Note: Descriptions are shown in the official language in which they were submitted.
53
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The present invention relates to certain new polyether
compounds, to several processes for their production and to
. .
their use as medicaments which have an influence on metabo-
, lism, in particular as lipid absorption inhibitors.It has already been disclosed to prepare polyethers
consisting of ethylene oxide and propylene oxide groupings
(compare U.S. Patent 2,674,619). It is also known that
polyoxyalkylenes with molecular weights of about 1,000 to
about 11,000 have surface-active properties and in addition
.:.
~: 10 can also be used in pharmaceutical formulations. The use
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of polyoxyalkylenes with a molecular weight of about 2,000
to 10,000 and an ethylene oxide content of 50 to 90~o as anti-
thrombotic agents is claimed and described in U.S. Patent
Specification 3,641,240. In this Patent Specification it
is expressly pointed out that the polyoxyalkylene to be used
should contain at least 50~o of ethylene oxide.
Polyoxyalkylenes which can be used as laxatives are
, . - . .
described in U.S. Patent 3,202,578. In addition to the
laxative action, an action on the cholesterol level in the
blood is also mentioned in this Patent Specification.
~ According to the statements of this Patent Specification,
; those polyoxyalkylenes which have a molecular weight of 7,500
-.
- and contain 80qo of ethylene oxide are particularly suitable
for use as compounds which lower the cholesterol level.
The present invention provides certain new compounds
which are polymeric oxyalkenes (polyethers) of the following
: general formula I: CH
: , 3
: H0-(CH2-CH2-0)x-(aH-aH2-O)y~(aH2 aH2 )z (I)
.:
in which
`,
~e A 18 192 - 2 -
.,
`:
... .
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X, Y and Z are numbers havlng values such that sa1d
compound of formula I has a molecular weight of about 4000 and
-- such that the propylene oxide:ethylene oxide ratio, Y: (X+Z), is
` about 70:30.
The polyether compounds of the general formula (I)
according to the invention may be prepared by a process in
which propylene glycol is reacted by means of a polyaddition
reaction in the presence of an alkali metal hydroxide, first
with propylene oxide and thereafter with an appropriate amount
of ethylene oxide and the alkali metal hydroxide is then
neutralised with a mineral acid, usually an aqueous mineral
acid, and, after dehydrating the polyether, is removed by
filtering off the salt.
In a further aspect of the present invention provides
a process for the production of a compound according to the
invention in which a compound of the general formula II
CH3
HO-(CH-CH2-O)y-H (II)
in which Y has the same meaning as defined hereinbefore in
` formula (I) is reacted with an appropriate amount of ethylene
oxide so as to produce a said compound of general formula I
as defined hereinbefore.
Conveniently the reaction is carried out in the
presence of an inert solvent.
Upon completion of the reaction, the reaction mixture
is neutralised with an acid and the alkali metal hydroxide is
,
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53
removed in the form of an insoluble salt by filtration.
The compound of formula II may be prepared by reacting
- propylene glycol with propylene oxide so as to produce said
compound of the general formula II as defined hereinbefore.
The polyether compounds according to the invention
- have a narrow molecular weight distribution.
The characterisation of the composition of the poly-
meric oxyalkylene compounds may be carried out analytically by
. .
determining the molecular weight from the hydroxyl number.
The ethylene oxide content may be determined from the lH-NMR
spectrum.
The polyether compounds according to the invention
show, surprisingly, very powerful actions in the treatment of
disorders in fat metabolism and carbohydrate metabolism. In
particular, they effect a lowering of the increased cholesterol
:::
level in serum and in tissue and simultaneously reduce hyper-
triglyceridaemia. The compounds according to the invention are
suitable for the treatment of hyperlipoproteinaemias, arterio-
-~ sclerosis and adiposity and for the treatment of metabolism
disorders caused by these.
; It is to be described as exceptionally surprising that
the polyether compounds according to the present invention have
such a pronounced hypolipidaemic action precisely at a molecular
weight of about 4,000, and in the specific propylene oxide/ethyl-
ene oxide ratios mentioned. Since the compounds according to
. .
the invention are at the same time very well tolerated, in
addition to having this powerful action, they are an enrichment
, of pharmacy.
''`'``'
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1 4~3
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As stated above, the invention also relates to the use
in human and veterinary medicine of the compounds of the
invention.
~he present invention provides a pharmaceutical
composition containing as active ingredient a compound of
the invention in admixture with a solid or liquefied gase-
ous diluent, or in admixture with a liquid diluent other than
a solvent of a molecular weight less than 200 (preferably
less than 350) except in the presence of a surface active
agent.
~he in~ention further provides a pharmaceutical
; composition containing as active ingredient a compound of
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` the invention in the form of a sterile and/or isotonic aque-
ous solution.
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~he invention also provides a medicament in dosage
- unit form comprising a compound of the invention.
~ The invention also provides a medicament in the form
; of tablets (including lozenges and granules), dragees,
capsules, pills, ampoules or suppositories comprising a
compound of the invention.
- "Medicament" as used in this specification means
physically discrete coherent portions suitable for medical
administration. "Medicament in dosage unit form" as used in
this specification means physically discrete coherent units
suitable for medical administration each containing a daily
dose or a multiple (up to four times) or sub-multiple (down
to a fortieth~ of a daily dose of the compound of the inven-
tion in association with a carrier and/or enclosed within
an envelope. Whether the medicament contains a daily dose or,
for example, a half, a third, or a quarter of a daily dose
~e A 18 192 - 5 -
4~i3
will depend on whether the medicament is to be administered
once or, for example, twice, three times or four times a
day respectively.
The pharmaceutical compositions according to the
invention may, for e~ample, take the form of ointments, gels,
- pastes, creams, sprays (including aerosols), lotions,
suspensions, solutions and emulsions of the active ingredient
in aqueous or non-aqueous ~luents, syrups, granulates or
powders.
The diluents to be used in pharmaceutical compositions
(e.g. granulates) adapted to be formed into tablets, dragees,
- capsules and pills include the following:
(a) fillers and e~tenders, e.g. starch, sugars, mannitol,
and silicic acid; (b) binding agents, e.g. carboxymethyl
` 15 cellulose and other cellulose derivatives, alginates,
gelatine and polyvinyl pyrrolidone; (c) moisturizing agents,
e.g. glycerol; (d) disintegrating agents, e.g. agar-agar,
calcium carbonate and sodium bicarbonate; (e) agents for
,~....... .
` retarding dissolution e.g. paraffin; (f) resorption
accelerators, e.g. quaternary ammonium compounds; (g) sur-
face active agents, e.g. cetyl alcohol, glycerol monostearate;
(h) adsorptive carriers, e.g. kaolin and bentonite; (i)
lubricants, e.g. talc, calcium and magnesium stearate and
solid polyethylene glycols.
The tablets, dragees, capsules and pills formed from
the pharmaceutical compositions of the invention can have the
customary coatings, envelopes and protective matrices, which
may contain opacifiers. They can be so constituted that they
release the active ingredient only or preferably in a
particular part of the intestinal tract, possibly over a period
.. ...
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1~14S3
of time. The coatings~ envelopes and protective matrices
may be made, for example, of polymeric substancea or waxes.
The ingredient can also be made up in microencapsulated
form together with one or several of the above mentioned
.. .
diluents.
The diluents to be used in pharmaceutical compositions
adapted to be formed into suppositories can, for example,
be the usual water-soluble or water-insoluble diluents,
such as polyethylene glycols and fats (e.g. cocoa oil and
:
high esters ~e.g. C14-alcohol with C16-fatty acid~) or mix-
tures of these diluents.
The pharmaceutical compositions which are ointments,
.i
pastes, creams and gels can, for example, contain the usual
diluents, e.g. animal and vegetable fats, waxes, paraffins,
starch, tragacanth, cellulose derivatives, polyethylene
glycols, silicones, bentonites, silicic acid, talc and zinc
i
oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and
sprays can, for example, contain the usual diluents, e,g.
lactose, talc, silicic acid, aluminium hydroxide, calcium
silicate, and polyamide powder or mixtures of these sub-
stances. Aerosol sprays can, for example, contain the usual
propellants, e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions
and emulsions can, for example, contain the customary dil-
uents (with, of course, the above mentioned exclusion of
solvents having a molecular weight below 200 except in the
presence of a surface-active agent), such as solvents,
dissolving agents and emulsifiers; specific examples of such
diluents are water, ethyl alcohol, isopropyl alcohol, ethyl
~e A 18 192 _ 7 _
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carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
-^ propylene glycol, 1,3-butylene glycol, dimethylformamide,
~ oils [for example, ground nutoil], glycerol, tetrahydrofurfuryl
: .
- alcohol, polyethylene glycols and fatty acid esters of
sorbitol or mixtures thereof.
For parenteral administration, solutions and emulsions
should be sterile, and, if appropriate, blood-isotonic.
~he pharmaceutical compositions which are suspensions
. . .
can contain the usual diluents, such as liquid diluents, e.g.
. ,,
water, ethyl alcohol, propylene glycol, surface-active agents
(e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite
.. : .
and sorbitane esters), microcrystalline cellulose, aluminium
metahydroxide, bentonite, agar-agar and tragacanth or mixtures
thereof.
All the pharmaceutical compositions according to the
i invention can also contain colouring agents and preservatives
;~ as well as perfumes and flavouring additions (e.g. peppermint
oil and eucalyptus oil) and sweetening agents (e.g. saccharin).
~he pharmaceutical compositions according to the invention
generally contain from 001 to 9905, usually from 0.5 to 95%
` of the active ingredient by weight of the total composition.
.
In addition to a compound of the invention, the pharma-
:. .
ceutical compositions and medicaments according to the invention
can also contain other pharmaceutically active compounds.
They may also contain a plurality of compounds of the invention.
Any diluent in the medicaments of the present invention
; may be any of those mentioned above in relation to the pharma-
ceutical compositions of the present invention. Such medica-
ments may include solvents of molecular weight less than 200
as sole diluent.
Le A 18 192 - 8 -
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.',
: ..,
:
~ ~he discrete coherent portions constituting the medica-
.
ment according to the invention will generally be adapted, by
virtue of their shape or packaging, for medical administration
- and may be, for e~ample, any of the following: tablets,
(including lozenges and granulates), pills, dragees, capsules,
suppositories and ampoules. Some of these forms may be made
up for delayed release of the active ingredient. Some, such
as capsules, include a protective envelope which renders the
portions of the medicament physically discrete and coherent.
The preferred daily dose for administration of the
medicaments of the invention is from 2.5 mg to 25g, preferably
from 25 mg to 10g, of active ingredient.
The production of the above-mentioned pharmaceutical
compositions and medicaments is carried out by any method
known in the art, for example, by mixing the active ingredient(s)
with the diluent(s) to form a pharmaceutical composition
(e.g. a granulate) and then forming the composition into the
medicament (e.g. tablets).
This invention further provides a method of combating
(including prevention, relief and cure of) the above-mentioned
diseases in human and non-human animals, which comprises ad-
ministering to the animals a compound of the invention alone
or in admixture with a diluent or in the form of a medicament
according to the invention.
It is envisaged that these active compcunds will be
administered perorally, parenterally (for example, intra-
muscularly, intraperitoneally, or intravernously), rectally
or locally, preferably orally. Preferred pharmaceutical
compositions and medicaments are therefore those adapted for
oral administration, such as pills, tablets, dragees and
e A 18 192 - 9 -
45~
:.
capsules. Administration in the method of the invention is
preferably orally.
` In general it has proved advantageous to administer
amounts of from 0.05 mg to 500 mg, preferably from 0.5 mg to
200 mg, per kg of body weight per day to achieve effective
results. Nevertheless, it can at times be necessary to deviate
,:; .:
from those dosage rates, and in particular to do so as a
function of the nature and body weight of the huma~ or animal
subject to be treated, the individual reaction of this subject
to the treatment, the type of formulation in which the active
ingredient i9 administered and the mode in which the administra-
tion is carried out, and the point in the progress of the disease
orinterval at which it is to be administered. Thus it may
in some cases suffice to use less than the above-mentioned
.: .
j~ 15 minimum dosage rate, whilst other cases the upper limit
,, .
-:. -
mentioned must be exceeded to achieve the desired results.
; Where larger amounts are administered it can be advisable to
'''~`J''",.' divide these into severa], for example from 2 to 6, individual
1.~. . .
administrations over the course of the day. An individual
` 20 administration preferably contains from 0.1 to 100 mg of
active ingredient per kg of body weight.
-' ExamPle
93.5 g of propylene glycol and 62 g of 50% strength
potassium hydroxide solution are initially introduced, under
nitrogen, into a 10 1 glass flask provided with a heating
bath, stirrer, reflux condenser and device for metering in
epoxide. The mixture is dehydrated by azeotropic or vacuum
distillation. Thereafter, a polyaddition reaction is carried
out at 100 - 120C, first with 4,707 g of propylene oxide
and then with 1,200 g of ethylene oxide. The potassium
Le A 18 192 - 10 -
hydroxide is neutralised by adding dilute sulphuric acid. After dehydrating
the polyether and removing highly volatile constituents by distillation, the
potassium sulphate formed is removed by filtration. The hydroxyl number of
the polyether was determined to be 28.0, corresponding to a molecular weight
-` of 4000. Measurement of the 'H-NMR spectrum corresponded to an ethylene
oxide content of 20.0% by weight.
Example 2
Reaction of 4,134.5 g of propylene oxide and 1,800.0 g of ethylene
; oxide with 93.5 g of propylene glycol in the presence of 62.0 g of 50%
10 strength potassium hydroxide solution according to the process described in
Example 1, gave a polyether having a hydroxyl number of 28.0, corresponding
to a molecular weight of 4000. The content of ethylene oxide, determined
from the NMR spectrum was 30% by weight.
Example 3
Reaction of 3,506.5 g of propylene oxide and 2,400,0 g of ethylene
oxide with 93.5 g of propylene glycol in the presence of 62.0 g of 50%
strength potassium hydroxide solution according to the process described
in Example 1, gave a polyether having a hydroxyl number of 28.0, corresponding
, to a molecular weight of 4,000. The content of ethylene oxide determined
20 from the NMR spectrum was 40% by weight.
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