1-q] isoquinoline-5,6-diol hydrobromide (the hydrogen bromide
addition salt of ~; L and M = H, Rl and R2 = OH and R3, R4 and R5 = H).
Procedure A:
.
By following the procedure of example 10, ~)5,6-dimethoxy-(4a,13~
trans)--2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,73 cyclohepta[l,2,3-de] pyrido[2,1-
a] iscquinoline described in example 8, was transformed into the title compound;mp 325-328 C; NMR (DMS~d6)~ 1.85 (m, 6H), 5.15 (m, lH), 6.6 (s,lH), 7.2
(m, 4H), 8.3 (broad, lH), 9.3 (broad, lH), 9.75 (broad, lH); Anal Calcd for C~l-15 H23NO2.HBr: C, 62.69% N, 6.01% N, 3.48%; Found: C, 62.43% H, 6.23% N,
3.42%.
Procedure B:
The title compound also was prepared as follows: 4,5-dimethoxy-
1,7,8,12b-tetrahydrobenzo[6,7] cyclohepta[l,2,3-de] isoquinoline (2,0 g, 6.7 mmoles,
20 described in example 3) was dissolved in acetone (75 mL). Benzyl bromide
(4 mL) was added to the solution. The mixture was heated at reflux for 18
hr. After cooling, diethyl ether (100 mL) was added to the mixture. The solid
in the mixture precipitate was collected by filtration and washed with diethyl
ether and dried. The collected solid (2.8 g) was suspended in diethyl ether
25 (50 mL) and the suspension set aside. A solution of phenoxybutylmagnesium
bromide was prepared from magnesium (730 mg) and 4-phenoxybutylbromide
(6.9 g~ in diethyl ether (30 mL). The latter solution was added to the suspension
OI the collected solid under nitrogen with vigorous stirring. A clear solution~
containing some insoluble material, was obtained after 15 min of shaking.
30 The reaction mixture was then poured into ice water containing ammonium
chloride (10 g). The resulting mixture was extracted twice with diethyl ether.
e ~ ' ? ~
-33 AHP-8165
The extract uas dried (MgSO,~) and evaporated to dryness. The residue was
purified by chrornatography on silica gel using hexane and diethyl ether es
eluants. Pooling of the pure fractions gave (+~ (3,12b-trans)-4,5-dimethoxy-
3-(4-phenoxybut~1)-2-(phenylmethyl~1,2,3,7,8,12b-hexahydrobenzo[6,7] cyclo-
hepta[l,2,3-de] isoquinoline as a colorless oil, which crystallized from boilinghexane to give 2.2 g of solid, mp 115-117 C and NMP~ (CDC13) ~ ~.7 (broad,
6H), 3.7 (s, 6H), 4.45 (t, J = 3.5Hz, lH), 6.35 (s, lH), 7.6 (m, 14H).
The latter compound (5.5 g, Q.01 mol) was dissolved in acetic acid
(120 mL). The solution was shaken in an atmosphere of hydrogen in the presence
of 10% (w/w) palladium on charcoal (1 g) at 20-22 C and normal pressure.
After completion of the reaction, the mixture was removed from the atmosphere
of hydrogen and heated on a steambath. The hot suspension was filtered through
cellulose powder. The filter cake was washed with hot acetic acid. The filtrate
was evaporated to dryness. The residue was dissolved in benzene and the solu-
tion evaporated several times to remove moisture from the residue. Thereafter,
the residue was partitioned between ethyl acetate and dilute aqueous ammonium
hydroxide. The organic phase was separated, washed with water, dried (MgSO4)
and evaporated to dryness to give (+) (3,12b-trans)-4,5-dimethoxy-3-(phenoxybutyl~
1,2,3,7,8,12b-hexahydrobenzo[6,7] cyclohepta[1,2,3-de~ isoquinoline suitable
for the next step. A sample of the latter compound recrystallized from chloro-
form-hexane had mp 135-136 C and NMR (CDC13) ~ 1.8 (m, 6H), 3.7 ~ 3.78
(2s, 6H), 4.35 (broad, 2H), 6.4 (s, lH), 7.1 (m, 9H).
The latter compound (1.4 g, 3.1 mmol) was dissolved in chloroform
(10 mL). The solution was cooled to 4 C. To the cooled, stirred solution,
a solution of boron tribromide (2.8 mL) in chloroform (5 mL) was added dropwise.25 The reaction mixture was allowed to stand at 20-22 C for 2 hr. Thereafter,
the reaction mixture was cooled again to 4 C and while being stirred, was
subjected to the immeaiate dropwise addition of ethanol (7 mL) and after 1
hr the dropwise addition of diethyl ether (100 mL). After stirring at 20-22 C
for 12 hr, the resulting precipitate was collected, washed with diethyl ether
30 and dried to give (+)(3,12b-trans)-3-(bromobutyl)-1,2,3,7,8,12b-hexahydrobenzo-
[6,7] cyclohepta[l,2,3-de] isoquinoline-4,5-diol hydrobromide as a white solid
-34- AHP-8165
(1.42 g), NMR (DMSO-d6) ~ 1.85 (m, 6H), 2.9 (m? 2H), 3.6 (m, 6H), 4.4 (m, lH),
5.0 (t, J = 5.5 Hz, lH), 6.50 (s, lH), 72 (m, 4H), 9.15 (broad, 2H).
A solution of the latter compound (1.9 g, 4 mmol) in 2-ethoxyethanol
(50 mL~ was heated at 160 C for 6 hr. The reaction mixture was then cooled
to 4 C. The precipitate was collected, washed with diethyl ether and dried
5 to give the title compound (1.14 g), identical to the product obt~ined by procedure
A of this example.
By following the procedure of procedure B of this example but
replacing 4,5-dimethoxy-1,7,8,12b tetrahydrobenzo[6,7J cyclohepta[l,2,3-de~-
isoquinoline with ~n equivalent amount of 5,6-dimethoxy-1,7,8,12b-tetrahydro-
10 benzo{6,7] cyclohepta~l,2,3-de] isoquinoline, described in example 3, (~)t4a,13
trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo[6,7] cyclohept~[l,2,3-de] pyrido-
[2,1-a] isoquinoline-6,7-diol was obtained. The hydrobromide of the latter com-
pound had mp 321-323 C; NMR (DMS~d6) ~ 1.75 (m, 6H), 4.95 (m, lH), 6.65
(s, lH), 7.15 (s, 4H), 8.7 (s, lH), 9.4 (s, 2H); Anal Calcd for C21H23NO2.HBr:
15 C, 62.69% H, 6.01% N, 3.48%; Found: C, 62.83% H, 6.08% N, 3.4896.
(+)(4a,13b-trans)-2,3,4,4a,8,9,13b,14-Octahydro-lH-benzo[6,7] cyelo-
hepta[l,2,3-de] pyrido[2,1-a] isoquinoline-6,7-diol hydrobromide also is obtained
by subjecting (~6,7-dimethoxy-(4a,13~trans)-(3-hydroxy,13~cis)-2,3,4,4a,8,-
9,13b,14-octahydro-lH-benzo[6,7] cycloheptan,2,3-de] pyrido[2,1-a] isoquinolin-
20 3-ol, described in example 7, serially to the procedures of examples 8 and
10 via (+)6,7-dimethoxy-(4a,13b-trans)-2,3,4,4a,8,9,13b,14-octahydro-lH-benzo-
[6,7] eyclohepta~,2,3-de] pyrido[2,1-a] isoquinoline.
