Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~L3~3Z6
The invention relates to novel esters having anabolic activity
adapted for oral administration, and more particularly to certain novel 17~-
esters of nandrolone (= l9-nor-testosterone), and to methods for the prepar-
ation thereof.
Nandrolone and many 17~-esters thereof are known as substances with
anabolic activity, possessing only slight a~drogenic actlvity in comparison
with testosterone and the 17~-esters thereof. In particular, nandrolone-
17~-esters derived from aliphatic carboxylic acids with 9-1~ carbon atoms
are potent anabolic agents. One of the best known nandrolone esters is
nandrolone decanoat~, which as an oily solution under the trade maTk Deca-
~urabolin finds use in medicine as an injection preparation with a pronounc-
ed alld protracted protein-sparing effect.
As already noted, the nandrolone-17~-esters are administered
parenterally, predominantly by the intramuscular route. When given orally
they are scarcely active, or in any cas0 much less active. An advantage of
parenteral administration is that a good effect can be achieved with a re-
latively lo~ dosage. The use of 17~-esters results furthermore in a depot
effect, so that an effective plasma nandrolone level is not only obtained
rapidly after an intramuscular injection, but this nandrolone level may also
persist for several weeks.
There are also objections to the parenteral form of administration.
A patient is not usually capable of giving him- or herself an injection;
for this, a doctor or a trained nurse is almost always necessary. Further-
more, repeated yarenteral administration may cause local reactions. A
further disadvantage associated with the parenteral administration of long-
acting preparations is that the action thereof cannot be interrupted or stop-
ped. An oral administration form would therefore be far more preferable
. . ",
:~ :.. : . ,
: : ", :
- :-: . : ,
. . . : . :: . : ~ , :
~: .: ,, : . ~ , . .
~L3~Z6
than a parenteral form.
It has been found that certain nandrolone esters, specifically the
esters derived -from aliphatic carboxylic acids with 9-18 carbon atoms, are
orally active if they are administered in combination with a non-steroidal
lipoid substance. This is the more surprising since the nandrolone-17~-esters
derived from aliphatic carboxylic acids ~ith less than 9 or more than 18
carbon atoms are distinctly less active orally under these conditions.
The invention relates to a group of such esters which are novel.
Accordingly, the invention provides novel 17~-esters of nandrolone having
the formula
Rl
O - C - (CH2)n ~ 1 3
R2 (1)
l I
O ~ ~\~.
, ~Yherein n ~ O or l; ~1 ~ alkyl Cl-lQ C~; R2 ~ ~ or alkyl ~1-10 C~; R3 = an
aliphatic or cycloaliphatic gr~oup having 6-~12 C-atoms, ~hic~ group may contain
one or more rings having 5-12 C-atoms, with the proviso that the total number
of C-atoms in the ester group is in the range oE 9-16 C-atoms.
According to the invention, the novel esters are prepared by a
process which comprises reacting nandrolone with an appropriate organic carboxy-
lic acid or functional derivative thereof in a sol~ent and in the presence of
a watel~-binding agent or a base. Functional derivatives include particularly
the acid chloride and the acid anhydride. A suitable base which may be used
-- 2 --
;~
- ; :, ' , ' ' , ", ~ ,, , r
`: ':: :, ', .;, . ` '
26
for the reaction is pyridine.
in the new compounds according to the invention, it is preferred
that n is zero, Rl is methyl, R2 is hydrogen, and ~3 is an aliphatic group
having 6-12 carbon atoms ~hich may contain one or more rings having 5-8 car-
bon atoms.
As examples of aliphatic carboxylic acids from which the nandrolone
esters o~ the invention are deri~ed, the following can be given: ~-(and ~-)
methyl-caprylic acid, ~-~and ~-~methyl-pelargonic acid, ~-(and ~-)methyl-
capric acid, ~, ~-dimethyl-pelargonic acid and ~-~and ~-)methyl-~-cyclohexyl
propionic acid. The nandrolone ester is preferably deri~ed from the ~- or ~-
etl~yl-substitllted and cyclic isomers of capric acid, undecanoic acid, lauric
.ICid, tridecanoic acid, or ~yristic acid.
The esters may be formulated ~ith a pharmaceutically acceptable
nonsteroidal lipoid for oral administration. By pharmaceutically acceptable
nonsteroidal lipoids are meant plant and animal oils and fats consisting of
the mono-, di- and triglycerides of various fatty acids or containing these
as main constituents; fatty acid esters of alcohols; hi~her aliphatic alco-
hols; saturated and unsaturated fatty acids; the commercially available
syntlletic and semi-synthetic mono-, di- and triglyceride oils and glycerol
ethers; certain types of wax and mixtures of two or more of the above-noted
substances. T~e lipoid substance is preferably liquid at normal temperature,
that is, at a temperature in the range of about 10C to about 35C. The
~androlone ester is then dissolved in the lipoid substance and the solution
is incorporated into a preparation or, as the case may be, converted into
a pharmace-ltical form. At normal temperature, part of the ester may be pre-
sent in the liquid lipoid as a suspension, in which case the quanti~ies of
ester and lipoid substance are mutually adjusted in such a way that at body
-- 3 --
. . ~ , , . . .: .
, ;
- ~ ,.: .: . . :- . . :.
. ~ :....... : . : .;. . :. .: :, :,
::: : .; . . ::; .,, :
:;. . ;,
3~Z6
temperature the ester is completely dissolved in the lipoid substance. The
intensification of the oral activity of the nandrolone esters according to
the invention appears to be the greatest ~hen a lipoid substance liquid at
normal tempeTature is used.
E~amples of lipoid substance which may be used in ~he preparation
according to the invention are: arachis oil, castor oil, sesame oil, lin-
seed oil, soya bean oil, sunflower seed oil, olive oil, fish liver oil, ethyl
oleate, oleyl oleate, glyceryl trioleate, glyceryl diolate, glyceryl mono-
oleate, cetyl alcohol, stearyl alcohol, capric acid, undecenoic acid, unde-
canoic acid, lauric acid, oleic acid, synthetic glycerides of saturated fatty
acids, with 8 to 10 or 12 carbon atoms such as the commercial products
Syndermin* GTC and Miglyol* 812, polyoxyethylene derivatives of glycerol,
. such as the conlmercial product Labrafil* 1944, bee's wax and mixtures of two
or more of these substances.
The invention herein referred to provides an oral pharmaceutical
preparation with anabolic activity. By incorporating an orally active
mineralocorticoid into the preparation, the invention also of~ers the pos-
sibility of preparing an orally active pharmaceutical formulation which pos-
sesses mineralocorticoid properties in addition to anabolic properties.
Pharmaceutical preparations with both anabolic and ~ineralocorti-
coid actions, effective on subcutaneous administration, are known. As ~n
e~ample, the commercially available preparation Docabolin*, for intramuscular
injection, can be cited.
Such preparationsJwhich in addition to powerful protein-sparing
and roborant properties also have a normalizing effect on a reduced blood
pressure, are used for various indications including hypotension, debilitat-
ing conditions, conditions associated with exhaustion, during convalescence,
* Trade mark
_ ~ _
. .-: - . ~ : ,
~ , . - ,. . .
,;:;
~ :, .. .
. .
~39~6
burns and infantile dystrophy.
As orally active mineralocorticoid, one or more esters of desoxy-
corticosterone are incorporated into the anabolic preparation according to
the invention, such esters being preferably derived from an aliphatic car-
boxylic acid with 9-18 carbon atoms.
The desoxycorticosterone ester may be derived rom the same alipha-
tic carboxylic acid as the nandrolone ester, and is preferably derived from
the carboxylic acids with lO-12 carbon atoms.
The presence o~ the oily component results in a surprising intensi-
fication of the oral activity of the desoxycorticosterone ester.
The preparation according to the invention may be administered
~er os in various dosage forms, for example in the form of tablets, capsules,
grains, pills~ boli, dragees~ powders, granulates, microcapsules or chewable
tablets. In addition to the anabolic ester~s), the lipoid substance and
optionally the mineralocorticoid compound, the dosage ~orm may contain one
or more of the usual excipients, for example benzyl alcohol to increase the
solubility of the active agent in the oily component, water, thickening agents
such as gelatine or agar-agar, polyethylene glycols, lactose, starch, talc
or magnesium stearate. Other agents, such as preserva~ives, emulsifying
agents, stabilizing agents, wetting agents, flavours, dyes, fillers, binding
agents and/or coating agents may optionally be present.
The capsules may be so~t or hard gelatine capsules, in which the
active principle and the lipoid may be present in granular or Einely divid-
ed intimate admixture or may be present in the form of an oily solution or
suspension.
The combination of nandrolone-17~-ester and lipoid, when li~uid or
semi-liquid, may also be processed to solid oral ormulations such as pills
:. ::.: . ` . . :,
, . : , :,
. ....
~ h ~ 33Z~i
or tablets. For that pur~ose the oily solution of nandrolonc-17~-ester is,
for example, absorbed on calcium phosphate, lactose or cellulose derivatives
and then processed to tablets or pills in the usual way. Combinations of
nandrolone-17~-esters with lipoids, such as glycerylmono-oleate or capric
acid, wllich are solid or semi-solid at Toom temperature, but are liquid at
body temperature, may be granulated and processed to coated pills or tablets.
As already noted above, the nandrolone esters according to the
invention are preferably administered dissolved in lipoid substances liquid
at normal temperature, such as, for example, vegetable and animal oils,
oleic acid, linoleic acid or undecanoic acid. When a mineralocorticoid is
present, this is preferably also present dissolved in the oil, in addition
to the nandrolone ester.
The most suitable oral administration form for this liquid form
9~ the preparation according to the invention is the soft-shell gelatine
capsule or microcapsule. In accordance with a method usual in the technique,
the oily solution containing the active component(s) and optionally other
ingredients is encapsulated to soft-shell gelatine capsules or micro-capsules
with the desired dimensions and containing the desired amount(s) of active
substance~s). The micro-capsules can also be processed to tablets or pills
according ~o well-known pharmaceutical formulation methods.
The nandrolone-17~-ester~s) concentration in the preparation ac-
cording to the invention can vary within considerable limits, on the under-
standing that the amount of nandrolone-17~-ester~s) by weight does not
e~ceed the amount of lipoid substance by weight or in other words the nandro-
lone-17~-ester~s) concentration in the preparation is 50% by weight or less
and is usually in the range of 1-25% by weight.
As indicated above, the amount of lipoid by weight in the prepara-
.. . , .
.. : . .
: . . .
- .
- , ' ': ~
3!~:6
tion according ~o the invention is equal to or higher than the amount o~
nand~olone-17~-ester by weight. Depending on the other constituents present
in the preparation ~excipients, capsule, shell, coating) the amount of
lipoid substance per dosage unit will vary from 5 to 95% by weight and is
usually in the range of 20-80% by weight. The amount of nandrolone-17~-
ester(s) pcr dosage unit, for example a capsule or a tablet, may also vary
within l~ide limits, for example from 0.1 mg to 100 mg, and is preferably
between l mg and 50 mg.
When the desoxycorticosterone ester is present in the preparation
according to the invention, the amount thereo~ per dosage unit is within the
range 0.5 to 50 mg, and the requirement, that the amount of desoxycortico-
sterone ester by weig]lt does not exceed the amount of lipoid substance by
weight, also applies.
The exceptional anabolic properties of the preparations according
to the invention have been demonstrated in the known Hershberger test with
castrated rats. A number of nandrolone-17~-esters were administered orally
twice daily for 7 days as solutions in arachis oil. Nandrolone itself was
also tested in this way.
Nith nandrolone, its lower esters such as acetate and propionate,
and the nandrolone esters derived from aliphatic carboxylic acids with more
than 18 carbon atoms, given in dosages of 2x2.0 mg/day, the weight of the
M-levator ani was shown to increase by ~0%-60%, wllile with the es~ers of
tlle invention derived from aliphatic carboxylic acids with 9-18 carbon atoms,
such as the ~-methyl-decanoate, said increase is more than 150%.
Experiments with other lipoid substances, such as sesame oil, soya
bean oil, glyceryl trioleate, oleic acid and undecenoic acid, gave similar
results. It was obvious that nandrolone-17~-esters derived from aliphatic
: ., .,,: . ~
-:. : ;. : : . . .
.,:. .~ , ~, ,.
;. , ~, -
;:: ~ .. : . - :
~,,:, :
- " . ~ .
. . ~., ,. . :
392~
carboxylic acids with more than 8 and less than 18 C-atoms, in the presence
of a lipoid substance, are much more active on oral administration than the
other esters, and that specifically the esters with 10-14 carbon atoms are
; very active. In clinical studies a distinct protein-sparing effect was
demonstrated when a daily dosage of 1-3 dosage units of an anabolic prepara-
tion according to the invention was given for a few weeks.
The invention is further illustrated by means of the following
examples:
Exam~
Soft-shell gelatine capsules
A sterile solution of a nandrolone-17~-ester according to the in-
vention in arachis oil, containing 83.33 g per litre, was prepared, and
this solution was encapsulated in soft-shell gelatine capsules, with due
regard for aseptic precautions. The soft-shell gelatine capsules obtained
had a content of 0.12 ml, so that the amount of active substance present was
10 mg per capsule. The capsule wall consisted of 68.1% gelatine, 15.5%
glycerol, 13.7% sorbitol, 0.4% sodium ethyl-propyl p-hydroxybenzoate, 0.5%
TiO2 and 1.8% Cochineal Red ~dye).
Two nandrolone-17~-esters in various lipoid substances were pro-
cessed in this way to give soft-shell capsules, for which details are given
in table A.
Table A ;~
lipoid capsule mg active
ester substance content substance/capsule
-17~-a-methyl- oleic acid 0.08 5
decanoate
-17~-~-methyl-~- linseed oil 0.08 5
cyclohexylpropio-
nate
~ __
.. ..
.
~39Z6
Example II
Tablets
Nandrolone-17~-ester 10.0 mg
Capric acid 20.0 mg
Lactose 1~0.0 mg
Potato starch 80.0 mg
250.0 mg
The nandrolone-17~-ester e.g. nandrolone-17~ -methyldecanoate,
was dissolved with gentle warming in capric acid, after which the solution
was homogenously absorbed in the lactose. Ater mixing with potato starch
and a little water, the granulate thus obtained was dried. The dry granulate
was tabletted in the usual way.
Tablets of the following compositions were prepared in a similar
way:
Nandrolone-17~-ester 5.0 mg
Glyceryl mono-oleate 50.0 mg
Lactose 150.0 mg
Potato starch ~5.0 mg
300.0 mg
Nandrolone-17~-ester 10.0 mg
Desoxycorticosterone undecanoate 10.0 mg
Stearyl alcohol/bee's wax 20.0 mg
Lactose 130.0 mg
Potato starch 80.0 mg
250.0 mg
_ g _
:: : :. . : : :
; , : :: : , ,: : .: -
:: : . .~ ~
~3~Z~;
Example III
Hard-shell gelatine capsules (a) (b)
Nandrolone-17~-ester 20.0 mg 10.0 mg
Desoxycorticosterone dodecanoate - 10.0 mg
Lauric acid 100.0 mg 100.0 mg
Lactose 130.0 mg 130.0 mg
250.0 mg 250.0 mg
The nandrolone-17~-ester was dissolved in lauric acid at 50C (in
case tb) together with the desoxycorticosterone dodecanoate). The solution
was homogenously absorbed in the lactose and the cooled solid mixture was
powdered. ~lard-shell gelatine capusles were filled wi~h the ~inely-divided
mixture ~250 mg mixture per capsule).
Example IV
Soft-shell gelatine capsules
Soft-shell gelatine capsules with contents as speci~ied below were
prepared in a way similar to that described in example I, using, for example,
nandrolone-17~- ~-methyldecanoate.
a) Nandrolone-17~-ester 10.0 mg
Desoxycorticosterone decanoate 5.0 mg
Oleic acid to 0.18 ml
b) Nandrolone-17~-ester 5.0 mg
Desoxycorticosterone decanoate 10.0 mg
Arachis oil to 0.24 ml
- 10 -
. :. .. ..
- ,. . . . -.. : . . . .
.. .. . . .
~3~Z~
Example V
Preraration of novel esters
To a solution of 5 g nandrolone in a mixture of 50 ml pentane and
5 ml pyridine were added dropwise in 1 hour 5 ml of ~-methylcapric acid.
The rcaction mixture was stirred for 1 hour and then neutralised with an
aqueous solution of sodium-bicarbonate, whereafter the organic layer was
separated, washed with a solution of sodium-bicarbonate and with water till
neutral. The organic layer was evaporated till dryness. The residue was
chromatograp~led over a column of silicagel with toluene/acetone 9/1, yield-
ing 6.3 g nandrolone-17~- ~-methylcaprate, oil with [~]D0 = +33 ~in dioxane).
In a similar manner the following 17~-esters of nandrolone were
prepared:
~-methylcaprate, oil with [u]20 = +35.7
~,~-dimethylcaprate, ~a]D = +39.6
~-methyl-~-cyclohexyl-propionate, [~]20 = +35
~-cyclohexyl-butyrate, ~]20 = +350
~-methyl-tridecylate, [~]D0 = +27.3
3',5',5'-trimethylcaproate, oil with [~]D0 = +47 4
3',7'-dimethylcaprylate, oil with ~]D = +35.8
~,~ -diethyl-caproate
~-butyl-oenanth~te
~,~ -dimethyl-pelargonate
: ,
,
