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AHP-7266
BACKGROUND OF THE INVENTION
(a) Field of the Invention
The present invention relates to novel benzot4,5~cyclohepta~1,2,3-de]-
pyrido[2,1-a]isoquinoline derivatives having useful pharmacologic
properties. More specifically, 2,3,4,4a,12,13,13a,14-octahydro-lH'
benzo[4,5]cyclohepta[1,2,3,de]pyrido[2,1-a]isoquinoline and derivatives of
1,2,4,4a,12,13,13a,14 octahydro-3H benzot4,5]cyclohepta[1,2,3-de~pyrido
[2,1-a]isoquinolin-3-ol substituted on position 3 with a lower alkyl group
of this invention are useful as minor tranquilizers. In addition, processes
for their preparatlon~and intermediateS used in their preparation are dis-
c!osed.
(b) Prior Art
A number of octahydrobenzo[6,7]-(or~5,6])cyclohepta[1,2,3-de~pyrido-
(or pyrrolo-)[2,1-a]isoquinoline and decahydrobenzo[6,7]-(or~5,6]-)
. ~ .
cyclohepta[l,2,3-de]azepino[2,1-a]isoquinoline derivatives are described
by F.T. Bruderlein and L.G. Humber, U.S. Patent 4,054,569, Issued October
18, 1977, to be central nervous system depressants useful for treating
psychoses and neuroses. Drugs used for treating these conditions
are designated major tranquilizers, Although the compounds of th7s in-
vention are isomeric with those described in U.S. Patent 4,054,569, the
compounds of this invention differ by having a phenylene group at a d7fferent
position and by being useful as minor tranquilizers, i.e. for treating
symptoms of anxiety.
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AHP-7266
SUMMARY OF THE INVENTION
; The compounds of this invention are represented by formula I
., .
2 ~ 6
4~ :
~ R
R2
. _
. in which Rl and R2 are hydrogen or R is lower alkyl and R is
; hydroxy, or a therapeutically acceptable acid addition salt thereof.
:: . The compounds oF this invention are prepared by selecting a process
: from the group consisting of:
(a~ ~hen a compound of formula I in which R is lower alkyl and R ts
hydroxy Is required, reacting 1,2,4,4a,12,13,13a,14-octahydro-3~benzo-
r4,5]cyclohepta~1,2,3-de]pyrido[2,1-a]isoquinolin-3-one with a Grignard
reagent of formula R -(magnesium halide) in which R is lower alkyl and
the halide is chlorine, bromine or iodine,or reacting 1,2,4,4a,12,13,13a,14
octahydro-3H-benzo[4,5]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3-one
with an organolithium reagent of formula Rl-Li in which R is lower alkyl;
~: (b) when a compound of formula I in which Rl and R are hydrogen isrequired, reducing .3,4,12,13,13a,14-hexahydro-lH-benzo[4,5]cyctohepta-
[1,2,3-de]pyrido[2,1-a]isoquinolin.ium chlor3de;w.i,th zlnc po~der, o~ rea~ting
1 ,2,4,4a,12,13,13a,14~octahY.dro-3l~-benzoi~4J5]cyclohepta~lJ2~3-de]pyrid
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AHP~7266
[2,1-a]isoquinolin-3-one with 1,2-ethanedithiol and boron trifluoride
etherate and reacting the resulting intermediate with Raney nickel; and
~c) when a therapeutically acceptable acid addition saIt of a
compound of formula I in which Rl and R2 are as defined herein is required,
reacting the compound o~ formula I in which R and R are as defined herein
with a therapeutically acceptable acid.
A preferred process for the preparation of the compounds of this
invention comprises selecting a process from the group consisting of:
(a) when a compound of formula I in which Rl is lower alkyl and R2
is hydroxy is required, reacting 1,2,4,4a,12,13,13a,14-octahydro-3H-
benzo~4,5]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3-one with an
: organolithium reagent of formula Rl-Li in which Rl is lower alkyl;
(b) when a compound of formula I in which Rl and R2 are hydrogen is
required, reducing 2,3,4,12,13,13a,14-hexahydro-lH-benzot4,5]cyclohepta-
~1,2,3-de~pyrido[2~l-a]isoquinolinium chloride with zinc powder; and
(c) when a therapeutically acceptable actd additlon salt of a com-
. pound of formula 1 7n which Rl and R2 are as defined hereln Is requlred,
reacting the compound of formula I in which R and R are as defined
herein with a therapeutically acceptable acid.
Another aspect of this invention involves a method of~producTng
tranquilizing effects in a mammal which comprises administering to said
mammal an effecttve tranquilizing amount of a compound of formula 1, or
; a therapeutically acceptable salt thereofO
Still another aspect of this invention involves a pharmaceutical
. composition comprisTng a compound of formula 1, or a therapeutically
acceptable salt thereof, and a pharmaceutically acceptable carrierO
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AHP'7266
DETAILS OF THE INVENTION
The term "lower alkyl" as used herein means straight chain alkyl
radicals containing from one to six carbon atoms and branched chain alkyl
radicals containing up to four carbon atoms and includes methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl.
Also included in this invention are the stereochemical isomers of
the compounds of formula 1. Such stereochemlcal Tsomers are obtained
; in substantially pure form by classical separation tachniques and by
sterically controlled synthesls. Separated stereochemical isomers are
:; arbitrarily identifed as Isomer A or B.
Individual enantiomers, which might be separated by fractional
crystallization of the diastereomeric salts thereof, are also included.
The term "therapeutically acceptable addition salt" as used herein
means the therapeutically acce`ptable acid addition salts of the compound
.1 of formula 1. The acid addltTon salts are prepared by reacttng the base
i~ form of the appropGiate compound of formula I with one or more equivalents,
-~ preferably with an excess, of the appropriate acid in an organic solvent,
for example, dtethyl ether or an ethanol-diethyl ether mixture. These
salts, when administered to a mammal, possess the same pharmacologic
activities as the corresponding base. For many purposes it is preferable
to administer the salts rather than the base compounds. Suitable acids to
form these salts include the common mineral acids, for instance, hydrohalic,
e.g. hydrobromic and hydrochloric acid, sulfuric or phosphoric acid;
as well as the organic acids, for instance, formic, acetic, maleic,
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AHP'7266
fu~aric, citric or tartaric acid; or acids which are sparingly soluble in
body fluids and which impart slow-release properties to their respective
salts such as pamoic or tannic acid or carboxy,methyl cellulose. The
addition salts thus obtained are the functional equivalent of the parent
base compound Tn respect to their therapeutic use. Hence, these addition
salts are tncluded within the scope of this invention and are li~ited
only by the requirement that the acids employed in forming the salts be
therapeutically acceptable.
The useful tranquilizer activity of the compounds of formula I or
therapeutically acceptable acid addition salt thereof can be demonstrated
1n standard pharmacological tests which exemplify tranquilizer actlvity.
For example, one test for tranquilizer activity is demonstrated in
the pharm2cological control of aggressive behavior In mice accordlng to
` the method described by L. ValzellT et al., Eur.J.Pharmacol., _, 144~1967).
In this test, male Swiss albino mice, weighing about 20 + 2 grams are
isolated for four weeks at room temperature and fed a normal balanced
dle~. To test the aggressive behavior the drug is administered intra-
peritoneally and after 30 minutes the mice are grouped in threes.
The aggressiveness of the drug treated mice is evaluated by observing each
group of mice for five minutes. In this test, the foilowing compounds
of farmula I tnhibit the flghting behavior of the mice: isomer B of
3~tert-butyl-1,2,4,4a,12,13,13a,14-octahydro-3H-benzo~4,5]cyclohepta-
~1,2,3-de]pyrido~2,1-a]isoquinolin- } ol hydrochloride ~escribed in
Example 6) at a dose of lO mg/kg ~f body weight ~a~s~s a 72~ inhibit;on
~ of fighting behavior and isomer A of 2,3,4,4a,12,13,13a,14-octahydro-
- IH-benzo~4,5]cyclohepta~1,2,3-de~pyrido[2,1-a]isoquinoline hydrochloride
(described in Example 8) at a dose of 10 to 15 mg~kg of body weight
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AHP-7266
causes a 50% inhibition of fighting behavior.
Another test for tranquiiizer activity uses rats which have been
made hyperirritable by septal lesions in the brajn, according to the
method described by J.V. Brady and W.J.H. Nauta, J.Comp.Physiol.Psycol.,
46, 339(1953~. The tranquilizer activity of a drug is indicated by an
inhibition of the hyperirritability of these rats. In conducting this
; test, the rats are made hyperirritable by a septal lesion and after 24
hours, the dru~ is administered intraperitoneally to the hyperirritable
rats. The rats are observed 30 minutes after drug administration for
inhibition of hyperirritability. The following compounds of formula I
exhibit tranquilizer activity by causing the indicated inhibition of
- hyperirritable rats; isomer B of 3rtert-butyl-1,2,4,4a,12,13,13a,14-
. ~ octahydro-3H-benzot4,5]cyclohepta[1,2,3-de]pyrido~2,1-a]isoquinolin-3-ol
hydrochloride (described in Example 6) at a dose of 25 mg/kg of body
weight causes a 33% inhibition and isomer A of 2,3,4,4a,12,13,13a,14-
octahydro-lH-benzot4,5]cyclohepta[1,2,3-de]pyrido[2,1-a]lsoqulnoline
hydrochloride (described in Example 8) at a dose of 25 mg/kg of body
weight causes a 28% inhibition.
When the compounds of formula I of this invention are used as minor
tranquilizer agents in mammals, e.g. rats and mice, they are used a!one
or in combination with pharmacologically acceptable carriers, the pro-
portion of which is determined by the solubility and chemical nature of
the compound, chosen route of administration 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 preferred
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AHP-7266
to use the compounds of formula I in solution in a sterile aqueous
vehicle which may also contain other solutes such as buffers or preserva-
tives, as well as sufficient quantities of pharmaceutically acceptable
salts or of glucose fo make the solution isotonic.
When the compounds of formula I are employed as minor tranquilizers
in mammals, orally effective amounts of the ~ompounds are
administered to the mammal, either alone or combined with pharmaceutically
acceptable excipients in a dosage form, i.e. capsule or tablet, or the
compounds are administered orally in the form of solutions or suspensions.
The tablet compositions contain the active ingredient in admixture
with non-toxic pharmaceutical excipients known to be suitable in the
manufacture of tabletsO Suitable pharmaceutical excipients are, for
;; example, starch, miIk sugar, certain types of clay and so forth. The
tablets may be uncoated or they may be coatad by known techniques so as
to delay disintegration and absorption in the gastrointestinal tract and
thereby provide a sustained action over a longer perlod.
The aqueous suspensions of the compounds of formula I contaTn the
actTve ingredTent in admTxture wTth one or more non-toxTc pharmaceutical
excTpTents known to be suitable in the manufacture of aqueous suspensions.
SuTtable exci,pients are, for example, methyIcellulose, sodium alginate,
gum acacTa, lecTthin and so forth. The aqueous suspensions may also
contain one or more preservat7ves, one or more colouring agents, one or
more flavouring agents ana one or more sweetening agents.
Non-aqueous suspensTons may be formulated by suspendTng the actTve
Tngredient in a vegetable oTI, for example, arachTsaoTI, olTve oTI,
sesame oTI, or coconut oTI, or in a mineral oTI, for example lTquTd
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AHP-7266
paraffin, and the suspenslon may contain a thickening agent, for example
beeswax, hard paraffin or cetyl alcohol. These compositions may also
contain a sweetening agent, a flavouring agent and an anti-oxidant.
The dosage of the therapeutic agents of formula I will vary with
the form of administration and the particular compound cnosen~ Further-
more, it will vary with the particular host under treatment. Generally,
treatment is initiated with small dosages substaDtially less than the
. ,
optimum dose of the compound. Thereafter, the dosage is increased by
small increments until the optimum effect under the clrcumstances is
reached. In general, the compounds of formula I are most desirably
admlnistered for tranquilizing purposes at a concentration level that will
generally afford effective results without causing any harmful or dele-
terious side effects and preferably at a level that is in a range of from
about 0.01 mg to about 500 mg per kilogram body weîght per day, although
as aforementioned variations will occur. However, a dosage level that is
tn the range of from about 0.1 mg to about 50 mg per kiiogram body weight
per day is most desirabiy employed in order to achieve effective results.
PROCESS
For the preparation of the compounds of formula 1, the preferred
starting material is 6,7-dihydro-5H-dibenzo~a,c]cyclohepten-5-one,
described by H. Rapaport and A.R. Williams, J. Amer. Chem. Soc., 71,
~ 1774t19i9~.
.. ... . .. ..
~ Reaction of the above starting material with a Wittig reagent, pre-
, , .
pared from two molar equivalents of triethyl phosphonoacetate and two
molar equivalents of sodium hydride in tetrahydrofuran at O C for 10
to 20 minutes, in a solution of tetrahydrofuran under an atmosphere of
_g_
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AHP-7266
nitrogen at 60 to 70 C for 60 to 80 hours affords 6,7-dihydro-5H-dibenzo-
[a,c]cycloheptene-5-ylidene-acetic actd ethyl ester. Hydrogenation
of the latter compound in ethanol in the presence of 10% palladium on
carbon under a hydrogen atmosphere at 80 to 120 pounds per square inch
pressure and at 20 to 30 C for 20 to 30 m7nutes gives 6,7-dihydro-5H-
dibenzota,c~cyclohepten-5-ylacetic acid ethyl ester. This oompound is
hydrolyzed, preferably under alkaline conditions using 1.5 to 4.0 molar
equivalents of sodium or potassium hydroxide in an aqueous solution of
methanol or ethanol at 60 to 100 C for one to five hours,followed by
acidification of the solutlon with hydroch~oric acid, to obtain
6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-acetic acid.
Curtius degradation of this acid affords 6,7-dihydro-5H-dibenzo-
[a,c]~yclohepten-5-ylmethylamine hydrochlorTde. Preferred conditions
for the Curtius degradation are treating the above acid with 5 to 15 molar
o
equivalents of thionyl chloride at 50 to 80 C for 0.5 to 2 hours to
obtain the correspond7ng acid chlortde, reacting a solutton of the acid
chloride wtth two to three molar equtvalents of sodlum aztde in acetone
o
at -10 to 30 C for 10 to 30 mtnutes to obtain the correspondtng acid
azide, heating a solution of this acid azide in toluene at 100 to 110 C
for one to three hours, adding three to four molar equivalents of concentrated
hydrochloric acid and heating the resultant solution at 70 to 110 C
for 1.5 to 3 hours to obtain 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-
ylmethylamine hydrochloride. An aqueous solution of the latter hydro-
chloride salt and one to two molar equivalents of a carbonate or hydroxide
of sodium or potassium is stirred at 20 to 30 C for two to ten minutes
and the solution i5 extracted with chloroform. The chloroform extract is
evaporated to give the free base of 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-
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S-ylmethylamine.
The latter primary amine is reacted with two to three molar
equivalents of formic acid-acetic anhydride reagent, prepared by heafing
an equimolar solution of formic acid and acetic anhydride at 60 C for
two hours, at 20 to 30 C for 15 to 30 hours. The solution is made
alkaline with aqueous sodium or?potassium hydroxide and extracte'd with
a water immiscible organic solvent, preferably diethyl ether. Evaporation
of the extract gives 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yImethyl-
formamide.
The latter formamide is cyclized using an excess preferably five to
ten times excess by weight, of polyphosphoric acid at 150 to 175 C for
thres to four hours and the solution is poured into water at 0 to 5 CO
The aqueous solution is stirred at 0 to 5 C for 15 to 45 minutes, made
alkaline with sodium or potassium hydroxide and extracted with a water
immiscible organic solvent, preferably chloroform. Evaporation and
purtfication provides 1,11,1~,12a-tetrahydrobenzoE4,5]cyclohepta~1,2,3-
de]isoquinoline. Treatment of the latter compound with hydrogen chlorTde
in an inert solvent, preferably diethyl ether gives the hydrochloride
sait of 1,11,12,12a-tetrahydrobenzo[4,5]cyclohepta[1,2,3-de]isoquinolineO
1,11,12,12a-Tetrahydrobenzot4,5]cyclohepta[1,2,3-de]isoquinoline
or the hydrochloride salt thereof is condensed with 10 to 30 molar
equivalents of methyl vinyl ketone at 80 to 110 C for one to two hours
to obta~n an isomeric mixture of 1,2,4,4a,12,13,13a,14-octahydro-3H-
benzo[4,5]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3-one. The latter
isomeric mixture can be readily separated, preferably by chromatography
on silica gel, to obtain the individual stereochemical isomers, hereln
IdentTfied as isomers A or Bt said isomers having different asymmetric
centers at the junction of the two rings having the nitrogen atom in common.
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AHP-7266
Th~ latter compound, either as the isomeric mixture or as isomer
A or B, preferably as the separate isomer A or B, is converted to
the compound of formula I in which R is lower alkyl and R
is hydroxy by reacting the aminoketone with an appropriate
Grignard reagent of formula Rl-(magnesium halide) in which R is lower
alkyl and the halide is chlorine, bromine or iodine in an inert solvent,
for example, diethyl ether or tetrahydrofuran, according to the conditions
of the Grignard reaction. In this manner the corresponding compound of
formula I in which Rl is lower alkyl and R2 jS hydroxy is obtained.
Suitable reactioD times and temperatures range from 15 minutes to six
hours and -40 to 90 C, respectively.
Alternati~ely, 1,2,4,4a,12,13,13a,14-octahydro-3H-benzo[4,5]cyclohepta-
[1,2,3-de]7soquinolin-3-one,either as the isomeric mixture Pf ~somers -
A or ~, preferab1y as the separate isomer A or B, is reacted with an
_appropriate organolithium reagent of formula Rl-Li in which Rl is lower
alkyl under the same conditions described hereln-before for the Grignard
; reaction. In this manner the correspondTng compound of formula I in which
- Rl 7s lower alkyl and R2 jS hydroxy is obtained.
Conversion of the above described 6,7-dihydro-5H-dibenzo[a,c }
cyclohepten-5-ylmethylamine by a series of reactions affords the compound
of formula I in whicn R and R are hydrogen. The first s~ep in this
reaction sequence involves the condensation of 6,7-dihydro-5H-dibenzo[a,c]-
cyclohepten-5-ylmethylamine with 1.1 to 3.0 molar equivalents of
O
2-oxotetrahydropyran at 130 to 160 C for 1.5 to 3 hours. Ethanol and
an aqueous solution of 1.1 to 3.0 molar equivalents of potassium carbonate
is ad~ed, the resultant solution is stirred at 60 to 70 C for 15 to 30
hours and N-(6,7-dihydro-5H-dibenzora,c]cyclohepten-5-ylmethyl)-5-
hydroxypentanamide is isolated. Cyclization of the latter compound is
.
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achieved by heating with an excess, preferably 10 to 20 times by weight,
of phosphorous oxychloride at 90 to 110 C for two to four hours, evaporating
the mixture, heating a solu+ion of the residue in water and ethanol at
pH 8 to 9 (zdjusted with sodium or potassium hydroxide)at 70 to 100 C
for 0.5 to 2.0 hours and acidifying the solution to pH I to 3 with concentra-
ted hydrochloric acid to obtain a solution containing 3,4,12,13,13a,14-
hexahydro-lH-benzo[4,5]cyclohepta[1,2j3-de]pyrido[2,1-a]isoquinolinium
chloride. Thls compound can be isolated from the solution ana subjected
to the following reduction or this solution can be subjected directly to
the reduction. In a preferred method, the latter solutlon is diluted
;with additional water and ethanol and an excess, preferably one to two times
by weight, of zinc powder is added. The mixture is stirred at 70 to 100 C
for three ~o five hours and followTng purificationr the isomeric mixture~or,
- by separation by conventional techniques, e.g. by chromatography, theindivTdual isomers A and B of the corresponding compound of formula I in which
Rl and R2 are hydrogen are obtained.
Alternatively, the latter compounds of formula I in whlch R and R
are hydrogen can be obtained by the followtng reduction. For this reductb n,
either the isomeric mixture or the individual isomer A or B of the a~ove
described l,2,4,4a,12,13,13a,14-octahydrcr3H-benzo~4,5]cycloheptatl,2,3-de]-
pyrido~2,1-a]isoquinline-3-one is reacted with 20 to 30 molar equivalents
of 1,2-ethanedlthiol and four to eight molar equivalents of boron
trifluoride etherate in acetic acid at 20 to 30C for 20 to 30 hours.
DilutTon of the solution with water, extraction with a water immtscible
organic solvent, preferably chloroform, and evaporation gives a residue.
The residue is reacted with one to ten times by weight of Raney nickel
in tetrahydrofuran at 50 to 70C for four to ten hours and purif7cation
of the reaction mixture gives the corresponding compound of formula I in
which Rl and R are hydrogen.
The following examples illustrate further this invention.
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EXAMPLE ....1
6.7-Dihydro-5H-dibenzora.clcyclohepten-5-yiacetic Acid
Triethyl phosphonoacetate (45g,o.2mol) was added during 15
min- at 0 C to sodium hydride (0.2 mol, 8.49 of a 56~ suspension in
mineral oil) in tetrahydrofuran (85 ml). This mixture was added at
22C to a solution of 6,7 dihydro-5~-dibenzo~a,c3cyclohepten-5-
one' [prepared as described by H. Rapaport and A.R. Williams,
J. Amer. Chem. Soc., 71 1774 (1949)] (22.6 9, 0.108 mol) in tetra-
hydrofuran (80 ml). After refluxing for 72 hrs in a nitrogen
atmosphere, the mixture was poured into ice water. Extraction with
diethyl ether, drying and evaporating afforded an oil which was
chromatographed on silica gel. Elution wlth benzene gave 6,7-
dihydro-5H-dibenzo [a~ç]cyclohepten-5-~lldine-acetic acid ethyl ester
(22-4 9, 74.2~ Ymax 3 172& cm It was dissolved in ethanol
(500 ml) and hydrogenated in the presence of lOg Pd on charcoal
(4.09) for 24 hr at 100 p.s.i. The catalyst was removed by fiItration
and potassium hydroxtde t15 9) was added. The mixture was refluxed
for 1.5 hr in a nitrogen atmosphere and cooled to 5 C.The mixture was
adjusted to pH 2 by the addition of cold hydrochloric acid. The mixture was
extracted with chloroform and the extract was dried and evaporated.
The resTdue was crystallized from chloroform to obtain the title
i 20 compound (85~ yi~eld), mp 187-190 C and anal. calculated for
C17H1002: C, 80.93%; H, 6.39~ and found: C,80.50%; H, 6.44~.
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AHP-7266
EXAMPLE 2
6.7-DihYdro-5H-dibenzora.clcyclohepten-5-vlmethylamine Hydrochioride
6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yiacet7c acld
(61.59, 0.244 mol, described in Example 1) was heated at
reflux with thionyl chloride (195 ml) for one hr. The thionyl
chloride was-removed by distillation and the remaining acid
chloride was dissolved in acetone (300 ml). A solution of sodium
azide (39.1 9, 0.6 mol) in water (160 ml) was added during 20
min.at -10 to 0 C. The mixture was allowed to come to room tem- -
perature, then was poured into iced water (800 ml). Extraction
with methylene chlorTde afforded the crude acid azide (79 9),
3 2140 cm 1. It was dissolved in toluene (400 ml), heated
at reflux for 2 hrs, and then cooled to 22 C. Concentrated
hydrochioric acid (80 ml) was added $nd the stirred mixture was
kept at 70 C for one hr, then heated at reflux for one hr,
The precipitated product was isolated by fiItratlon, washed with dlethyl
ether and dried to afford the title product, m p 227-229 C when
crystallized from a methanol-diethyl ether mlxture, anal. calculated
i for C16H17N.HCI: C, 73.97%; H, 6.98%; N, 5.39%; Cl, 13.65~ and
found: C, 73.60%; H, 6.79%; N, ~.39%; CL, 3.96%.
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AHP-7266
EXAMPLE 3
6 7-Dihydro-5H-dibenzora,clcyclohe~ten-5-y!methvlformamlde
6,7-Dihydro-5H-dibenzo[a,c]cyclohepten-5-ylmethylamine, obtained
from the hydrochloride salt (16 9, 0.062 mol, described in Example 2) by
treatment with sodium hydroxide, was treated for 20 hrs at 22C with
formic-acetic anhydride prepared by heating acetic anhydride (14.6 9,
0.14 mol) with formic acid (6.6 9, 0.14 mol) at 60C for 2 hrs. The
mixture was poured into ice water, made alkaline with a 10% aqueous
sodium ~ydroxide solution and extracted with diethyl ether to afford
iO the title product, mp 107-109C when crystallized from a chloroform-ethermixture, anal. calculated for C17H17 N0 C, 81.24%; H, 6.82~; N, 5.57% and
found: C, 81.34%, H,6.90%; N, 5.58%.
,:
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AHP-7266
EXAMPLE 4
1~11.12.12a-Tetrahvdrobenzor4.51cyc!ohepta[1,2,3-de]isoquinoline
6,7-Dihydro-5H-dibenzo[a,c]cyclohepten-~-ylmethylformamide
(607 9, 0.027 mol, described in Example 3) was stirred with polyphosphoric
-~ acid (50 9) for 3.5 hrs at 155-160C then poured into ice water.
- After stirring for 30 minutes the solution was made all<aline with a 30%
aqueous sodium hydroxide solution. Extraction with chloroform gave a
residue which was chromatographed on neutral alumina (Woelm, Activity 11).
Elution with benzene gave the title product as a solid softening at 100-
103C ~CaHxcl3 1634 cm 1; Mass spectrum, m/e 233 (~.W. 233).
,,
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AHP-7266
EXAI`~,PL~ 5
1.2J4,4a,12,13.13a 14-Octahydro-3H-benzor4 slcycloheptarl~2,3-delpyrido-
r2.1-alisoquinolin-3-one
1,11,12,12a-Tetrahydrobenzor4,5]cyclohepta[1,2,3-de]isoquinoline
hydrochloride (2 3.5 9, 0.087 mol),prepared from the corresponding free
base (described in Example 4) with anhydrous hydrogen chloride in diethyl
ether, and methyl vinyl ketone (200 ml) were combined and heated at
100C for 1.5 hr. On cooling to 20C a solid precipitated. It was
isolated by filtration and distributed between chloroform and 10% aqueous
sodium hydroxide. The chloroform phase afforded a semi-solid which was a
mixture of two compounds detectable by thin layer chromatography. It was
chromatographed on si1ica gel using benzene-ethyl acetate (12:1) as the
eluant. The first compound eluted was crystallized from benzene-hexane to
obtatn the less polar isomer, isomer A, of the title compound, mp 172-174C,
anal. calculated for C21H21NO: C, 83.13%; H, 6.98%; N, 7.63% and found:
C, 83.26%; H, 7.09%; N, 4.63%. Continued elution and crystallization from
benzene-pentane gave the more polar isomer, isomer B of the title
compound, mp 197-203C, anaJ. calculated for C21H21NO: C, 83.13%; H, 6.98%;
N, 7.63S =nd found: C, û3.27s; H, 7.11S; H, 4.4ZS.
';
~,
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4~
AHP-7266
_AI~IPLE 6
3-tert-Butvl-1.2.4.4a 12.13 13a 14-Octahvdro-3H-benzor4 ,5~YC lohepta-
rl,2.3-delpyrido~2.1-alisoquino~in-3,ol tl: R = tert-butyl and R = hydroxy)
To a solution of tert-butyl lithium in pentane (50 ml of a 1.8M
solution) was added during 30 min at 0-10C, a solution of isomer A of
1,2,4,4a,12,13,13a,14-octahydro-3H-benzo[4,5]cyclohepta[1,2,} de]pyrid~-
[2,1-a]isoquinolin-3-one (3.03 9, 0.01 moi. described in Example 5). The
mixture was kept ~t 10C for 1.5 hrs t~en at 22C for 16 hr. After addition
of 10% aqueous amn10nium chloride ~50 ml) the organic phase was separated,
dried and evaporated to afford a gum which was chromatographed on neutral
alumina (Woelm, Activity 11). Elution with benzene-hexane (9:1) afforded
isomer A of the title com~ound as an oil, ~Cmaxcl3 3615 cm . It was
converted to its hydrochloride salt with anhydrous hydrogen chloride in
diethyl ether and crystallized from diethyl ether-methanol to obtain the
hydrochlorTde salt of isomer A of the title compound, mp 276-279C,
anal. ~calculated for C25H31N0. HCI: C, 75.44%; H, 8.11%; N, 3.52%;
Cl, 8.91% and found: C, 75.44%, H, 8.11%; N, 3.35%; Cl, 8.81%.
In the sa,me manner but replacing isomer A of the starting materTal
with the corresponding isomer B, described in Example 5, gave isomer B of
the title compound, ~maHxcl3 3615 cm I and isomer B of the hydrochloride
salt of the title compound, mp 305-307C, anal. calculated for C25H31NO.HCI:
C, 75.44%; H, 8.11%; N, 3.52%; Cl, 8~91% and found: C, 75.32%; H, 8.23%;
N, 3.24%; Cl, 8.84~.
In the same manner but replaclng tert-butyl lithium with an
equivalent amount of methyl lithium, propyl llthlum or 3-methylbutyl
Iithium, the following compounds of formula I are obtained, respectively:
3-methyl-1,2,4,4a,12,13,13a,1 4 octahydro-3H-benzo~4,5]cycloheptarl,2,3-de]-
pyrido[2,1-a]isoquinolin-3-ol, } propyl-1,2,4,4a,12,13,13a,14-octahydro-
3H-benzo[4,5]cyclohepta~1,2,3-de]pyrido[2,1-a]isoquinolin-3-ol and 3-(3-
methylbutyl)-1,2,4,4a,12,13,13a,14-octahydro-3H-benzo[4,5]cyclohepta-
~l~2~3-de]pyrido~2~l-a]isoquinolln-3-ol.
;
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--19--
~ 81~S AHP-7266
EXAMPLE 7
,
N-(6,7-Dihydro-5H-dibenzora,c]cyclohepten-5-ylmethyl)-5-hydroxypelltanamide
6,7-Dihydro-5H-dibenzo[a,c]cyclohepten-5-ylmethylamine obtained
from the hydrochloride saIt (60.5 9, 0.234 mol, described in Example 2)
by treatment with~sodium hydroxide, was combined with 2-oxotetrahydropyran
( 35 9, 0.35 mol) and heated at 150C for 2 hrs. Ethanol (250 ml) was
added to the cooled mixture followed by a solution of potassium carbonate
(50 9, 0.36 mol) in water (150 ml). The mixture was stirred at 60C for
20 hrs, the ethanol was removed by evaporation under reduced pressure and
chloroform was added. The chloroform phase ~as dried and evaporated to
give a gum. It was crystallized from a benzene-diethyl ether mixture to
afford the title compound; mp 55-70C, anal. calculated for C21H25N02:
C, 77.98%; H, 7.79%; N, 4.33% and found: C, 77.39%, H, 7.97%; N, 4.05%.
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AHP-7266
EXAMPLE 8
2 3,4.4a,12 13.1~ /14-Octahydro-lH-benzo~4 ~ cloheptaLI.2.3-del~yr_do-
r2~1-ali$oauinoline(1_ R and R = H)
N-(6,7-Dihydro-5H-dibenzo[a,c]cyclohepten-5-ylmethyl)-5-hydroxy-
'pentanamide (25 9, 0.077 mol described in Example 7) was combined wlth
phosphorus ~ ychloride (250 ml) and the mixture was heated at reflux
for 3 'hrs. The phosphorus oxychloride was evaporated under reduced
pressure, the residue was dissolved in ethanol (250 ml), water (75 ml) was
added followed by saturated aqueous sodium hydroxide until a pH of 8-9
was reached. The mixture was heated at reflux for one hr. To this
mixture was added concentrated hydrochloric acid (100 ml), ethanol (100 ml)
and water tlOO ml) to obtain a solution containing 3,4,12,13,13a,14-hexahydro-
lH-benzor4,5]cyclohepta[1,2,3-de]pyridor2,1-a]isoquinolinium
chloride. Zinc powder (30 g) was added portionwise durina 30
minutes and the stirred mixture was heated at reflux for 3.5 hrs. After
filtration, the filtrate was fractionally distilled to remove ethanol, and
the remaining solution was made alkaline with concentrated aqueous ammonium
hydroxide an~ extracted with chloroform to afford an oil (25 g) which was
chromatographed on 1.2 kg of neutral alumina (Woelm, Activity 11). Elution
_ wTth hexane-benzene (9:1), evaporation of the eluates an'd crystallizatlon of the
residue using pentane gave the less polar isomer, isomer A of the title
compound; mp 118-120C, ana !. calculated for C21H23N: CJ 87.15%; H, 8.01%;
N, 4.84% and found: C, 86.23%, H, 8.26%; N, 4.76%. To a solut10n of Isomer
of the title compound in methanol-chloroform, hydrogen chloride gas was
~ added and the mixture was evaporated. The resTdue was crystallized from
; methanol-diethyl ether to obtain isomer A of the hydrochloride salt of the
title compound; mp 310-313C, anal. caIculated for C21H23N. HCI: C, 77.40%;
H, 7.42% and found: C, 77.41%; H, 7.44%.
Continued elution of the above column with hexane-benzene (I:l)and
evaporat'ion of the eluates gave a res'idue of the more polar isomer, isomer B of
the t7tle compound; mass spectrum,-m/é 289 and nmr (C~C13)~ 1.50 and 1.75 (m,6H),
2.45 (m, 6H), 3.35 (two doublets, IH) and 3.76 (~, IH). The hydrochloride
salt of isomer B of the title compound was prepared in the same manner as
described above and crystallized from methanol-diethyl ether; mp 278-283~!C,
anal. calculated for C21H23N. HCI: C, 77.40%; H, 7.42%; N, 4.30%; Cl, 10.88%
and found: C, 76.86%; H, 7.33%, N, 4.04, Cl, 10.74%.
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AHP-7266
EXAMPLE 9
2~3~4~4a~l2~l3~ ~ l4-nctahvdro-!H-benzor4~5l ~cloheptarl.2t3-delpyrido-
r2.1-alisoquinoline(l: R and R ~ H)
A solution of isomer A of 1,2,4,4a,12,13,13a,14-octahydro-3H-
benzo[4~5]cycloheptarl~2~3-de]pyrjdo[2~1-a]isoquinolin-3-one (416 mg, 1.37
mmoles, described 3n Example 5), acetic acid (20ml), ethanedithiol (3 ml~ and
boron trifluoride etherate (I ml) was allowed to stand at room temperature
overnight. The reaction mixture was poured into water and extracted with - -
chloroformO The organic solution was washed twice with 5~ aqueous sodium
hydroxide solution, water, dried and evaporated to give a yellow-paste
(578 mg).
The residue was dissolved in tetrahydrofuran and added to a hot
stirred mixture o Raney njckel (15 9) in tetrahydrofuran (70 ml) and the
m7xturs was refluxed for 3 hrs. Additional Raney nickel (10 9) was added
and heating with stirring continued for 2 - hrs. The mixture was coolled
and fiItered and the fiItrate was treated with-hydrogen chloride gas. The
mixture was evaporated and the residue was crystallized from methanoi-diethyl
ether to obtain the hydrochloride salt of isomer A of the title compound,
i 20 mp 310C (identical to the hydrochloride salt of isomer A of the title compound of Example 8).
-22
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