Note: Descriptions are shown in the official language in which they were submitted.
P.C. 5874
``~ 1094071
Following the introduction of reserpine and chlorpromazine in
psychotherapeutic medicine in the early 1950's, great effort has been expended
in the search for other tranquilizing agents having improved biological
profiles, several of which are y-carboline derivatives, also known in the art
as derivativès of pyrido[4,3-b]indole.
It has now been found fhat certain trans-2-substituted-5-aryl-2,3,4,
4a,5,9b-hexahytro~ pyridol4,3-b]intole derivatives are extremely effective
as tranquilizing agents.
In U.S. 3,687,961 8-fluoro-2-~3-(4-fluorophenglanilino)propyl]-
1,2,3,4-tetrahydro-y-carboline was disclosed as a useful tranquilizer for warm-
blooded animals. In U.S. 3,755,584 structurally related compounds with fluorir e
in the 6- or 8-positions and a specific E~substituted phenylalkyl iety at
the 2-position were found to have similar activity.
U.S. 3,983,239 tiscloses hexahydro-y-carbolines of the formula
~1 ~ J~-(Cl2)3 ~ ~ ,
-R
1 2
where R is methyl or ethyl and R i8 hydrogen, methyl or ethyl. The stereo-
chemical relationship of the hydrogen atoms attachet to the carbon atoms at the
4a and 9b positions is not mentioned in this reference. ~owever, one would
expect them to~be in a cis relationship baset on the method of formation
of the hexahydro-y-carboline nucleus from a 1,2,3,4-tetrahydro-y-carboline
precursor by catalytic hydrogenation in the presence of platinum, a method
well known in the art to intrcduce hydrogen atoms in a cis-configuration to a
carbon-carbon double bond. The compounds claimed are neuroleptic agents said
to be useful in the treatment of schizophrenia.
1094071 `
U.S. 3,991,199 discloses hexahydropyrimidor4,3-b]indoles, usetul as
analgesics and sedatives, some of which are of interest as tranquilizers, some
as muscle relaxants and many of them show hypotensive activity; the compounds
di~clo8ed are of the fonmula
xa H,
_Ra
ya ~ ;
.,
and their pharmaceutically suitable salt~, where the hydrogens attached to the
carbon atoms in the 4a and 9b positions are in tran~ relationship to each other
and where: when Y is -H, X is -H, -Cl, -Br, -CH3, -tert-C4Hg or -OCH3; and
when Y is -CF3, X is -H; and Ra is hydrogen, 3-chloro-2-butenyl; 2-bromo-
A11yl; benzyl; benzyl ring-substituted with methyl, methoxy or chloro; phen-
10 ethyl; 3-pheny~propyl; 3-phenylpropyl ring-substituted with chloro, bromo or
methoxy; furfuryl; 2-thenyl; Cl-C5 alkyl; C3-C5 alkenyl; C3-C5 alkynyl;
- cinnamyl; cinnamyl ring-substituted with chloro, bromo, or methoxy; 3-phenyl-
2-propynyl; C3-C7 cycloal~yl; C4-C8 cycloalkylmethyl; (methylcyclopropyl)-
~methyl; (cis-2,3-dimethylcyclopropyl)methyl; C6-C8 cycloalkenylmethyl; C6-C8
cycloalkadienylmethyl; (2,3-dimethylcycloprop-2-en-1-yl)methyl; exo-7-nor-
carylmethyl; (cis-1,6-dimethylendo-3-norcaren-7-yl)methyl; (4-me~hylb~cyclo-
~2~2.230c~-l-yl)methyl; ~4-methylbicyclo~2.2.2]oct-2-en-1-yl)methyl;
(bicyclo~2.2.2~hept-2-yl)methyl; (bicyclo~2.2.2~hept-2-en-S-yl)methyl; 1-
adamantylmethyl; or 2-adamantylmethyl.
. .
- 2a_
1094071
Recently issued Belgian patent ~o. 845,3~8 (Derwene No. 00043Y) tis-
closes 5-phenyl-hexahydro-~-carbolines, optionally substituted at positions 2
ant 4 by methyl or ethyl and at position 3 by alkyl havin~ fro~ 1 to 3 carbon
atoms, allyl or propargyl. They are useful as antidepressants.
Recene West German Offenlegungsschrift 2,631,836, Derwent ~io.
0973aY, discloses structurally related octahydropyrido[4',3':2,3]indolo[1,7-
ab]fl]benzazepines which may be depicted by the above formula in which ya is
an ethylenic bridge between the two benzene rings, Xa is hydrogen and Ra i5
CH2CH2COCH3 or CH2CH200C6~5. They are said to be useful as analgesics and
tranquilizing agents.
U.S. 4,001,263 discloses S-aryl-1,2,3,4-tetrahydro-y-carboline
tranquilizers of the formula
~; ~N-Rb
~. ~
where X and Z may be hydrogen or fluoro and values of ~b include those given
above for R in formula (I). It has now, unexpectedly, been found that the
trans-2,3,4,4a,5,9b-hexahydro-1~-pyrido~4,~-b3indoles of the present invention
have markedly superior tranquilizing activity when compared with the corres-
ponding 1,2,3, ~ tetrahytro-y-carbolines.
1094071
The tranquilizing agents of the invention are racemic 2-
substituted-5-aryl-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indoles
of the formula (I):
X ~ N-R ---(I)
~y
and the pharmaceutically-acceptable salts thereof, wherein the hydrogen
atoms in the 4a position and 9b position are in a trans relationship to
each other and X and Y are the same or different and are each hydrogen
or fluoro; R is a member selected from the group consisting of
~ /=VZ
~(CH2)m~M~ ~ ( 2)m ~ wherein n is 3 or 4,
m is 2 or 3,
O OH
l! ~
M is -C- or -CH-; and Z is a member selected from the group consisting
of hydrogen, fluoro or methoxy.
-- 4 --
1094071
Still further preferred tranquilizing agents of the
present invention are the racemic compound of the formula
Xl ~ ^(CH2)n-M- ~ 1 ---(II)
_,
~Yl
and the pharmaceutically acceptable salts thereof, wherein the
hydrogens attached to the carbon atoms in the 4a and 9b positions
are in a trans-relationship to each other and Xl and Yl are the
same or different and are each hydrogen or fluoro; n is 3 or 4;
O OH
Il I
M is -C- or -CH- and Zl is a member selected from the group con-
sisting of hydrogen, fluoro and methoxy.
Other preferred tranquilizing agents of the invention
are the racemic compounds of the formula
Xl ~ N-(CH ) -Ch=CH- ~ 2 ---(III)
~Yl
and the pharmaceutically acceptable salts thereof, wherein the 4a
and 9b hydrogens are in the same trans-relationship as above, X
and Yl have the values set forth above, m is 2 or 3 and Z2 is
fluoro or methoxy.
j~ :
~09~07i
The invention further provides methods for the treat-
ment of schizophrenic manifestations in mammals which comprises
orally or parenterally administering to a mammal in need of
such treatment a tranquilizing amount of a compound selected
from those of the formulae (II), (III) and (IV).
Also provided are pharmaceutical compositions active
as tranquilizing agents comprising a pharmaceutically acceptable
carrier and a compound selected from those of the formulae (II),
(III) and (IV).
The compounds of the present invention have a markedly
and unexpectedly superior tranquilizing effect over the above
mentioned tranquilizing agents of the prior art.
Especially preferred tranquilizing agents of the in-
vention are the racemic mixtures of:
trans-8-fluoro-5-(~-fluorophenyl)-2-[4-hydroxy-4-(~-fluoro-
phenyl)butyl]-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole,
trans-S-phenyl-2-[4-hydroxy-4-(~-methoxyphenyl)butyl]-2,3,4,4a,5,9b-
hexahydro-lH-pyrido[4,3-b]indole,
-- 6 --
1094071
trans-8-fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4~ eehoxyphenyl)butylJ-
2,3,4,4a,5,9b-hexahydro-IH-pyrido~4,3-b]indole,
trans-5-phenyl-2-(4-hydroxy-4-phenylbutyl)-2,3,4,4a,5,9b-hexahydro-lH-pyrido-
~4,3-b]indole,
trans-8-fluoro-5-(p-fluorophenyl)-2-(4-hydroxy-4-phenylbutyl)-2,3,4,4a,S,9b-
hexahydro-lH-pyrido[4,3-b]indole,
trans-5-phenyl-2-~3-~-fluorobenzoyl)propyl]-2,3,4,4a,5,9b-hexahydro-IH-pyrido-
[4,3-b3indole,
trans-8-fluoro-5-(p-fluorophenyl)-2-[3-~p-fluorobenzoyl)propyl]2,3,4,4a,5,gb-
hexahydro-lH-pyrido[4,3-b]indole,
trans-8-fluoro-5-~-fluorophenyl)-2-[4-~-fluorophenyl)-3-butenyl]-2,3,4,4a,5,9b-
hexahydro-IK-pyrido[4,3-b3indole,
trans-&-fluoro-5-~-fluorophenyl)-2-[4-(~-methoxyphenyl)-3-butenyl]-2,3,4,4a,
5,9b-hexahydro-lH-pyrido[4,3-b]indole,
trans-8-fluoro-5-(o-fluorophenyl)-2-[4-hydroxy-4-(~-fluorophenyl)butyl]-2,3,4,
4a,5,9b-hexahydro-lH-pyrido~4,3-b]indole,
trans-5-phenyl-2-~4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-
lH-pyrido[4,3-b]indole,
trans-8-fluoro-5-~-fluorophenyl)-2-[4-(~-fluorophenyl)-3-butenyl]-2,3,4,4a,5,
9b-hexahydro-lH-pyrido~4,3-b3indole.
~094071
The following reaction scheme is illustrative of the
processes which may be employed for synthesis of the 4a,9b-trans-
2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indoles of formula (X)
wherein X and Y are as previously defined:
X ~ (2) H X ~ N-R2
~y ~Y
(VIII)
(IX)
(IX) (1) ClCO2C2H5 X ~ NH
~2) KOH~ C2H5H/H2 ~ N ~
~Y
~X)
- 8 -
10~071
A preferred value for R2 is benzyl for reasons of economy. However, other
values of R2 which will also serve in the above scheme will be obvious to
those skilled in the art. Examples of such alternate values for R2 are benzyl
moieties substitutet in the benzene rin~ by, for example, one or more members
selected from the group consisting of methyl, methoxy, nitro and phenyl; and
benzhydryl.
The reduction of the tetrahydro-y-carbolines of formula (VIII) to
form the 4a,9b-trans-hexahydro compounds of formula (IX) is carried out in an
ether solvent, usually tetrahydrofuran. In order to assure complete reduction
10 ~ a molar excess of borane/tetrahydrofuran complex (BH THF) is ordinarily employed
and a 100 to 200X lar excess of said complex is preferred. While the reaction
may be carried out at a temperature in the range of about -1~ to 80C., a temp-
erature of from about O to 65 C. is preferred. Ordinarily, a solution of tne
starting material of formula (VIII) in tetrahydrofuran is atded to an ice-
cooled solution of BH3-THF. After the addition is complete the reaction mixture
. is heated to reflux and maintained at this temperature for a period of about one
to two hours or more. The reaction is ordinarily carried out in the presence
of an inert gas such as nitrogen. When the reaction is substantially completed,
the solvent is evaporated and the residue is acidified with an excess of an acid
such as, for example, 2 to 12 molar hydrochloric acid. A preferred acidulant
is a mixture of equal volumes of acetic ac~d and 5 molar hydrochloric acid. The
acid~fied mixture is ordinarily heated at reflux for 1 to 2 hours or more. The
desired product may then be isolated, for example, by e~aporation of any
residual ether solvent and a portion of the acid mixture and the precipitated
product collected by fil~ration and washed. In an alternate method of isolation
of the product (IX), after the reflux period the reaction mixture is filtered,
the filtrate cooled and made alkaline by addition of, for example, sodium
hydroxide, potassium hydroxide or sodium carbonate. The basic mixture is ex-
tracted with a water immiscible or~anic solvent such as, for example,
g
iO94071
chloroform, methylene chloride or benzene, the extracts evaporated and the
residue purified by s~lica gel column chromatography, eluting, for example, with
ethyl acetate or mixtures of hexane/ethyl acetate.
The reduction of tetrahydro-y-carbolines by BH3-T~F followed by acid
treatment yields hexahydro- r carbolines in which the hytrogens attached to the
carbon atoms in the 4a and 9b positions are in a trans-relationship, see, for
example, U.S. 3,991,199.
The 2-benzyl compounds of formula (IX) are then converted to the cor-
responding 2-hydrogen compounds of formula (X). In general, this may be accom-
plished by treating the compound of formula (IX) with a molar excess of a loweralkyl chloroformate ester such as, for example, the methyl, ethyl, propyl or
isobutyl ~ster in the presence of a suitable reaction-inert organic solvent,
followed by alkaline hydrolysis. Preferred as chloroformate ester is ethyl
chloroformate because of its- ease of availability and efficiency. By a
suitable reaction-inert organic solvent is meant one which will substantially
.dissolve the reactants under the conditions of the reaction without the
formation of byproducts. Examples of such solvents are aromatic hydrocarbons
such as benzene, toluene and xylene; chlorinated hydrocarbons such as chloroform
and 1,2-dichloroethane, diethyleneglycol dimethylether and dimethylsulfoxide.
An especially preferred solvent is toluene.
To the mixture of star ang material of formula (IX) in said reaction
~nert organic solvent is added up to about a ten molar excess of the chloroformate
ester. For reasons of economy a molar excess of about 3 to 5 is preferable.
~ The res~lting mixture is then heated at a temperature of trom about 80-150C.,
typically at the reflux temperature of the mixture, for periods of about 6 to
24 hours or more. Ordinarily, refluxing is carried out overnight for reasons
of convenience. ~he reaction mixture is t~en evaporated in vacuo and the residue
taken up in an alcohol-water mixture, an alkali, for example, sodium hydroxide
-- 10
10940 71
or potassium hydroxide, is added in about 10-30 molar excess based
on the amount of starting material of formula (IX), and the resulting
mixture heated at reflux, typically overnight. The solvent is then
evaporated and the residue partitioned between water and a water im-
miscible organic solvent such as, for example, chloroform, methylene
chloride or ethyl ether and the organic phase evaporated to dryness.
The residual product of formula (X) may be used as is or further puri-
fied by standard methods known in the art, for example, by column
chromatography on silica gel.
In the case of compounds of the formula ~IX) wherein both
X and Y are hydrogen and R2 is benzyl, the corresponding compound of
formula (X~ may be obtained by catalytic debenzylation employing hydro-
gen and a palladium-on-carbon catalyst. The reaction is typically
carried out employing the hydrochloride salt of the compound (IX) at
a temperature of from about 50 to 100C, preferably 60-75C, and
hydrogen pressures of about 20-100 p.s.i. ~1.4-7 kg/cm ) in the pre-
sence of a reaction-inert solvent, for example, methanol, ethanol,
isopropanol, ethyl acetate or mixtures thereof with water. When the
hydrogen uptake is complete, the catalyst is removed by filtration and
the hydrochloride salt of the product of formula ~X) is precipitated
by addition of a nonsolvent, for example, ethyl ether, benzene or
hexane. Alternatively, the free base of formula (X) may be isolated
by evaporating the filtrate from the debenzylation to dryness, par-
titioning the residue between aqueous alkali, for example sodium
hydroxide, and a solvent such as chloroform on ethyl ether. The free
base is then isolated by standard methods such as those described
above.
~,~ - 11 -
1094071
The free bases of formula ~X) serve as precursors
for the novel compounds of formula ~VI) as illustrated by the
followin~ reaction sequence wherein X, Y, Z and n are as pre-
viously defined.
S (X) ~ ~- (CH2) n--lCOH ~C~ (CH2) n lC-~
~XII) ¦ ~XIII) z
OH
~XIII) ~ ~ -(CH2)nCH
¦ ~VI)
~y
~ - 12 -
10940~7~
The acylation of the compounds (X? to form the intermediates of formula (XIII)
may employ the acids of formula (XII) or the corresponding acid chlorides or
acid bromides. When the acids of formula (~II) are employed in the acylation,
approximately equi lar amounts of said acid ant compount of formula (X) are
contacted in the presence of a reaction-inert organic solvent and certain
condensing agents known in the art for forming peptide bonds. Such agents include
carbodiimides, for e a mple, dicyclohey lcarbodiimide and l-ethyl-3-(3-dimethyl-
aminopropyl) carbodiimide hydrochloride, and alkoxyacetylenes, for example,
methoxyacetylene and ethoxyacetylene. The preferret condensing agent is
dicyclohexylcarbodiimide. Examples of said solvents which may be employed are
dichloromethane, chloroform, tetrahydrofura~, ethyl ether and benzene. While
the reaction may be carried out at a temperature of from about -10 to 50 C.
with sati~factory results, it is preferred to employ a temperature of from
about 0 to 30 C. At this temperature the reaction is ordinarily complete
in a few hours. The product of formula (XIII) is isolated, for example, by
filtering to re ve insoluble material and evaporation of solvent. The resulting
product is ordi~arily of sufficient purity for use in the next step.
The intermediate of formula (XIII) is then reacted with lithium
aluminum hydride as described above in the preparation of 2-meehyl compounds
of formula (XI). The product of formula (VI) is isolated also as described
- above and purified, for example,by column chromatography on silica gel.
B~
1~94071
An alternate methot for providing the 4a;9b-trans-compounts of formula
(Vl) in admixture with the corresponding dehydrated compounds of formula (VII)
is illustrated as follows:
X ~Z
~ (CH2)n 1 ~ (l)BH3/ether
~V)
' Y
(Vl) + ~ N-(CH2)m-CH=CH
-
1 ~
~ IVII )
In which X, Y, Z, n and m are as previously defined. The reaction with borane
in ether solvent preferably in tetrahydrofuran and subsequent treatment with acid
is carr~ed out under the conditions described above for preparation of the 2-
benzyl compound~ of formula (IX). The product~ (Vl) and (~II) are separated,
; for example by column chromatography on silica gel.
The relative amounts of products (Yl) and (VII) will vary depending
upon the amount of acid, for example, hydrochloric acid, and the time of heating
at reflux after the reduction w~th BH3-THF has taken place. Hi8her amounts of
acid and longer reflux times fa~or the dehydrated product of formula (VII); while
lower amounts of acid and shorter reflux periods favor the formation of the product
(Vl).
, .
B ~
` 1094071
The compounds of formula (YI) may also serve as precursors of the
free bases of formula X. This is carried out employing, for example, ethyl
chloroformate followed by alkaline hydrolysis as described above for the
debenzylation of the com2ounds of formula (IX~ wherein ~ is benzyl, eo obtain
the free bases of formula (X).
Oxidation of the compounts of formula (Vl) e~ploying reagents and
conditions which are known to selectively convert secondary alcohols to the
corresponding ketones, provides the novel products of formula
., g Z
~ ( 2)n ,, ~
- I~
l ~ (XIV)
wherein X, Y, Z and n are as previously defined. Examples of such oxidizing
agents which may be employed in this reaction are potassium permangana~e,
potassium dichromate and chromium triox~de and the preferred reagent is
chromium trioxide in the presence of pyrldine. In carrying out this reaction
with the preferred reagent, the starting alcohol of for~ula (Vl) in a reaction-
~ inert solvent, for example, dichloromethane, chloroform or benzene, is added
to a mixture containing up to a ten molar excess of chromium trioxide anda similarly large molar excess of pyridine and the mixture stirred, ordinsrily
at room temperature, until the reaction is substantially complete. Ordinarily,
B ~
10940~7~
from about 15 minutes to one hour will suffice. The product is isolated,
for example, by removal of insoluble material by filtration, extracting the
filtrate with a dilute aqueous aIkali such as sodium hydroxide solution, drying
the organic layer and evaporating to drynesg. The regidual product may be further
purified, if desiret, for example, by column chromatography.
Preparation of Starting Materials
2-Benzyl-5-phenyl-1,2,3,4-tetrahydro- rcarboline is obtained by the
Fischer indole synthesis employing N,N-diphènylhydrazine ant N-benzyl-4-piperi-
done. The mono or difluoro-substituted star~ing tetrahydro-y-carbolines of
formula (VIII) wherein at least one of X or Y is fluoro and R2 is benzyl, are
prepared from the corresponding compounds of formula (VIII) wherein R2 is
hydrogen by reaction w~th a benzyl halide such as benzyl bromide, in equ$molar
amounts. The requisite compounds cf formula (VIII, R2 = H) are prepared as
described in U~S. 4,001,263. The starting tetrahydro-y-carbolines (V) are
described in the same reference.
The other starting materials are either commercially available,
the~r preparation is explicitly reported in the chemical literature or they
can be prepared by methods known to those skilled in the art. For example,
the phenylhydrazines are commerc~ally available or are synthesized by reduction
of the phenyldiazonium salt as reviewed by Wagner and Zook in "Synthetic
Organic Chem~stry", John Wiley & Sons, New York, N.Y., 1956, Chapter 26; the
l-substituted-4-piperidones are commercial reagents or prepared by the method of
McElvain and Rorig, J. Am. Chem. Soc., 70, 1826 ~1948); the req~isite 3-
benzoylpropionic acid~ and 4-benzoylbutyric acids are either commercially
available or prepared ~y modification of the procedure af "Organie Synthesis",
Coll. Vol. 2, John Wiley and Sons, New York, N.Y., 1943, P. 81.
r~
1~ _ ~,~_
~ D
1094071
As has been previously mentioned, the basic compounds of the present
invention can form acid addition salts. Said basic compounds are converted to
their acid addition salts by interaction of the base with an acid either in an
aqueous or nonaqueous medium. In a similar manner, treatment of the acid addi-
tion salts ~ith an equivalent amount of an aqueous base solueion, e.g., alkalimetal hydroxites, alkali metal carbonates ant alkali metal bicarbonates or with
an equivalent amount of a metal cation which forms an insoluble precipitate with
the acid anion, results in the regeneration of the free base form. The bases
thus regenerated may be reconverted to the same or a different acid addition
~alt.
In the utilization of the chemotherapeutic activity of said salts of
the compounds of the present invention, it is preferred, of course, to use
pharmaceutically acceptable salts. Although water-insolubility, high toxicity,
or lack of crystalline nature may make some particular salt species unsuitable
or less desirable for use as such in a given pharmaceutical application, the
water insoluble or toxic salts can be converted to the corresponding pharma-
ceutical accep~able bases by decomposition of the salt as describet above, or
alternately, they can be converted to any desirèd pharmaceutically acceptable
acid addition salt.
2~ Examples of acids which provide pharmaceutically acceptable anions
are hydrochloric, hydrobromic, hydraiodic, nitric, sulfuric, sulfurous, phos-
; phoric, acetic, lactic, citric, tartaric, succinic, maleic and gluconic acids.
As previously indicated, the compounds of the present invention are
readily adapted to therapeutic use as tranquilizing agents in mammals.
1094071
The tranquilizing agents of the present invention are characterized
by relief of such schizophrenic manifestations in humans as hallucinations,
hostility, suspiciousness, emotional or social withdrawal, anxiety, agitation
ant tension. Standard procedures of deeecting and comparing tranquilizing
activity of compounds in this series and for which there is an excellent
correlation with human efficacy is the antagonism of amphetamine-induced
symptoms in rats test, as taught by A. ~eissman, et al., J. Pharmacol. Exp.
Ther., 151, 339 (1966) and by Quinton, et al., Nature, 200, 178 (1963).
The y-carbolines and the pharmaceutically acceptable salts thereof,
which are useful as tranquilizers, can be admini~tered either as individual
therapeutic agents or as mixtures of therapeutic agents. They may be adminis-
tered alone, but are generally administerèd w~th a pharmaceutical carrier
selected on the basis of the chosen route of administration and standard
pharmaceutical practice. For example, they can be administered orally in the
form of tablets or capsules containing such excipients as starch, mil~ sugar,
or certain types of clay, etc. They can be administered in the form of
elixirs or oral suspensions with the active ingredients combined with
emulsifying and/or suspending agents. They may be injected parenterally,
and for this use they, or appropriate derivatives, may be prepared in the form
of sterile aqueous solutions. Such aqueous solutions should be suitable buffered,
if necessary, and should contain other solutes such as saline or glucose to
render them isotonic.
Although the use of the present invention is directed toward the
` treatment of mammals in general, the ~referred subiect is humans. Obviously,
the physician will ultimately determine the dosage which will be st suitable
for a particular individual, and it will vary with age, weight ar~ response of
the part~cular patient~ as well as with the nature and extent of ehe symptoms
an~ the pharmacodynamic characteristics of the particular agent to be
B ~
, .
~094071
administered. Generally, small doses will be administered ini-
tially, with a gradual increase in the dosage until the optimum
level is determined. It will often be found that when the com-
position is administered orally, larger quantities of the active
ingredient will be required to produce the same level as pro-
duced by a smaller quantity administered parenterally.
Having full regard for the foregoing factors, it is
considered that a daily dosage of the compounds of the instant
invention in humans of approximately 0.5 to 100 mg., with a pre-
ferred range of 1 to 25 mg., will tranquilize effectively. In
those individuals in which the compounds of the present invention
have a prolonged effect, the dose can be 5 to 125 mg. a week,
administered in one or two divided doses. The values are illus-
trative, and there may, of course, be individual cases where
higher or lower dose ranges are merited.
All of the compounds of formula (I) have at least two
asymmetric centers resulting from the reduction of the 4a,9b-
double bond to the trans-fused system. In addition, if the 2-
position substituent (R) includes a grouping capable of existing
in stereoisomeric forms, all the resulting diastereoisomers are
also included in the invention.
The following examples are provided solely for the
purpose of illustration and are not to be construed as limitations
of the invention, many variations of which are possible without
departing from the spirit or scope thereof.
- 19
, r,~
,t~
1094071
EXAMPLE 1
_ -trans-2-benzyl-2,3,4,4a,5,9b-hexahydro-5-phenyl-lH-pyrido-
~4,3-b]indole Hvdrochloride
To a solution of 0.140 moles of borane in 150 ml. of tetrahydrofuran
stirret at 0 C. in a ehree-necked round bottom flask fitted with magnetic
stirrer, thermometer, condenser and addition funnel, and maintained under a
` nitrogen at sphere, was added a solution of 23.9 g. (0.071 mole) of 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indole in 460 ml. of dry tetrahydro-
furan. The addition was carried out at such a rate as to maintain the reaction
temperature below 9 C. When the adtition was completed the resulting mixture
was heated to reflux and maintained at this temperature for one hour. The
solvent was then evaporated in vacuo to afford a white solid mass which was
suspended in 40 ml. of dry tetrahydrofuran and heated, slowly at first, with
180 ml. of a 1:1 by volume mixture of acetic acid and 5W hydrochloric acid.
The resulting suspension was heated at reflux for one hour, then cooled.
Evaporation of tetrahydrofuran and part of the acetic acid resulted in precipi-
tation of a white solid which was separated by filtration and washed with
water. The solid was resuspended in tetrahydrofuran, filtered, washed with
ethyl ether and air dried to afford 16.7 g. (63%) of the desired trans-isomer.
M.P. 256-260 C.
Evapora~ion of ~he mother liquor gave an additional 7.2 g. of product
contaminated with a small amount of the cis-isomer.
When the above procedure i~ repeated, but employing the appropriately
substituted 2-benzyl-5-phenyl-1,2,3,4-tetrahydropyrido[4,3-b]indole as starting
material, the following 4a,9b-trans-compounds are obtained in like manner as
~heir hydrochloride salts.
B ~
1094071
X ~;-CH2C6H5
X Y X Y
H ~-fluoro H o-fluoro
F H F m-fluoro
F p-fluoro F o-fluoro
EXAMPLE 2
-~E~-5-Phenyl-2 2 3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole
A suspension of 4.17 g. _ -trans-2-benzy1-5-phenyl-2,3,4,4a,5,9b-hexa-
hydro-lH-pyrido[4~3-b~indole hydrochloride in 150 ml. of absolute ethanol was
hydrogenated at~50 p.s.i. and 60-70C. using 1.0 g. of 10~ Pd/C catalyst, over
a two-hour period. The catalyst was removed by filtration and to the filtrate
was added sufficient ethyl ether to precipitate the hydrochloride of the desired
product, 2.76 g. ~87%), M.P. 235-237C.
The hydrochloride salt was converted to free base by partitioning
between ether and dilute sodium hydroxide solution. The ether layer was dried
over sodium sulfate and evaporated to afford the title compound (97~ yield),
~.P. 74-76C.
B ~,
1094071
EXAMPLE 3
dl-trans-8-Fluoro-5-(~-fluorophenyl)-2-[4-hydroxy-4-(~-fluoro-
phenyl)butyl~-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b~indole
hydrochloride and
_ -trans-8-Fluoro-5-(p-fluorophenyl)-2-[4-(p-fluorophenyl)-3-
butenyl~-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b~indole hydro-
; chlorite
In a 1000 ml. reaction vessel equipped with magnetic stirrer, dropping
funnel and maintained under a nitrogen atmosphere were placed 177 ml. of 0.94
molar borane in tetrahydrofuran. The solutio~n was cooled in an ice bath and to
the cold solution was added over 30 minutes a solution of 25 g. (0.0555 mole)
of 8-fluoro-5-(p-fluoropbenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl~-2~3~4~5
tetrahydropyrido[4,3-b]indole in 295 ml. of tetrahydrofuran. The resulting
mixture was stirred at ambient temperature for 20 minutes, then heated at
reflux for rwo hours. The reaction mixture was cooled and concen~rated ~n vac-
uo to obtain a liquid residue. To this was added a mixture of 50 ml. each of
acetic acid and 5N hydrochloric acid whereupon vigorous gas evolution took
place. The mixture was heated at reflux for one hour, cooled to room temperature
and filtered. The filtrate was cooled in ice and made alkaline by addition of
50X (w/w~ sodium hydroxide solution. ~le basic mixture was extracted twice
with 150 ml. portions of chloroform, the combined organic layers dried over
magnesium sulfate and evaporated to dryness in vacuo to obtain a yellow foamed
solid, 25 g. Silica gel thin-la-yer chromatography, employing a 1:1 by volume
hexane/ethyl acetate solvent system, revealed two products. The foamed solid
was chro~atographed on a column of silica gel, eluting with 1:1 by volume
hexane/ethyl acetate and monitoring the fractions by TL~. The fractions con-
taining only the faster moving ~roduct, i.e. 8-fluoro-5-(p-fluorophenyl)-2-[4-
fluorophenyl)-3-butenyl~-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-blindole
were evaporated to dryness taken up in acetone and converted to the hydrochlo-
ride salt by addition of anhydrous hydrogen chloride in acetone, the resulting
.
_ ,~ _
~094071
white solid was collected by filtration and dried to obtain 1.5 g. of the 3-
butenyl compound, M.P. 270-273 C.
The fractions containing only the slower moving 8-fluoro-5-(p-fluoro-
phenyl)-2-~4-hydroxy-4-(p-fluorophenyl)butyl]-2~3~4~4a~5~9b-hexahydro-l~-
pyrido~4,3-b]indole were concentrated, taken up in ethyl ether and converted to
hydrochloride salt by addition of anhydrous hydrogen chloride to obtain 10.8 g.
of this product, N.P. 241-245 C.
- The proportion of the faster moving 3-butenyl compound is increased,
up to lOOZ, by suitable increase in the acidi~y and period of heating at reflux
in the acetic/hydrochloric acid mixture.
EXAMPLE 3A
When the procedure of Example 3 was repeated, but starting with 8-
fluoro-5-(o-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyll-2,3,4,5-tetra-
hydropyrito[4,3-b]indole, the faster moving co~ponent from silica gel chromato- -
lS graphy was identified a-~ trans-8-fluoro-5-(o-fluorophenyl)-2-[4-(p-fluorophenyl)-
3-butenyl]-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b¦indole, M.P. 141-142C.
The slower moving component was identified as trans-8-fluoro-5-(o-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]-2,3,4,4a,S,9b-hexahydro-1~-pyrido[4,3-b]-
indole, M.P. 195-197C.
B .2 3
~ 24~ ~
10940~7'1
EXAMPLE 4
Employing the appropriate compounds of fonmula (V) as starting
materials in the procedure of Example 3, the indicated 4a,9b-trans-product~
of formulae (VT) and (VII) were obtained and ~eparated in each case. In
the products of formula (VII) m - n-l.
~`~C~N-(G~2):~G!~
,~ (V)
: Y
~I N-(GN2~.-G~
(~3 (VI) ' .
.Y
N-(CH2)mCH=CH
~ ~Z
~ (VII)
~2
10940'71
n x Y - z
3 F p-fluoro m-fluoro
3 F p-fluoro H
3 H p-fluoro p-methoxy
3 F H o-methoxy
3 H H ~-fluoro
4 F p-fluoro p-fluoro
4 F p-fluoro p-methoxy
4 F p-fluoro H .
4 F H o-fluoro
4 F H m-methoxy
4 H p-fluoro ~-fluoro
4 H p-fluoro H
4 ~ H H
4 H o-fluoro ~-fluoro
3 H o-fluoro ~-fluoro
3 H m-fluoro m-fluoro
3 F o-fluoro ~-methoxy
3 H m-fluoro H
20 ~ 4 F o-fluoro o-fluoro
4 F m-fluoro ~-methoxy
r~
B
1094071
E2AMPLE 5
_ -crans-8-Fluoro-5-(p-fluorophenyl)-2~3~4~4a~5~9b-hexahydro-
lH-DYrido r 4,3-bl~ndole
.
A. To a solution of 5.6 g. (12.4 mmole) of _ -trans-8-fluoro-5-(~-
fluorophenyl)-2-~4-hydroxy-4-(~-fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-lH-
pyrido~4,3-blindole in 40 ~1. of toluene was added 5.3 ml. (55.7 mmole) of
ethyl chloroformate. The resulting mixture refluxed overnight then evaporated
to dryness to obtain a residual gum. To the gum was added 200 ml. of a 9:1
by volume mixture of ethanol/water. After the gum was dissolved, 15 g. of po-
tassium hydroxide was added and the resulting mixture refluxed overnight. The
solvent was evaporated in vacuo and the residue partitioned between water and
chloroform. The organic extracts were washed with water, dried over sodium
sulfate and evaporated to dryness. The residual oil was taken up in ethyl
acetate and passed through a silica gel column eluting first with ethyl acetace
to remove by-products then eluting the desired product with 1:1 by volume ethyl
acetate/methanol. The fractions containing the title compound were combined and
evaporated to dryness to obtain 1.5 g. (43%) of yellow gum which crystallized
upon standing, M.P. 115~117C.
B. Alternately, _ -trans-2-benzyl-8-fluoro-5-(p-fluorophenyl)-2,3,4,-
; 4a,5,9b-hexahydro-lH-pyridot4,3-b]indole hydrochloride is refluxed in the pre-sence of excess ethyl chloroformate or the corresponding methyl, isopropyl or
n-butyl chloroformate esters, then hydrolyzed and worked up by the procedure
described above to obtain the title compound.
_ ,~
1094071
EXAMPLE 6
Employing the appropriate starting material in each case and employing
the procedures of Example SA or 5B, the following products are similarly ob-
tained:
_ -tran3-5-(~-fluorophenyl)-2,3,4,4a,5,9b-hexahytro-lH-pyrito[4,3-b]-
indole,
_-trans-8-fluoro-5-phenyl-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]-
indole,
_ -trans-5-(o-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-lH-pyrido~4,3-b~-
_ -trans-5-(o-fluorophenyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-lH-
pyrido[4,3-b~indole,
_ -trans-5-(m-fluorophenyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-lH-
pyrido[4,3-b]indole,
_ -trans-5-~m-fluorophenyl)-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]-
indole.
1094071
_ -trans-2-t4-Hydroxy-4-phenylbutyl)-5-phenyl-2,3,4,4a,5,9b-
hexahydro-lH-pyrido[4,3-b]indole Hydrochlorite
A. To the suspension arising from the admixture of 865 mg. (4.20 mmole)
of dicyclohexylcarbodiimide and 748 m8. (4.20 mmole) of 3-benzoylpropionic acid
in 30 ml. of dichloromethane at 0C. was added 1.0 g. (4.0 mmole) of _ -trans-
5-phenyl-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole in 10 ml. of the same
solvent. The resulting mixture was q~irret and allowed to warm to room temper-
ature over 2 hours. After cooling again to 0C. the reaction mixture was fil-
tered, washed with dichloromethane and the f~iltrates evaporated to obtain a re-sidue of _ -trans-2-[(3-benzoyl)propionyl]-5-phenyl-2,3,4,4a,5,9b-hexahydro-lH-
pyrido[4,3-b]indole which was used without purification in the next step.
B. The residue from above was dissolved in 50 ml. of tetrahydrofuran and
heated to reflux. A filtered solution of lithium aluminum hydride in the same
solvent was added until gas evolution ceased (molar excess), and the resulting
mixture was stirred at reflux for 5-10 minutes, then cooled. Anhydrous powdered
sodium sulfate, 17 g., was added followed by 0.5 ml. of water. The resulting
mixture was stirred at room temperature for 30 minutes, filtered, and the fil-
trate evaporated to dryness in vacuo. The residue was chroma~ographed on a
column containing 80 g. of silica gel, eluting with 4:1 (v/v) ethyl acetate/
methanol to afford the free base of the ~itle compound after evaporation of
solvent. The free base was con~erted to the hydrochloride salt by dissolving
` it in ether, adding a saturated solution of anhydrous hydrogen chloride in ether
until precipitation was complete, filtering and drying to afford 1.04 g., M.P.
222-224~C. Infrared spectrum (KBr), ~: 2.97, 3.43, 4.00 (broad), 6.25, 6.68,
6.88, 7.51, 7.96, 8.18, 8.45, 9.82; Mass spectrum, M/e, 398, 292, 263, 249, 220,207, 192 (100~); W (methanol) ~ ax 245 (~ ~ 0.653 x 10 ), 270 (~ = 0.914 x 10 ).
~ . ~ , ~
B ~
.~
10940q1
IB ~ -
Employing the appropriate starting material in each case selected
from the free bases provited in Examples 2 ant 5 ant the appropriaee 3-benzoyl-
propionic acid, the following _ -trans-compounds were prepared by the procedure
S or Example ~. Products were isolated as the hydrochloride salts except as
indicated.
~ 2 H2CH2CH ~ Z
.
X y Z M.P., C. Yield, %
F F H 220-223 18
H H F 239-245 39
~ H HCH30 amorphous 54
solid (a)
F F CH30 45-48.5 (b) 31
(a) Mass spectrum, M/e: 428, 411, 263
(100~), 220, 206, 204; Infrared spec-
- 15 trum (KBr), ~: 2.98, 3.42, 4.07
~broad),6.20, 6.26, 6.70, 6.88, 8.04,
8.54, 9.77, 12.05.
(b) Melting point and yield data are
for the free base.
.
J 9
1094071
r~- q
EaUhMPLE ~
Starting with the appropriaee _ -trans-hexahydro-lH-pyrido[4,3-b~-
indole selected from the products of Examples 2, 5 and 6 and the appropriately
qubs~ituted 3-benzoylpropionic or 4-benzoylbutyric acid, the following compounds
are obtained by the method of Example ~.
X ~ N-(CH2) -CH-
~,
'~X
`
~ n X Y Z
3 F p-fluoro m-fluoro
3 F p-fluoro o-methoxy
3 F H p-fluoro
3 H p-fluoro p-methoxy
' 3 H o-fluoro m-methoxy
3 F H H
3 H m-fluoro H
3 H H m-fluoro
4 F p-fluoro p-fluoro
4 F p-fluoro p-methoxy
. 4 F o-fluoro a
4 F H H
4 F H m-methoxy
4 H p-fluoro H
4 H m-fluoro o-fluoro
' 4 H o-fluoro p-methoxy
4 H H o-me~hoxy
3 H E~fluoro ~-fluoro
25 ' 3 ~ o-fluoro o-fluoro
3- F m-fluoro p-fluoro
3 H m-fluoro p-fluoro
3~
_ ,~ _
1094071
r ~ EXAMPLE~
~B~
_ -trans-S-Phenyl-2-~3-(p-fluorobenzoyl)propyl]-3,4,4a,5,9b-
hexahYdro-lH-pYrido[4.3-b~indole H~drochloride
In a 25 ml. reaction vessel equippet with magnetic stirrer and
maintainet under a nitrogen at sphere were placed 0.82~ ml. (8.0 mg., 10.3
mmole) of dry pyridine and 10 ml. of dichloromethane. To the solution was
added 517 mg. (5.17 mmole) of chromium trioxide and the resulting dar~ red sus-
pension stirred for 15 minutes at room temperature. A s~lution of 359 mg.
(0.862 ole) of _-trans-5-phenyl-2-~4-hydroxy-4-(p-fluorophenyl)butyl]-
2,3,4,4a,5,9b-hexahydro-I~-pyridor4,3-b~in'dole free base in 5 ml. of dichloro-
methane was added in one portion. The reaction mixture quickly changed to a
brown suspension. This was stirred at ambient temperature for 30 minutes.
The insoluble material was removed by filtration, washed with dichloromethane
and the combined filtrate and washings were extracted with 20 ml. of 10~
sodium hydroxide solution. The organic layer was dried (MgS04) and evaporated
to dryness in.vacuo to afford a gum. The gum was purified by column chroma-
tography on silica gel,-eluting with 1:1 by volume hexane/ethyl acetate.
The fractions containing the desired product were combined,evaporated to a
yellow gum, the gum taken up in ethyl ether and treated with anhydrous hydro-
gen chloride. The resulting suspension was evaporated to dryness, slurried
with 3 ml. of cold tichloromethane. A colorless solid formed which was col-
lected by filtration and dried to afford 20 mg. of the title compount, M.P.
244-246.5 C.
.
1094071
,1
r EXA~$'LE ~
~B
_ -trans-8-Fluoro-5-(~-fluorophenyl~-2-~3-(~-fluorobenzoyl)propyl]-
2,-3~4,4a,5~9b-hexahydro-lH-pyridot4,3-b]indole Hydrochloride
To a 100 ml. flask containing 20 ml. of dichloromethane and 1.76 ml.
(21.9 mmole) of pyridine was added 1.09 g. of chromium trioxide and the result-
ing dark suspension was stirred at ambient temperature for 15 minutes. Then
was added in one portion a solution of 824 mg. (1.82 mmole) of _ -trans-8-
fluoro-5-(~-fluorophenyl)-2-~4-hydroxy-4-(p-fluorophenyl)buty~-2,3,4,4a,5,9b-
hexahydro-lH-pyridol4,3-bJindole free base (obtained from the hydrochloride salt
by making an aqueous solution alkaline with sodium hydroxide, extracting with
dichloromethane and evaporating the extracts to dryness) in 10 ml. of dichloro-
methane. The resulting red-brown suspension was stirred at ambient temperature
for one hour and worked-up by the same procedure employet in Example~Krto obtain
25 mg. of the te~ired product, M.P. 260-263 C.
1094071
iB' - ~
; EXAMPLE ~A~
Employing the appropriate starting material selectet from the products
o
obtained in ExampleJ~, ~Kr and ~ and oxidizing by the procedure of Example
affords the following 4a,9b-trans compounds:
~ (C82)n
n~ X Y Z
3 F p-fluoro H
~ 3 H H p-fluoro
: 3 H H p-methoxy
3 F p-fluoro p-methoxy
3 H p-fluoro p-methoxy
3 a o-fluoro m-methoxy
' 3 F H p-fluoro
3 F H H
3 H H H
3 F p-fluoro m-fluoro
3 H m-fluoro H
4 F p-fluoro p-fluoro
4 F p-fluoro p-methoxy
. 4 F o-fluoro H
20 ; 4 F H H
4 F H m-methoxy
; 4 H p-f;uoro H
4 H m-fluoro o-fluoro
4 H o-fluoro p-methoxy
4 H H o-methoxy
3 H p-fluoro p-fluoro
3 H o-fluoro o-fluoro
3 F m-fluoro p-fluoro
3 H m-fluoro ~-fluoro
.
_ "~ _
1094071
,B EXAMPLE ~tS
_ -trans-8-Fluoro-5-(p-fluorophenyl)-2-[4-hydroxy-4-(p-fluorophenyl)butyl]
2,3,4,4a,5,9b-hexahydro-lH-pyrido~4,3-b]indole acetace
Five grams of _ -trans-8-fluoro-5-(~-fluorophenyl)-2-[4-hydroxy-4-(p-
fluorophenyl)butyl]-2,3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indole hydrochloridein 75 ml. of water is treated with 3 ml. of water containing 1.0 g. of sodium
hydroxide, and the liberated free base extracted into 150 ml. of diethyl ether.
The ether layer is separated, driet over magnesium sulfate and treated with
1 ml. of glacial acetic acid. The organic solvent and excess acetic acid are
removed under reduced pressure and the reqLdue triturated with hexane and fil-
tered.
In a~similar manner, other acid addition salts, especially those which
are pharmaceutically acceptable, can be prepared.
_ ,~ _
- 1094071
,~
I B EXAMPLE ~
Test Procedures and Results
The effects of the compounds of the present invention on prominent
ampbetamine-induced symptoms were studied in rats by a rating scale modeled
after the one reported by Quinton and Halliwell, ant Weissman. Groups of five
rats were placet in a cavered plastic cage measuring approximately Z6 cm. x
42 cm. x 16 cm. After a brief period of acclimation in the cage, the rats in
each group were treated subcutaneously (s.c.)~with the test compound. They
were then treated 1, 2 and 24 hrs. later with d-amphetamine sulfate, S mg./kg.
intraperitoneally (i.p.). One hour after amphetamine was given each rat was
- observed for the characteristic amphetamine behavior of moving around the cage.
On the ba~is of dose-response data after amphetamine it was possible to deter-
mine the effective dose of the compound necessary to antagonize or block the
characteristic amphetamine behavior of cage movement for fifty percent of the
rats tested (ED5~). The ti~e of rating chosen coincides with the peak action
of amphetamine which is 60-80 min. after treatment with this agent.
Employing the above-described procedure, the following 4a,9b-trans
compounds were tested for their ability to block the behavior effects of
amphetAm;ne, the results being reported as the ED50 in mg./kg. at the
inticated times:
~N
~y ,
lO9A0~7~
B (Example ~hS Continued)
,_~
- i 0 ~ ~ o~
~ o o ~i ~ . c~- ~ ~i,~ ~i
3: ~ ~ o ~ ~ ~ ~ ~ ~ ~ ~ o
. . _~ O~,~ O o . o '`i _i o_i
C~i O O ~ ~ A VV O V C`~V V V
_
0~ _1 ' _1
~ . e~
_ O ~ ~ ~7 ~ ~ O
e~ 0t~ O O OO O
E~ ~~ ~ o
:~O _I_i _~ O C~l -
o ~ O O OO O V O V ~ -I VO--t
1:~
~i
_l . _l
j ~ ~ ~ o O
'. , .~ O O ~ O ~iC`l I ~ O
~1 ~ I I ~_I I~ ~ I O
, ' ~: OO -~ o C`~ o ~
_l O O O ~ O V O O _i _l O V
_i
I~ I I ~`i I
: ' ~ i
- ~ C~i ~ I ~ ~ -- ~i
~ ~ 1 S
_ c~ m ~ ~ _c.~ = ~ S O--
~ I ~ _~ :s I I n 1l ~ ~ -~
C~ ~ ~ 5 ~ ~
C~_O C~ O -- ~--O C~--O C~ O
~ :C ~ O ~: ~ 3 _ ~ -- O O
C~--O `O ~ `D C~--O ~O ~O ~ ~ ~ t~i
~ V`D ~ ~ 4 s c~o 4 4 4 ~i 4 ~i ~
o o o oo o o o o
o o b b o bo
4 ~ 4~~ ~ ~ ~ U~
~ ~ ol ~4 ~I 4 ~ ~1
Qi
i
3G
,~
lOg4071
r~
i B (Example 1~ Coneinued)
b C
~ --~ X
C~ ~ Z ~ ~ O
O
C~
_ ~ I o
. . ~I O ~
0~ ~q ~ _I O O _I
~ :~: ~ ~ I I I o aU~ ~
O ~1 A A ~~'1 0 A
O S
~I O
1.~ ~ o ~ 0~ 1 0 C~l
C~ ~ O C`~
~ _I ~q a)
~1 ~ I I t~ O O ~C ~:
O ~
- ~ O _ _l
C- Ui C
I ~ Ul I ~
C~ C~
~ :~ tJ I~ ~
I ~ I C i I ~,
`~ ~~ S I ~ C~
~ . O ~ ~ ~~1 1
U'l ~ I~') C O 't~
5 0
0~~ ~ ~ ~ ~ ~ C~^ ~ o r
h ~1 ~ ~Cr` O
C
I ~
I ~ ~J U)0 C ~ C:`--O
Y I ^~ ~ ~ ~ U
I X ^~
;~ 3~~ C~l ~ 0
O 'O _I C ~U ~ O . . I
~ :~ I ~ ~ J ~ n u~
O r ~ o~~ a ~ o ~ .
:~ I ~ O C C ~ ~ ~ ) U
CJ C~ t3 tJ ~ -- ~ h :~ O
X ~ ~ ~ ~ U
3-1
~,
lO9A071
r ~ EXA~LE 3
Tablets
A tablet base is prepared by blending the following ingretients in
the proportion by weight indicated:
Sucrose, U.S.P. . . . . . . . . . . 80.3
Tapioca starch . . . . . . . . . . 13.2
Magnesium seearate . . . . . . . . 6.5
Into this tablet base there is blended sufficient trans-8-fluoro-5-
~ -fluorophenyl)-2-[4-(p-fluorophenyl)-4-hydroxybutyl]-2,3,4,4a,5,9b-hexahytro-
lH-pyrido[4,3-b]indole hydrochloride to provide tablets containing 1.0, 2.5,
5.0 and 10 mg.~of active ingredient per tablet. The compositions are each com-
pressed into tablets, each weighing 360 mg., by conventional means.
3~
_ _~
~0940`71
1~ .
~ EXAMPLE ~n~
~; ,
Capsules
A blend is prepared containing the following ingredients:
Calcium carbonate, U.S.P. . . . . . . . 17.6
Dicalcium phosphate . . . . . . . . . . 18.8
Magnesium trisilicate, U.S.P. . . -. . . 5.2
Lactose, U.S.P. . . . . . . . . . . . . 5.2
Potato starch . . . . . . ~ . . . . . . 5.2
Magnesium stearate . . . . . . . . . . 0.8
To this blent is adtet a second portion of magnesium stearate (0.35 g.)
and sufficient trang-5-phenyl-2-(4-hydroxy-4-phenylbutyl)-2,3,4,4a,5,9b-hexa-
hydro-lN-pyrido[4,3-b]indole hydrochloride to provide capsules containing 1.0,
2.5, 5.0 and 10 mg. of active ingredient per capsule. The compositions are
filled into conventional hard gelatin capsules in the amount of 350 mg. per
capsule.
.
3 ~
` ~Og40~7
r~ EXA~l:E 3g
SusPension
A ~uspension of trans-8-fluoro-5~ fluorophenyl)-2-[4-hydroxy-4-(P-
methoxyphenyi)butyl]-2,3,4,4a,5,9b-hexahydro-lX- w rido~4,3-b]indole acetate
5 i8 prepared with the following composition:
Effective ingredient . . . . . . . . . . . . . g. 25.00
70% aqueous sorbitol . . . . . . . . . . . . . g. 741.2g
Glycerine, U.S.P. . . . . . . . . . . . . . . g. 185.3S
Gum acacia (10% solu~ion). . . . . ; . . . . .ml. 100.00
Polyvinylpyrrolidone . . . . . . . . . . . g- 0-50
Distilled water, sufficient to make 1 liter.
To this suspension, various sweeteners and flavorants are adted to improve
the palatability of the suspension. The suspension contains approximately
25 mg. of effective agent per millil~ter.
/g
EXAMPLE ~K~
Sesa~e oil i~ sterilized by heating to 120C. for 2 hrs. To this
oil, a sufficient quantity of pulverized trans-8-fluoro-5-(p-fluorophenyl)-2-
[4~ fluorophenyl)-4-hydroxybutyl~-2,3,4,4a,5,9b-hexahydro-LH-pyrido[4,3-b]-
indole hydrochloride to make a 0.025~ suspension by weight. The solid is
thoroughiy dispersed in the oil by use of a colloid mill. It is then filtered
through a 100-250 mesh screen an-d poured into sterile vials and sealed.
./A
