Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
36
- l -
4-12219/~
Process for the manufacture of a new dextrorotatory basic derivative of
9,10-ethanoanthracene, and phanmaceutical compositions containing this
compound
The present invention relates to processes for the
manufacture of a ne~ dextrorotatory basic derivative of 9,10-ethano-
anthracene and of the acid addition salts thereof, and to pharma-
ceutical compositions containing these new substances.
The compound prepared according to the invention is
S-(l)-a-[(methylamino)methyl]-9,10-ethanoanthracene-9(lOH)-ethanol of
the formula
OH
1 2 ~ 2 N~-- Cr~
X (I)
and is the (~)-antipode of the .acemic -~methylamino)me,hyl~-S,10-
ethanoanthracene-9(lO~)-ethanol described in US ?atent specifir&~ion
4 017 5~2 and correspo~ding patent specifica~ions of other countries
having the Swiss p-iority of 23.2.1971, Acid addition salts or the
compound of ~he formula I are in particula. phar~aceuticaLly
acceptable salts, such as the hydrobromide, phosphate, ~ethane-
sulfonate, ethanesulfonate, 2-hydro~yethanesulfonate, acetate, lactate,
malonate, succinate, fumarate, maleate, malate, tartrate, citrate,
benzoate, salicylate, phenylacetate, mandelate or embonate, and
especially the hydrochloride, as well as in ,,eneral readily
crystallising salts with optically active acids, besides those
,., ~
'~
r
f
~,
5t3~ -
already mentioned~e.3. also the (1:1) salt with bis-O,O'-(p-toluoyl)-
D-tartaric acid. Because of the close relationship between the free
base and its acid addition salcs, reference to the base and to its
acid addition salts will be understood by analogy as applying also to
the acid addition salts and the free base respectively.
S-(+)-a-[(Methylamino)methyl]-9,10-ethanoanthracene-9(10H)-
ethanol and its acid addition salts possess valuable pharmacological
properties. In particular, they are very highly active in tests which
are characteristic of antidepressants. A distinct antagonism of hypo-
thermia induced in male mice by 2 mg/kg sc. of reserpine [Askew,
Life Sci. 10, 725 (1963), and Benz and Waser, Doctoral Thesis 1971,
Pharmacol. Inst. of the University of ZUrich~ can be observed even
in doses from 0.3 mg/kg of the hydrochloride of the compound oE the
!: :
formula I, and is more pronounced than the action of multiple doses
~;~ of the corresponding racemate. The ptosis induced in male rats by
2 mg/kg sc. of reserpine [Rubin et al., J. Pharmacol. Exp.
Therap. 120, 125 (1957)1 is clearly reduced by 0.1 mg/kg p.o. of
the hydrochloride of the compound of the formula I and relieved by
0.3 mg/kg p.o., whereas the corresponding racemate, which is likewise
essentially highly potent~ only relieves the ptosis completely when
administered in a substantially higher dosage.
The neurobiochemical action of the hydrochloride of the
compound of the formula I is observed in a pronounced inhibition of
the uptake of noradrenaline in the heart of rats according to the
method of L. Maître, M. Staehelin and H. Bein, Biochem. Pharmacol. 20,
2169 (1971), with an ED50 of about 0.3 mg/kg p.o., whereas the
ED50 of the corresponding racemate is in the region of about 1.5 mg/kg
S` p.o., and also in a pronounced inhibition of the noradrenaline
depletion caused by H 77/77 (3-hydroxy-4,a-dimethylphenethylamine) in
:~ the brain of rats as an indirect indication of the inhibition of the
:~ uptake of noradrenaline [A. Carlsson, H. Corrodi, K. Fuxe and T.
:'; ~
. .
5`
~.'; ';`
:s
~3L'~5~36
-- 3 --
Hoefkelt, Europ. J. Pharmacol. 5, 367 (1969)] with an ED50 of about
2 mg/kg p.o. compared with an ED50 of about 10 mg/kg p.o. of the
corresponding racemate. The endogenic concentrations of
noradrenaline and of dopamine in the brain of rats, measured in
accordance with the method of P. Waldmeier, de Herdt and L. Maltre
[Chir. Chem. 20, 81, (1974)] are influenced neither by the hydro-
chloride of the compound of the formula I in doses up to lO0 mg/kg
and up to 30 mg/kg p.o. respectively, nor by the corresponding
racemate in doses up to lO mg/kg and up to 100 mg/kg respectively.
The findings relating to the uptake of noradrenaline suggest
that the pronounced antagonism of the compound of the for~ula I and
of its acid addition salts to reserpine is based on a corresponding
influence on the transportation and metabolism of noradrenaline. At
any rate, the far more than twofold increase in potency in these
tests cannot be explai.ned by the fact that only the (~)-antipocle
present in the known racemate is active, and this increase must there-
fore be considered surprising.
':
In a series of further assays~ the compound of the formula I,
tested in the form of the hydrochloride, is about as potent to at
most twice as potent as the corresponding racemate. F.qual doses of
both compounds have about the same effect, e.g. in the antagonism
of histamine toxicity in guinea pigs, in the test of the exploratory
activity of mice [A. Delini-Stula and R. Meier, N~uropharmacology,
-~ 15, 383-388 tl976)], and in the aggression induced in mice by footshock [Tedeschi et al., J. Pharmacol. Exptl. Therap. 125, 28 - 34
(1959)], whereas in the antagonism of catalepsy induced in rats
by tetrabenazine after oral administration, and in the potentiation
of anesthesia induced in mice by G 29 505 [2-(4-allyl-2-methoxy-
phenoxy)-N,N-diethylacetamide] after intraperitoneal administration
[W. Theobald and R. Domenjoz, Arzneimittelforsch. 9,285-286 1959)],
the hydrochloride of the compound of the formula I is as potent as
the corresponding racemate in about half the dosage.
!
~,
,,;
,j.
.,' .
'
:
~,`; ` `
~;
';
-- 4 --
The compound of the formula I and the corresponding racemate
have about the same acute toxicity when administered orally and intra-
venously. In concentrations about half as high, the compound of the
formula I had the same negative inotropic action as the racemate on
the isolated left atrium of guinea pigs which had received premedi-
cation with reserpine, whereas the negative chronotropic action of
the compound of the formula I on the isolated right atrium was weaker
than that of the racemate. The comparison of the action of 1 mg/ml
of each of the two compounds on isolated atria of guinea pigs which
have not received premedication with reserpine and of those ~hich
have, indicates an appro~imately identical cardiostimulating action.
'.`~
It follows from the above and further assays that the
significant increase in the reserpine antagonism, and in the
inhibition of the noradrenaline uptake, as well as the approximately
twofold tetrabenazine antagonism effected by the compound of the
formula I and its acid addition salts as pharmacological properties
especially characteristic of antidepressants, in comparison to the
racemate and its acid addition salts is in no way accompanied by a
similar increase in toxicity and/or side-effects. S~ a-~(Methyl-
amino)methyl]-9,10-ethanoanthracene-9(10~)-ethanol of the formula I
and its pharmaceutically acceptable salts can be employed as
antidepressants, especially for the treatment of emotional depressions.
,r,, ~
(+)-~-[(~ethylamino)methyl]-9,10-ethanoanthracene-9(lOH~-
ethanol of the formula I and its acid addition salts are obtained
i according to the invention by
: a) resolving the racemic ~-[methylamino)methyl]-9,10-ethanoanthra-~ cene-9(10H)-ethanol and isolating s-(~ -[(methylamino)methyl]-9,10-
:,,
ethanoanthracene-9(10H)-ethanol, if desired in the form of an acid
addition salt, or
; b) reacting a compound of the formula II
.~
~?,
?',~
.,,~,. .
Sr
,?~ ~
C~.~2~ C -2 ~1 (II),
A H
with a compound of the formula III
X - CH (III)
: wherein one of ~1 and X2 is the amino group and the other is a
reactive esterified hydroxyL group, and Yl is a free hydroxyl group,
and Xl together with Yl can also be an epoxy group, and A is the
. 9,10-ethanoanthracen-9tlOH)-yl radical, or
c~ in a compound of the formula IV
' g Zl . 22
'; C1~2~--Cj --C~2 - ~ - C~3 (ItJ)
A H
~. in which at least one of Zl and Z2 is a removable radical and the,~ other may be hydrogen, or Zl and Z2 together are a divalent removable
radical, and A is the 9,10-ethanoanthracen-9(lOH)-yl radi~al, remov-
ing Zl and/or Z2~ or
,~ d) reducing a compound which differs from the compound of the
. formula I only in that, in said compound, a carbon atom adjacent to
~. the nitrogen atom is attached to this latter through a double bond or
j~ is substituted by a hydroxyl group or an oxo radical, optionally to-
gether with lower aLkoxy, or
e) the addition of ethylene to S--[(methylamino~methyl~-9(lOH)-
' anthracene, or
, f) reactlng a compound of the general formula V
X
,:',
:~ :
:,~ .
,; . .
1~L4~5~3~
- 6 -
H CO-R
( H ~ - - C~ 2 ~ CX 3 ( V )
A OH
~ .
in which Rl is an unsubstituted or substituted hydrocarbon radical
or an unsubstituted or substituted heterocyclic radical, and A is
the 9,10-ethanoanthracen-9(lOH)-yl radical, with a strong oxygen-con-
taining inorganic or organic acid or with a halide thereof, and hyd-
rolysing the intermediate obtained, and, if desired, converting the
resultant s-(+j-~-[(methylamino)methyl]-9,10-ethanoanthracene-9(lOH)-
~ ethanol into an acid addition salt and/or liberating the base from
`; ~ a resultant acid addition salt.
' ~ ~
~; The resolution and isolation in accordance with process a)is accomplished in a manner known per se. For e~a~lple, it is possible
to convert the racemate with salt-Eor~ing opticaLly active acids,
such as organic carboxylic or sulfonic acids, e.g. the (D)- and (L)-
forms of tartaric acid, bis-O,O'-(p-toluoyl)-tartaric acid, malic
~:
acid, mandelic acid, camphorsulfonic acid, quinic acid, lactic acid,
lutamic acid or asparaginic acid, into acid addition salts. The
mixtures obtained of tbe corresponding salts can be resolved into
the diastereoisomeric salts on the basis of physicochemical
;differences, e~g. the solubility or crystallisability, and, if desired,
the optically active (*)-base liberated from the salt.
The (rj-base can also be separated from the racemate by
?,~, fractional crystallisation from a suitable solvent, if appropriate
also from an optically active solvent, or by chromatography, especially
thin-layer chromatography, on an optically active carrier.
r: : :
A reactive esterified hydroxyl group in a compound of the
formula II or III is especially a hydroxyl group which is esterified
`: :
s~
:' ~: ~ : , :
' :: ~
,::,
~!
~14~g~
~ 7 -
with a strong organic or inorganic acid, in particular wi~h a hydro-
halic acid, such as hydrochloric, hydrobromic or hvdriodic acid, or
with an arylsulfonic acid, such as a benzenesulfonic acid ~hich is
mono-, di- or polysubstituted by lower alkyl or alkoxy radicals,
e.g. those mentioned above, or by halcgen atoms, such as chlorine
or bromine atoms, e.g. p-toluenesulfonic acid or p-bromobenzenesul~
fonic acid, or with a lower alkanesulfonic acid, e.g. methanesulfon-
ic acid, or, especially as ~2~ also a hydroxyl group esterified
by sulfuric or methylsulfuric acid. Xl together with Yl can also form
an epoxy bridge.
,, -:
:~ The reaction according to process b) is carried out in
;'~ conventional manner, preferably in the presence of a solvent and, if
~ desired, in the presence of a condensation agent, e.g. a basic
!,'`~,~ condensation agent, preferably at elevated temperature and optionally
:; ~
~ in a closed vessel under pressure. A basic condensation agent i.s e.g.
::- an alkali hydroxide or carbonate, e.g. sodium hydroxide or potassium
carbonate, or a tertiary amine, e.g. triethylamine or pyridine.
In the starting materials of the general formula IV for
J" process c3, removable radicals Zl and Z~, as also divalent removable
~; radicals formed by Zl and Z2 together, are radicals which can be
removed e.g. by solvolysis, especially hydrolysis, or by reduction,
.~
~ e.g. hydrogenolysis.
, '` .
Suitable radicals Zl and Z2 which are removable by
solvolysis, especially hydrolysis, are e.g. acyl radicals, such as
alkanoyl radicals, especially unsubstituted or halogenated, e.g.
fluorinated, lower alkanoyl radicals, such as the acetyl radical or
the trifluoroacetyl radical, and also e.g. aroyl and aryl-lower
alkanoyl radicals, such as the benzoyl or phenylacetyl radical, or
acyl radicals of carbonic acid hemiesters, e.g. lower alkoxycarbonyl
radicals, such as the methoxycarbonyl, ethoxycarbonyl or tert-butoxy-
~'
.,.; .
~:
~ .
~ ` '
~ . ' . ' ...... . . .
~,s ~ . :
- 8 -
carbonyl radical, or aralko~ycarbonyl radicals, such as the benzyloxy-
carbonyl radical, as ~ell as e.g. silyl radicals, such as the
trimethylsilyl radical.
~ divalent radical formed by Zl and Z2 is e.g. a geminal
divalent hydrocarbon radical, especially a lower alkylidene radical,
such as the methylene, ethylidene or l-methylethylidene radical
(isopropylidene radical), or an aralkylidene radical, such as the
benzylidene radical, and e.g. a phosphorylidene group, especially a
lower alkoxyphosphorylidene group, such as the methoxy- or
ethoxyphosphorylidene group.
The removal of Zl and/or Z2 by hydrolysis is carried out with
hydrolysing agents, e.g. in the present of acids, e.g. dilute mineral
acids, such as sulfuric acid or hydrohalic acids, especially hydro-
chloric acid, or if Zl and Z2 are acyl radicals, preferably in
the presence of bases, e.g. alkali metal hydroxides, s~lch as sodium
hydroxide, in suitable organic or organic-aqueous solvents, at low
temperaturs, e.g. at room tmeperature, or preferably with heating. The
removal of a divalent radical formed by Zl and Z2 by hydrolysis can
be effected in analogous manner.
Radicals Zl and Z2 which are removable by reduction are e.g.
l-aryl-lower alkyl radicals, such as the benzyl radical, or l-aryl-
lower alkoxycarbonyl radical, such as the benzyloxycarbonyl radical,
which can be removed e.g. by hydrogenolysis~ for example by reduct-
ion with catalytically activated hydrogen, such as hydrogen in the
presence of a hydrogenation catalyst, e.g. a palladium or platinum
catalyst. Aralkylidene radicals, such as the benzylidene radical,
formed by Zl and Z2 together can likewise be removed by hydrogenolys-
is. However, Zl or Z2 can also be a 2-haloalkoxycarbonyl radical,
e.g. the 2,2,2-trichloroethoxycarbonyl radical or the 2-iodoethoxy-
carbonyl radical, which can be removed by reduction. A suitable
'
i::
~, ~ '; ` :
~,,~ .
.?~
..
`` :3L~L4~
method of reduction is metallic reduction (nascent hydrogen), e.g.
the action of metal or metal alloys and also amalgams, pre~erably
in the presence of hydrogen donors, such as carboxylic acids, alcoh-
ols or water. In particular, ~inc or zinc alloys in acetic acid are
used. Further suitable reducing agents are chromium(II) compounds,
such as chromium(II) chloride or chromium(II) acetate. Z2 can also be
an arylsulfonyl group, such as the toluenesulfonyl group, which can be
removed in conventional manner by reduction with nascent hydrogen, e.g.
by an alkali metal, such as lithium or sodium, in liquid ammonia. The
removal of an arylsulfonyl group can also be accomplished with a
hydride, e.g. one of the simple or complex hydrides mentioned above
in connection with process c), preferably lithium aluminium hydride,
advantageously in the presence of an inert solvent, such as an ether-
eal organic solvent, e.g. tetrahydrofurane.
Starting materials for process d) containing a double bond
between the nitrogen atom and an ad;acent carbon atom are
S-a-~(methyleneamino)-methyl~-9,10-ethanoanthracene-9(lOH)-ethanol and
S-a [(methylimino)-methyl]-9,10-ethanoanthracene-9(lOH)-ethanol. The
compounds which are substituted in the ad;acent position to the
nitrogen atom by hydroxyl are s-~-[(hydroxymethylamino)methyl-9,10-
ethanoanthracene-9(lOH)-ethanol and S-l-(methylamino)-9,10-ethano-
anthracene-9(lOH)-propane-1,2-diol. The reduction of the above
mentioned four compounds can be carried out in conventional manner,
preferably with a simple or complex hydride, e.g. a borane, or with
a di-light metal hydride, e.g. an alkaline earth metal hydride, such
as sodium borohydride or lithium aluminium hydride, or with an
alkoxyaluminium hydride or alkoxyborohydride, e.g. one of those
referred to hereinafter.
:
It is also possible, however, to perform the reduction as a
` hydrogenation with hydrogen in the presence of a catalyst, such as a
platinum, palladium or nickel catalyst, or of a homogeneous catalyst,
~i ~
.,.
;~
~,, .
; . : ..
.t~ . :
~,s
~' ' . `, `
~i4~5~6
-- 10 --
e.g. a complex rhodium compound, such as a rhodium chlorotriphenyl-
phosphine comple~.
If a carbon atom adjacent to the nitrogen atom is
substituted by an oxo radical, the corresponding starting compounds
are, on the one hand, S-N-methyl-9,10-ethanoanthracene-9(10H)-
lactamide and, on the other, N-[3-(9,10-ethanoanthracen-9(lOH)-yl)-
2(S)-hydroxypropyl]-formamide, as well as lower alkyl esters of
carbamic acid which are substituted at the nitrogen atom by the same
radical, such as the methyl and ethyl ester. Their reduction can be
carried out by the conventional methods of amide reduction, for
example with a simple or complex hydride, such as a borane, e.g.
diborane, or with a complex di-light metal hydride, especially an
alkali metal aluminium hydride, such as lithium or sodium aluminium
hydride, in an ethereal solvent, such as diethyl ether or tetrahydro-
furane, or with an alkali metal alkoxyaluminium hydride or alkali
metal alkoxyborohydride, e.g. sodium dibutoxy aluminium hydride or
sodium trimethoxy borohydride, or with an alkaline earth metal
aluminium hydride, such as magnesium aluminium hydride, or with
sodium borohydride in a tertiary amine, such as pyridine or
triethylamine, or with aluminium hydride-aluminium chloride.
The introduction of the 9,10-ethano radical in accordance with
process e) can be effected in conventional manner, e.g. by reaction
of the anthracene derivative with ethylene by the Diels-Alder method,
advantageously in a suitable solvent, such as an aromatic
hydrocarbon, e.g. benzene or toluene, and at elevated temperature, e.g.
in the range from 50 to 250C, and/or under pressure, e.g. at 2 to
150 atmos.
In the starting materials of the general formula V for
process f), an unsubstituted or substituted hydrocarbon radical Rl is
e.g. lower alkyl, such as ethyl9 propyl, isopropyl, butyl or ~ert-
butyl, and especially methyl, as well as e.g. phenyl-lo~er alkyl, such
as benzyl or 2-phenylethyl, or phenyl, ~hilst in these or other
radicals Rl substituents can be e.g. halogen up to a~omic number 35,
lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, or aryloxy, e.g.
phenoxy. As a heterocyclic radical, Rl is e.g. furyl, such as
2-furyl, thienyl, such as 2-thienyl, or pyridinyl, such as 3- or
4-pyridinyl.
The corresponding starting materials of the formula ~ can be
obtained by conventional acylation methods from the free R~
[(methylamino)methyl~-9,10-ethanoanthracene-9(lOH)-ethanol obtained
as by~product in the separation of racemic a-[(methylamino)methyl]-9,10-
ethanoanthracene-9(lOH)-ethanol, in particular using carboxylic acid
halides or lower alkyl esters, or, especially for obtaining the
compound in which Rl is methyl and which is a particularly suitable
starting material, using anhydrides, such as acetic anhydride.
Suitable oxygen-containing inorganic or organic acids in
process f) are in particular concentrated sulfuric acid or
phosphoric acid, and also e.g. strong organic sulfonic acids, such as
aliphatic sulfonic acids, e.g. methanesulfonic acid, or aromatic
sulfonic acids, such as an unsubstituted or substituted phenylsulfonic
acid, e.g. 4-methyl-, 4-bromo-, 4-nitro- or 2,4-dinitrophenylsulfonic
acid, or naphthalenesulfonic acids, e.g. l-naphthalenesulfonic acid.
Suitable halides of these acids are especially the chlorides or
bromides, in particular thionyl chloride, and also e.g. thionyl
bromide, sulfuryl chloride, chlorosulfonic acid, phosphorus
trichloride, phosphorus pentachloride, phosphoroxy chloride or
methanesulfonyl chloride. It is also possible to employ mixed ester
halides corresponding to the above halides of polyvalent acids, such
as a lower alkoxysulfonyl halide, e.g. methoxy- or ethoxysulfonyl
chloride, or lower alkyl ester halides of phosphoric acid, e.g.
dimethoxyphosphoryl chloride.
.,
~' :
,...................... .
~,
~.1 ' .
- 12 -
;
The reactions with strong acids, especially concentrated
sulfuric acid or phosphoric acid, are carried out in the presence or
absence o solvents or diluents, e.g. acetic anhydride, in the
temperature range from about -50 to ~200C, and the reactions with
acid halides, e.g~ thionyl chloride, are carried out also in the
presence or absence of solvents or diluents, e.g. hydrocarbons or
especially chlorinated hydrocarbons, such as methylene chloride, in the
temperature range from about -10 to ~70 C, preferably from about
+10 to ~50C. It may be assumed that the reaction products of these
reactions are 2-Rl-5~9,10-ethanoanthracen-9(lOH)-yl)-4,5-dihydro-3-
methyl-oxa~olium salts, the anion of which corresponds to the acid
employed in the reaction or, if the reactions are carried out with
acid halides~is the corresponding halogen ion.
,,;,
,` The hydrolysis of the intermediates is carried out in acid:, or basic medium. Suitable acids are e,g. aqueous acids, such as
aqueous mineral acids, e.g. aqueous hydrochlQric acid, sulfuric acid
or phosphoric acid. The acid hydrolysis is carried out in a
~ temperature range from 0 to 120C, advantageously from 10 to 50C.
;f Exa~ples of suitable bases are aqueous lyes, such as those of alkali
metals or alkaline earth metals, such as sodium hydroxide or potassi-
um hydroxide, or the hydroxides of calcium or magnesium, and the
cited reagents are advantageously employed at elevated temperatureJ
~ e.g. in the range from 50 to 150C.
''i;:,
The hydrolysis can be carried out step~ise by hydrolysing an
~1 intermediate, optionally via the corresponding free base as inter-
mediate stage, in aqueous medium,to produce the corresponding ~-acyl
compound of the general formula V having inverse steric configuration
to that of the respective starting material of the formula V, and
~: subsequently hydrolysing this compound to a compound of the formula I.
~ ,'
?..~
~ ~4i~6
~ he process according to ) can also advantageously be carried
out by reacting a starting material of the general ~ormula V obtained
directly beEorehand without isolating it in the pure fonn, in the
same batch with a suitable acid or halide thereo~, and hydrolysing
the intermediate thereby obtained, like~ise without further puri-
fication.
:`
~ he optically active starting materials required for processes
b) to e) can be obtained either by resolution of known racem~c,
especially basic, starting materials in a manner known per se, or
in a manner analogous to that employed for obtaining the racemic
starting materials required for the preparation of the ~no~n race-
mate using optically active instead of racemic precursors.
Acid addition salts, especially pharmaceutically acceptable
acid addition salts, of the compound of the formula I, e.g. those
referred to above, can be obtained in conventional manner. For
exa~ple, a solution of the base in an organic solvent, e.g. methylene
chloride~ ethyl acetate, ethanol or isopropanol, is reacted with
the acid desired as salt component, or with a solution thereof in
the same or another organic solvent, such as ethyl acetate or di-
ethyl ether, and, if desired after cooling or concentrating or after
; addition of a solvent having poorer solubility for salts, e.g. di-
I ethyl ether, collecting the precipitated salt by ~iltration.
}
The present invention also relates to the compound of the
formula I and the pharmaceutically acceptable acid addition salts
thereoE for use as medicaments, especially as antidepressants,
e.g. for treating the disorders mentioned above, and also to their
use for the production of pharmaceutical, in particular antidepressant
i compositions.
,
';`
,:
,
.
?
., .
:,~r: -
r,
3L~4~5~16
The dosage of the compound of the formula I and its pharmaceut-
ically acceptable acid addition salts for war~-blooded animals depends
on the species, body weight and age, and on the individual condition
and the mode of application. The daily doses are bet~een about
0.05 and 3~0 ~mfkg, preferably between about 0~08 and 1.5 mg/kg of
body weight. On average, a daily dose of about 10 to about 150 mg,
preferably about 30 to about 75 mg, will be administered to a warm-
blooded animal having a body weight of about 70 kg.
The present invention also relates to pharmaceutical
compositions which contain the compound of the formula I or
pharmaceutically acceptable acid addition salts thereof. The
pharmaceutical compositions of the invention are in particular those
, :
for enteral, such as oral or rectal as well as paren~eral,
administration, which contain the pharmacologically active ingredient
alone or preferably together with at least one pharmaceutieally
.~ aeceptable earrier. Such eompositions contain the active ingredient,i.e. the eompound of the formula I or a pharmaeeutieal}y aceeptable
~ aeid addîtion salt thereof, in an amount and coneentration suitable
? ~ for the administration of the above daily doses in one or more,
s,~ preferably three, single doses.
Pharmaeeutieal eompoaitions of the invention in dosage~unit
formulations, such as sugar-coated tablets, tablets, eapsules,
suppositories or a~poules, contain, as aetive ingredient in eaeh
;t~ dosage unit, preferably 2~5 to 50 mg, especially 5 to 25 mg, of the
~ compound of the formula I or preferably of a pharmaceutically
:~` aeceptable acid addition sal~ of this base, together with at least
j~ one pharmaeeutieal earrier.
~.
Dosage unit formulations for peroral administration contain,
as aetive ingredient, preferably between 1 2 and 50 % of the eompound
, of the formula I or of a pharmaeeutically aeeeptable aeid addition
,~ ,
:'~
.,:,:
,;, ~ . -
,':,t ~
36
- ~5 -
:
salt thereof. They are prepared by combining the active ingredient
e.g. with solid pulverulent carriers~ such as lactose, s~ccharose,
sorbitol, mannitol; starches, such as potato starch, maize starch
or amylopectin, and also laminaria or powdered citrus pulp;
cellulose derivatives or gelatin, optionally with the addition o~
glidants, such as magnesium or calcium stearate or polyethylene
glycols, to produce tablets or cores for sugar-coated tablets.
The tablet cores are coated e.g. with concentrated sugar solutions
which additionally contain e.g gum arabic, talc and/or titaniumdioxide,
or with a lacquer which is dissolved in mobile organic solvents or
solvent mixtures. Colourants can be added to these coatings, e.g.
to identify different doses of active ingredient.
Further suitable dosage unit formulations for oral
administration are dry-filled capsules made of gelatin and also soft
sealed capsules made from gelatin and a plasticiser, such as
glycerol~ The dry-filled capsules can contain the active ingredient
in the form of granules, for example in ad~ixture ~ith fillers such as
maize starch, binders and/or lubricants, such as talc or magnesium
stearate, and optionally stabilisers, such as sodium metabisulfite
(Na2S205) or ascorbic acid. In soft capsules, the active ingredients
are preferably dissolved or suspended in suitable liquids, for example
in liquid polyethylene glycols, to which stabilisers can also be added.
:
S Suitable dosage formulations for rectal administration are e.g.
suppositories, which consist of a combination of an active ingredient
,f', with a suppository base. Examples of suitable suppository bases are
;,fi natural or synthetic trigiycerides, paraffin hydrocarbons, poly-
,f: ethylene glycols or higher alcohols. Gelatin rectal capsules, which
~` consist of a combination of the active ingredient with a base
~ material, can also be employed. Suitable base materials are e.g. liquid
'~ triglycerides, polyethylene glycols or paraffin hydrocarbons.
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~ mpoules for parenteral, especially intramuscular,
administration preferably contain a water-soluble pharmaceutically
acceptable salt of the compound of the formula I in a preferred
concentrasion of 0.5 to S %, optionally together ~ith suitable
stabilisers and buffer substances, in aqueous solution.
The following Examples illustrate the production of the
compound of the fonmula I and also o f a number of typical dosage
unit formulations~ but are not to be construed as implying any
restriction of the scope of the invention.
Example 1: 184.8 g (0.63 mole) of racemic -[(methylamino)methyl]-
9,10-ethanoanthracene-9(lOH)-ethanol and 127.5 g (0.315 mole) of
(-)-bis-O,O~-(p-toluoyl)-L-tartaric acid are dissolved in 2500 ml
of methanol at a temperature up to 40 C and the solution is then
allowed to stand at room temperature for 24 hours. The precipitated
crystals of R-(~ [(methylamino)methyl]-9,10-ethano-anthracene-9(lOH)-
ethanol (-)-bis-O,O'-(p.toluoyl)-L-tartrate~:l) are filtered with
suction and washed with two SO ml portions of ice cold methanol.
The filtrate is evaporated in a water-jet vacuum. The
residue is dissolved in 500 ml of methylene chloride and this
solution is extracted with three 100 ml portions of 2N sodium
hydroxide solution and then with two 100 ml portions of water. The
methylene chloride is evaporated off, affording 132.5 g of base
which is partially enriched with S-(+)-~-[(methylamino)methyl]-9.10-
ethanoanthracene-9(lOH)-ethanol.This base (0.452 mole) and 91.4 g
(0.226 mole) of (+)-bis-O,O'-(p-toluoyl)-D-tartaric acid are dissolved
in 1800 ml of methanol at 40C and the solution is allowed to stand
for 24 hours at room temperature. The precipitated crystals are
filtered with suction and dissolved in methanol. This solution is
concentrated to about a third of its volume and allowed to stand
for 24 hours at room temperature. The precipitated crystals are
filtered with suction and washed with a small amount of methanol,
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- 17 -
affording S-(+)-~-[(methylamino)methyL] 9,10-ethanoanthracene-9(10H)-
ethanol (+)-bis-O,O~-(p-toluoyl)-D-tartrate (1:1), which melts at 178C
with decomposition; [~]D =+63 (c=0.774 in methanol).
In order to obtain the free base, 4.9 g ~0.01 mole) of the
above salt is dissolved in 50 ml of methylene chloride. This solution
i9 extracted with three lS ml portions of lN sodium hydroxide solution
and then with two 15 ml portions of water, and thereafter evaporated
at about 14 mbar. The residual, crystallised S-(+)-a-[ (methylamino)
methyl]-9,10-ethanoanthracene-9(lOH)-ethanol melt at 106-107C,
Ea]D = ~9.5 (c = 1,06 in methanol.If desired, it can be recrystallised
from ether.
The hydrochloride is obtained by dissolving 88,4 g (0.13 mole)
S~ a-[ (methylamino)methyl]-9,10-ethanoanthracene-9(lOH)-ethanol
(+)-bis-O,O~-(p-toluoyl)-D-tartrate-(l:l) in 300 ml of methylene
chloride and, with stirring, adding at room temperature an ethereal
solution of hydrogen chloride until the supernatant vapours permanently
colour Congo paper blue. The hydrochloride of s-(+)-a-E (methylamino)
methyl]-9,10-ethanoanthracene-9(lOHj-ethanol crystallises out in the
process. After addition of 450 ml of ether, the crystals are filtered
with suction and then recrystallised once from ethanol/methanol.
The hydrochloride thus obtained melts at 231 to 232c; Ea]20 = +9
(c = 2.1 in methanol).
., .
Example 2: a) 1.9 ml of acetic anhydride are added dropwise at
~! ~ 5 - 10 C to a solution of 2.93 g (0.010 mole) of R~
.;~, E (methylamino~methyl]-9,10-ethanoanthracene-9(lOH)-ethanol in 8 ml of
~; dimethyl formamide. The solution is stirred for 4 hours at room
'. temperature, then poured into 60 ml of water and extracted with lOO ml
of ethyl acetate. The ethyl acetate solution is washed with saturated
sodium bicarbonate solution, dried over sodium sulfate and
concentrated in vacuo. Th~ residual crude R-(-)-a-[ (N-methylacetamido)
; methyl]-9,10-ethanoanthracene-9(lOH)-ethanol can be further processed
direct.
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- 18 -
b~ The crude ?roduct of a) (2.5 g) is dissolved in 6 ml of
methylene chloride. ~ith stirring, a ~ol~ltion of 0.77 ~1 of ~hionyl
chloride in 4 ~1 of methvlene chloride is added at 5 - 10 C in
the course of 15 minutes. The reaction solution is stirred for 2 hours
at 20C and then for 1 hour at 35C, and subsequently evaporated to
dryness at about 14 mbar (~ater jet vacuum).
c) The residue of b) is dissolved in 10 ml of ethanol, then
2.5 ml of water and 1.6 g of sodium hydroxide are added and the
mixture is refluxed for 3 hours. The reaction mixture is then
concentrated at about 14 mbar and, after addition of 50 ml of
ice~water, extracted with 100 ml of ethyl acetate.The e~hyl acetate
solution is washed neutral with water, dried over sodium sulfate,
and concentrated at about 14 mbar, affording as residue the crude
base with inverted configuration. The residue is dissolved in 10 ml
of methylene chloride and the hydrochloride of S-(-)-a-[(me~hyl~
~ amino)methyl]-9,10-ethanoanthracene-9(10H)-ethanol is precipitated
Q by addition o~ ethereal hydrogen chloride solution. The crystals are
.j filtered with suction and recrystallised from isopropanol,Melting
~ point 229-231C; [a]D = ~9~ (c = 2.1 in methanol).
,:
~ ~ The starting material for a) is obtained as follows:
r' 60 g of the R-(-)-a-[(methylamino)methyl]-9,10-ethano-
anthracene-9(lOH)-ethanol (-)-bis-O,O'-(p-toluoyl)-L-tartrate-(l:l) [cp.
~ ,~
Example 1, melting point 180C with decomposition, [a]D = -64C
(c - 1.135 in methanol)] are dissolved in 500 ml of me~hylene chloride
and extracting this solution with three 100 ml portions of 2N sodium
hydroxide solution and then with two 100 ml portions of water. The
methylene chloride is evaporated off and the residual R-(-)-a-[(methy~-
J,' amino)methyl]-9,10-ethanoanthracene-9(10~)-ethanol (m.p. 107-108~C). can be used direct for the acetylation according to a).
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- 19 -
Example 3: 2.93 g ~0.010 mole) of R~ (metbylamino)methyl]-9,10-
ethanoanthracene-9(lOH)-ethanol are dissolved in portions in 14 ml of
acetic anhydride. To this solution is added, ~ith stirring, a
solution of 1.75 g of 96 % sulfuric acid in 6 ml of acetic anhydride
and the mixture is then refluxed for 3 hours. The resultant solution
is concentrated at about 14 mbar and the reaction product resulting
from N-acetylation and cyclisation is taken up in 30 ml of lN
sulfuric acid and the solution is refluxed for 2 hours. After
addition of 50 g of ice the mixture is adjusted with aqueous ammonia
solution to pH 9 and extracted with two 50 ml portions of ethyl
acetate. The combined organic phases are dried over sodium sulfate
and evaporated to dryness. The residual crude base is dissolved in
10 ml of methylene chloride and the hydrochloride ofs -(~)-a-
[(~ethylamino)methyl]-9,10-ethanoanthracene-9(lOH)-ethanol is
precipitated by addition of ethereal hydrogen chloride solution~ The
precipitated crystals are filtered with suction and recrystallised
from isopropanol. ~lelting point: 228 - 230C.
, ~ .
Example 4: 3.9 g of the crude 5-(S)-[(9,10-ethanoanthracen-9(lOH~-
yl)methyl]-3-methyl-oxazolidine and 60 ml of 2N hydrochloric acid are
heated for 3 hours to 90C. Then 5N sodium hydroxide is added until
the reaction is alkaline. The reaction mixture is extracted with
methylene chloride and the organic phase is concentrated. The residual
crude S--(+)-~(methylamino)methyl]-9,10-ethanoanthracene-9(lOH)-
ethanol is dissolved in 10 ml of ethanol and 1 ml of a 10 ~
ethanolic hydrogen chloride solution is added. The hydrochloride of the
above base is crystallised by addition of ether. The crystallised
hydrochloride is filtered with suction and, if desired, further
purified as in Example 1 or 2.
,:
~ The starting material can be obtained as follows:
.:
a) 20.0 g of S-~-(aminomethyl)-9,10-cthanoanthracene-9(lOH)-
ethanol (obtainable e.g. in analogy to Example 1 above from the
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- 20 ~
corresponding racemic compound with a melting point of 176-177C
described in US patent specification 4 017 542, Example 1) are
heated in a mixture of 10 ml of 35% aqueous formaldehyde solution and
150 ml of formic acid for l hour to 95C. The reaction mixture is
concentrated in vacuo and the residue is made alkaline by addition
of 2N sodium hydroxide and extracted with methylene chloride. The
organic phase is concentrated~ affording as residue 5(S)-[(9,10-
ethanoanthracen-9(lOH)-yl)methyl]-3-methyl-oxazolidine.
Example 5: To a suspension of 0.7 g of lithium aluminium hydride in
20 ml of tetrahydrofurane is added a solution of l.; g of
N-[3-~910-ethanoanthracen-9(lOH)-yl)-2(S)-hydroxypropyl]-formamide
in 20 ml of tetrahydrofurane, and the mixture is refluxed for 4 hours.
The reaction mixture is cooled, then 1.4 ml of water are added,
followed by the subsequent addition of 1.4 ml of 15 % sodium
hydroxide and a further 5 ml of water. The precipitate is collected
by filtration and the filtrate is concentrated and the residue
,,
dissolved in 2N acetic acid. The acid solution is washed with ether
and then 10 % sodium hydroxide is added until the reaction is
alkaline. The solution is extracted with methylene chloride, then
the solvent is evaporated off and the residual crude S-(+)-~-
[(methylamino)methyl]-9,10-ethanoanthracene-9(lOH)-ethanol is
converted into the hydrochloride with a melting point of 231-232~C
as described in Example 1 or 2.
,i:
The substituted formamide employed as starting material can
~. be obtained as follows:
: a) (S)-~-(Aminomethyl)-9,10-ethanoanthracene-9(10H)-ethanol (cf.
: Example 4a) are refluxed for 2 hours in 75 ml of ethyl formate. The
cooled solution is evaporated to dryness at about 14 mbar. The residue
is dissolved in 75 ml of methylene chloride and this solution is
~,~ washed with 40 ml of lN hydrochloric acid, dried over sodium sulfate,
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- 21 -
and again evaporated to dryness at about 14 mbar. The residual
~-[3-(9,10-ethanoanthracen-9(10H)-yl)-2(S)-hydroxypropyl]-formamide
can be used direct for the reduction.
Example 6: In an autoclave, a solution of 10 g of s-~-[(methylamino)
methyl]-anthracene~9~lOH)-ethanol in 200 ml of benzene is heated
under a pressure of 70 atmos~ for 6 hours to 70C. The solution is
then extracted with 200 ml of 2~ hydrochloric acid. The acid extract
is made alkaline and extracted with methylene chloride. The organic
phase is concentrated and the residual crude S--(+)-[(methylamino~
methyl]-9,10-ethanoanthracene-9(lOH)-ethanol is converted into its
hydrochloride as described in Example 1.
Example 7: a) 100 g of the hydrochloride of S-(+)-~-[(methylamino)
methyl]-9,10-ethanoanthracene-9(10)-ethanol are mi~ed with 202 g
of lactose and 195 g of potato starch. The mixture is moistened with
an alcoholic solution of 10 g of stearic acid and granulated through
a sieve. After it has been dried, the granulate is mixed with 200 g
of potato starch, 250 g of talc, 3.0 g of magnesium stearate and
40 g of colloidal silica, and the mixture is compressed to lO,OOO
tablets each weighing 100 mg and containing 10 mg of active ingredi-
ent. The tablets can be provided with a breaking notch for a finer
ad;ustment of the dose.
,. ~
b) A granulate is prepared from 50 g of the hydrochloride of
S-(+)-~-[(methylamino)methyl]-9,10-ethanoanthracene-9~(lOH)-
ethanol, 223.40 g of lactose and an alcoholic solution of 7.5 g of
stearic acid. After it has been dried, this granulate is mixed with
56.60 g of colloidal silica1 200 g of talc, 20 g of potato starch and
2.50 g of magnesium stearate, and the mixture is compressed to
10,000 sugar-coated tablet cores. These cores are then coated with
a concentrated syrup consisting of 417.3 g of crystalline
saccharose, 6 g of shellac, 10 g of gum arabic, 0.2 g Qf colourant and
1.5 g of titanium dioxide, and dried. Each coated tablet weighs
120 mg and contains 5 mg of active ingredient~
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- 22 -
c) lOOO capsules each containing 10 mg of active ingredient are
prepared as follows: lO g of hydrochloride of S-(+~--[(methylamino)
methyl]-9,10-ethanoanthracene-9(1oH)-ethanol are mixed with 263 g
of lactose and the mixture is moistened unifor~.ly with an aqueous
solution oE 2 g of gelatin and granulated through a suitable sieve
(e.g. sieve III in Ph. Helv. V)~ The resultant cranulate is mixed
with 10 g of dried mai7e starch and 15 g of talc, and the mixture ls
packed uniformly into lOOO si~e 1 hard gelatin capsules.
d~ 100 suppositories each containing 20 mg of active ingredient
are prepared from a suppository base material consisting of 2.0 g oE
hydrochloride of S-(+)-a-[(methylamino)methyl]-9,10-ethanoanthracene-
9(10H)-ethanol and 168,0 g of adeps solidus,
;~
: e) 1000 ampoules are filled with a solution of the hydrochloride
of S~(~)--[(methylamino)methyl~-9~lo-ethanoanthracene-9(loH)-
ethanol in 1 litre of water and sterilised. One ampoule contains a
, 2.5 % solution of 25 mg of active ingredientO
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