Note: Descriptions are shown in the official language in which they were submitted.
zc~
.. . ` 1
The present invention relates to ~eri~h-
eral opiate antagonists.
Despite the various problems associated
with the use of opiates, such as tolerance and physical
5 de~endence, morphine-like drugs remain the products of
choice in the treatment of severe ?ain.
An often se~ous side effect of
~orphine-like drugs is constipation, which ls due to
their local action on the intestinal opiate rece~tors.
To palliate this type of side effect,
~hich is distressing to the patient, it has been ~ro
Dosed that a narcotic anta~onist having a weak ca~acity
of crossing the blood-brain barrier could signi icantly
reduce the constipation induced by the morphine-like
drugs without substantiall~ reducing the analgesic effects
thereof.
U.S. Patent No. 4176 186 describes
quaternary derivatives of mor~hine-like antagonists ~J~hich
~revent or eliminate the side effects of o~iates on the
intestinal motility. Among the compounds claimed in
said Patent, the preferred compounds are the quaternary
derivatives of N-allylnoroxymorphone, hereinafter
designated "naloxone".
Another compound, levallorphan bromo~
allvlate, has been described as periPheral narcotic
antagonist (Life Sci. 1982, 31, 2261).
It has now been found that bv reacting
levallorphan with a methyl halide, a compound is
obtained, herein designated"levallor~han halomethylate"
of formula :
..",
122Q20~
H0~ ~
C ~ / C~2-C~=C~2
CH3
wherein X re~resents chlorine, bromine
or iodine, which has ~ractically no ability to ~ass
- through the blood-brain barrier althou~h they maintain
a verv good peri~heral anta~onistic activi~v.
The term "levallorPhan halomethvl~
is used herein to distinguish the product prepare~as
described hereinabove from the compound, hereinafter
designated "levorohanol haloallylate", obtained by the
reaction of an allyl halide with ~vorphanol . This latter
alsop3ssess the formula I above, but it show~s a
difrerent physicochemical characteristic and no acti.vlty
as a oeripneral or central opiate antagonistic aaent.
Quaternization of the nitrogen atom
lS in 17 oosition introduces, indeed, a new asvmmetr~ center
and the two diastereoisomers can be obtained by
differentiated synthesis as indicated hereinabove as
well as in J. ~led~ Chem. 1~82 , 25, 1278-1280 where
~ the nreoaration of two diastereoisomeric compounds derived
from nalor~hine and morphine, resnectivelv, is described.
Thus, it is an object of the ~resent
invention to ~rovide a process for the oreparation of a
levallorphan halomethvlate of formula I, which com~rises :
a~ treatinq levallornhan with a methyl halide o formula
CH3 X, wherein X is as defined above, at a tem~erature
var~ing from room temperature (about 20C~ to 110C in a
polar solvent;
, y~
~. ~
~2S3~
b) isolatinq the product thus obtained;and
c) submittina said product to successive cr~stallizations
u~ to a constant rotatory Dower.
As a polar solvent, ei-ther a protic
solvent, such as an alcohol, or an a~rotic solvent,
such as dimethyiformamide, acetone, dimethylsulfoxide
and the like can be used.
The reaction time can vary from 2 and
120 hours according to the reaction temnerature; general-
ly, after 5-7 hours at 70-30C the reaction is over and
the ~roduct is isolated according to conventional tech-
niques, for exa.~le b~ precipitation or by eva?oration of
the solvent, ~referably under reduced ~ressure, bv
means of a rotary ~um~. If the residue still contains
small quantities of solvent and/or of water, their
complete elimination can be favoured b~y adding a low-
boilin~ solvent, ?referably acetone or absolute ethanol
and by evaporating under reduced pressure.
The levallor~han halomethylate diastereo-
isomer is isolated in ?ure state by re~eated cr~stalli-
zations, by utilizing an a~ro?riate solvent, ~referablyethanol, in order to eliminate the ot:~er diastereoisomer.
Thus, it is another object o_ the ~resent
invention to provide the levallor~han halomethylate
obtained by the process described above.
Levallor?han halomethylates, as ~ure
diastereoisomers, are novel nroducts.
~ In the volume Synthetic Analgesics, Ed.
D.H~P. Barton and W. Von Doerinq, Pergamon Press, 1974,
part II, Page 48, J. Hellerbach and al. have indicated,
in a summarizing table, a ~roduc~ of formula I above,
in which X is iodine, without any reference as to the
chemical synthesis of the ~roduct. In addition, the
~hysicochemical constants quoted therein are di~ferent
from those o~ the com~ound of Exam~le 1 below, ~articularly
l~ZV2~
the melting point. As regards the nharmacological
activity, a note at the bottom of the above mentioned
tabie indicates that the ~roduct is comprised ~mong
the compounds having a weak or no analgesic activity.
The antagonism of the levallorohan
halomethylates o~ the oresent invention to the consti-
patins effec~ of morphine ~as assessed according to the
test described by A.F. Green, Br. J. Pharmacol. Chemother.
1959, 14, 26, duly modified.
Three groups of fasting (20 hours)
female mice of about 20 g are used. To a control group,
a meal constituted by 0.2 ml of a mixtu~e of S~ arabic
gum (6 ml), flour (2 g) and charcoal ~l g) is administered
bv oral rout~. To the second grou~, l? mg/Xg of morohine
and, immediately afte~ards, the abo~e charcoal meal is
ad~inist2red subcutaneously. The third srou? is treated
with the antagonist under eYamination bV subcutaneous
route, then,after 5 minutes~ with 12 mg/~.g of morphine
by subcutaneous route and, im~ediately arterwards, with
the charcoal meal. After 30 minutes, the animals are
sacrificed to assess the portion of intestine through
which the charcoal has nassed, expressed as ~er cent
of the total leng~h of the small intestine.
The antagonism to the analgesic effect
of morphine was assessed according to the conventional
hot~plate analgesiatest (Eddy and Leinbach, J. Pharma-
col. 1953, 107, 385, modified bv Janssen and Jagenau,
~ J. Pharm. Pharmacol. 1957, 9, 3~1-400).
This method is ver~ sensitive ~or the
action of the opiate antagonists.
Female mice of 18 to 22 g are used.
The substances are administered in saline solution
(20 ml/kg) by subcutaneous injection 5 minutes before
the administration of morphine (24 mg/kg s.c.). Thirty
minutes after morphine, the animals are ~laced on the hot
~, . ,,~
12Z(~Z(~O
s
plate and the reaction times Oc the animals which oresent
the nociceptive reaction (licking of the paws) are
recorded.
The activity of the substances having
S a peripheral narcotic anta~onistic activity is assessed
on the basis of.the per cent inhibition of the
constipating and of the analgesic effect of mor~hine.
The dose which inhibits said effects by 50~ (ID50c for
the consti~ating effect and IDSOa for the analgesic
effect) has been extrapolated from the least sauares
log dose-response line by applving the analysis of the
variance bv linear re~ression.
The activit~ of a representative compound,
levallorphan iodomethvlate, has been assessed in compari-
lS son with that of its diastereoisomer levorphanol iodoally-
late, of the kno~m levallorphan bromoallylate, of a well-
known narcotic antagonist, naloxone, Oc naloxone
sulfomethylate, described in US Patent 4 176 186 and of
- nalorphine bromomethylate described in the above-
mentioned publication J. Med. Chem. l9S2, 25, 1278-1280.
The results are s~marized in table I.
~ABLE I
_ _ , . ~ . .~
Antagonism to Antagonism to
25 Compound efrect ing efCect ID50a/ID50c
IDSOa ID50c
.. _ _ I _ . ._I
levzllor-50 7.6 mg/kg 6.7
Pban iodo-
melhylate
30 levor?han- 50 50 n.d.
lvate
levallor-15.2 mg/kg15.6 mg/kg 0.97
phan bromo- (9.7 - 24.0)t8.5 - 28.9~
naloxone1.6 mg/k~ 5.8 mg/'kg 0.27
sulfomethy- (0.7 - 3,6) (2.9 - 11.5)
. ~ . __
,
,,
020~
~ABLE I cont.
Antagonism to Antagonism to ID50a/
Ca~ound ~ ing effect ~m50c
IDSOa ID50c
-- __
naloxone0.06 mg/Xg 0~8 mg/kg 0.08
(0.02 - 0.15) (0.5 - 1.2)
nalorphine8.6 mg/kg 3.7 mg/kg 2.32
~Fomomethylate (5~5 ~ 13.9) (1.7 - 8.1)
It results ~rom this table that nly
levallorphan iodomethylate does not cross the blood-
brain barrier while levor~hanol iodoallvlatP is inactive
and the other products cross, in a more or less pronounced
degree, the blood-brain barrier.
lS Furthermore, Table I sho~rs that levallor-
phan iodomet~vlate or the present invention exhibits an
activity more than twice higher than that of levallorphan
bromoallylate in the test of the antagonism to the
consti~atinS effect of morphine and that the latter, in a
very sensitive analgesia test shows a tendency to cross
the blood-brain bar~ier.
It follows that the representative
compound of the nresent invention does not show any
central effect thus provin~ to be practically ~ure
peripheral antagonist, whilst the reference com~ounds
- which nroved to be active possess also a more or less
evident centxal activitv.
The compounds of the present invention
are only slightly toxic and therefore, they are useful
as drugs.
Thus, it is a further object of ~he
present invention to ~rovide pharmaceutical com~ositions
having a peripheral oniate antagonistic activity contain-
.,~
~2~0200
ing, as active ingredient, a levallor han halomethvlatein admi~ture with a pharmaceutical carrier.
The pharmaceutical com~ositions having
peripheral opiate antagonistic action, according to the
S present invention, are useful in the treatment of patho-
logical conditions where there are altered rates of
exoqenous or endogenous opiates, or a hypersensitivitv
to opiates outside the central nervous system of mam~als.
Thus, the compositions of the ~resent
invention may be administered to mammals, animals and
h~man beings, with opiates in order to prevent the
side efrects, especially constipation, which derive in
particular from the activation of the ?eripheric opiates
receptors without compromising the analgesia or anv
other action induced by the stimulation of the central
receotors by the opiate.
In order to obtain the desired periDh-
eral antagonistic effect, the dailv dose 0c active
ingredient may vary between 0.05 and 200 mg ~er kg of
body-weight.
Each dosage unit ma~ contain from 1
to 500 mg of active ingredient in combination with a
pharmaceutical carrier. T~is dosage unit may be
administered to the mammals 1 to 4 times ner day.
The pharmaceutical compositions 0c
the present invention having a perioheral o~iate anta-
gonistic action may be formulated for oral, sublingual,
nasal, subcutaneous, intramuscular, intravenous, trans-
dermal or rectal administration, by mixing the active
ingredient of formula I hereinabove with conventional
pharmaceutical carriers.
The dosage unit forms include tablets,
capsules, powders, granules and oral solutions or sus-
oensions, suppositories and ampoules for parenteral
administration.
~hen a solid composition is nrepared in
... .
-- ~2~ 00
the form of tablets, the main active ingredient is mixed
with a ~harmaceutical carrier such as qelatine, starch,
lactose, magnesium stearate, talc, arabic gum or the
like. The tablets may be coated with saccharose or other
aporooriate substances or they may be treated so that
t~eir acti~iity is extended or delayed and that they
continuously reIease a Dredetermined amount of active
ingredient.
A oreoaration in ca~sules is ohtained
bv mixing the active ingredient with a diluent and bv
pouring the mixture obtained in soft or hard caosules.
A ~re?aration in the form o. syru?
or elixir may contain the active ingredient jointly
with an acaloric sweetening aaent, methyl?araben and
lS oropyloaraben as antise~tics, as well as a flavouring
agent and an appropriate dye.
Water-dis~ersible oowders or granulates
may contain the active ingredient mixed with disoersing
agen~s or wetting agents, or susoending agents such as
polyvinylpyrrolidone and the like, and with sweetening
or flavoring agents as well.
For rectal administration, suppositories
are prepared with bindins a~ents melting at rectal
tem~erature, for examle, cacao butter or oolyethylene-
glycOlS~
For oral administration in drops or
for parenteral administration, aqueous suspensions,
- isotonic saline solutions or sterile injectable solutions
are used, which contain pharmacologicallv compatible
dispersing and/or wetting aaents, for exam?le propylene-
glycol or butyleneglycol.
The active ingredient mav also be _or-
mulated in the form of ~.icrocaosules, possibly with one
or more carriers or additives.
The comDositions of the present invention
,. ,
12~0;~0C~
may contain, in addition to the levallorphan halo-
methylate, other active in~redients such as for examol~
narcotic analgesic such as morphine, codeine, bu~renor-
phine and the li~e, antitussives or other appropriate
drugs.
The following exam?les illustrate
the invention without, however, limiting it.
P~EPARATION
Levorphanol iodoallylate, utilized as
rererence oroduct in the nharmacolo~ical test described
hereinabove, has been orepared as ollows :
a mixture of 6 g o levor~hanol, 50 ml of methancl
and 20 ml of allyl iodide is stir-ed for 24 hours away
f_om the light and at room temperature, then lt is
evaporated to dryness under reduced pressure. The oily
residue is taken uo with acetone and the mixture is
stir-ed 1 hour at room temoerature. The solid oroduct
which forms is filtered and crystallized three times
from ~5% ethanol till constant ~ 200 Thus, 4 ~ of
levorohanol iodoallylate are obtained; m.p. 230C (déc.),
O = _ 33.9 (methanol, c = 0.2~).
E.Y~M~LE 1.
.
A mixture of 5 g of levallorohan,
70 ml of dimethylformamide and 6.7 g of met.~vl iodide,
is heated under stirring for 6 hours at the external
tem~erature of 80C, then it i5 concentrated under
reduced pressure while eliminating the solvent and the
excess of alkylating agent b~ addition of acetone. By
cooling the acetonic solution a solid product is
obtained which, after filtration and drving under reduced
presssure, melts at 225-227C. Bv recrystallization
from 50 ml of 90~ ethanol, 5 g o~ a white oroduct
are obtained; m.p. 230-232C. ~fter two further
crystallizationsup to constant rotatory power, pure
levallorphan iodomethylate ls obtained; yield 40~; m~p.
12;~0~
` 10
232-~34C (Tottoli method); f~ 20 = _ 64 + 1 (methanol,
c = 0,2%).
The protonic spectrum NMR obtained at
250 M~z in deuterated dimethylsulfoxide, by utilizing
tetramethylsilane as internal standard, presents a singlet
at 3.20 + 0.02 ppm, relative to the methyl group in the
17 posltion.
The other diastereoisomer, described
in PREPARATION, presents the same singlet at 3.04 +
lO 0.02 ppm.
EX~MPLE 2.
Tablets having the following composition :
levallorphan iodomethylate 50 mg
lactose 145 mg
15 Avicel* lOO mg
magnesium stearate 5 mg
are prepared by crushing the active ingredient to a
particle dimension of 0,4 mm size, by ~assing it through
a 0,4 mm sieve/ by mixing the crushed mixture with the
2Q other constituents and compressin~ to form tablet~.
In the same manner, tablets containing 40 mg of levallor-
phan iodomethylate are prepared.
EXAMPLE 3 .
Capsules containing levallorphan iodomethylate having the
following com~osition :
levallorohan iodomethylate 15 mg
lactose 120 mg
magnesium stearate 5 mg
are ore~ared by mixing intimately charges of the ingredlents
above and pouring the mixture into hard gelatine capsules.
In the same way, capsules containing 25 mg of levallorphan
iodomethylate are orepared.
EXAMPLE 4
__ .
lO 000 capsules with a content of active su~stance of 50 mg
are preoared from the following constituents : 500 g of
* - Trademark
11 12~02~0
levallorphan iodomethylate, 435 g of microcrystalline
cellulose, 5 g of amorphous silica gel. The above
constituents are mixed we~ and introduced into ca~sules
of hard gelatin of dimension 4.
EXAMPLE 5.
A sterile aqueous solution useful for parenteral use
and having the ~ollowing composition :
levallorphan iodometh~late 10 mg
water for injectable ~re~aration to2 ml
10 is prepared and introduced into sterile ampoules.
EXELIPLE 6.
Su~positories are pre~ared, ha~Jina the following
com~osition :
levallorphan iodomethylate 50 mg
lactose 250 mg
mass for suppositories to 1.7g
The levallorphan iodomethylate is mixed with the
lactose and the mixture is placed uniformly in sus~ension
in the molten mass for suppositories. The suspension
is ooured into cooled moulds to ~orm supnositories
weighing 1.7 g.
EX~IPLE 7.
. . .
Sugar-coated tablets each containing 30 mg of levallorphan
iodomethylate are prepared, using talc, lactose, corn
starch, sodium alginate, caster sugar, granulated sugar,
magnesium stearate, white shellac, gelatin for food,
erythrosin, titanium dioxide and white wax as ap~ropriate
carriers.
,
