Note: Descriptions are shown in the official language in which they were submitted.
~Z7655
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N-Benzoyl-retinylamines, their preparation, and pharma-
ceutical formulations containing these com~ounds
The present invention relates to novel N-ben~oyl-
retinylamines of the formula I
where R is hydrogen or methyl, their preparation, pharma-
ceutical formulations containing these compounds, and
their use as drugs.
The synthesis of N-acetyl-retinylamine and N-
formyl-retinylamine, for example, is known from the
literature (F. Kienzle, Helv. Chim. Acta 56 (1973),
1662 et seq.).
Further, it has been disclosed that N-acetyl-
retinylamine may be used for the systemic and topical
therapy of pre-cancerous conditions and carcinomas and
~or the systemic and topical prophylaxis o~ carcinomas
(M.B. Sporn et al. Nature 263 (1976), 110-113).
The cellular toxicity threshold, namely in res-
pect o~ the toxicity to tracheal cartilage in vitro, of
N-acetyl-retinylamine is above a molar concentration of
10 5 (Nature 263 (1976), 110-113), but this retinoid, in
biological experiments on hamster tracheal tissue
keratinized by vitamin A hypovitaminosis, exhibits an
activity only in molar concentrations as high as 9xlO 9.
The methods used are described by G.H. Clamon et al.,
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2 - O.Z. 0050/033447
Nature 250, (1974), 64-66 and ~.B Sporn et al., Nature
253, (1975), 47-50. The keratinization is regarded
as a pre-cancerous process.
We have found that the N~benzoyl-retinylamines
of the formula I exhibit particularly valuable pharmaco-
logical properties, since they have a substantially
higher therapeutic index
Whilst having a comparably low cellular toxicity,
the compounds according to the invention still inhibit
the keratinization of hamster tracheal tissue in lO lO
molar solution and are therefore more active, by from l
to 2 powers of ten, than N-acetyl-retinylamine
Accordingly, the invention further relates to
pharmaceutical formulations which contain, as the active
ingredient, a compound of the formula I, in addition to
conventional pharmaceutical carriers or diluents, with or
without conventional pharmaceutical excipients, and to
the use of a compound of the formula I for the prepara-
tion of a drug
Formulations which contain a compound according
to the inven1;ion, of the formula I, may be used prefer-
entially for the topical and systemic therapy of pre-
cancerous conditions and carcinomas of the skin, mucous
membranes and internal organs, and for the systemic and
topical therapy of acne, psoriasis and other dermato-
logical disorders accompanied by intensified or pathologi-
cally modified keratinization In contrast to free
retinic acid, the compounds according to the invention
do not irritate the skin and do not cause any A-hyper-
~lZ765~
- 3 - O.Z. 0050/033447
vitaminosis.
A preferred indication is the prophylacticand therapeutic
treatment of pre-cancerous conditions and tumors of the bladder,
the rnammary gland, the skin and the mucous membranes.
11~7~5S
_4 _ O . Z . 0050/033447
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` 1127ti55
- 5 - O.Z. 0050/033447
The compounds according to the invention have significant
tumor-inhibiting action. Growth control may be observed in cells
cultivated in vitro and may be detected by the method described
by R.Lotan et al in Journal of the National Cancer Institute 60
(1978), 1035-1041. The compounds also inhibit the proliferation
of spontaneously chemically or virally transformed cells in tissue
culture, the preferred culture being S 91 melanoma cells.
The compounds of the formula I, according to the
¦ invention, are prepared in the conventional manner by
reacting all-E-retinylamine with a reactive deri~ative of
benzoic acid or of p-toluic acid. Suitable re~ctive
acid derivatives are esters, anhydrides and, preferably,
acid halides, especially the acid chlorides. The re-
action is advantageously carried out in the presence of
a base, especially a tertiary amine, preferably pyridine,
in an inert solvent, such as a dialkyl ether or
chlorohydrocarbon,preferably in diethyl ether or methylene
chloride. Advantageously, it is carried out in the
absence of oxygen and moisture, for example under nitro-
gen as a blanketing gas.
The end products are worked up in the convention-
al manner,
The starting compound, all-E-retinylamine, can
be prepared according to F. Kienzle (loc. cit ) from
all-E-retinol via all-E-retinyl-phthalimide. A
further advantageous method of synthesis of N-retinyl-
phthalimide is the Wittig olefinization of the known
Cl5-phosphonium salt II with 2-methyl-4-phthalimido-
but-2-en-l-al III.
E~;
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N ~ III
II Wittig olefinization
; r isomerization
H2H-~, CH30H
--NH2
. ' 1
X~
F~ .
The present invention also embraces the prepara-
tion of therapeutic agents or formu~ations
which are obtained in the conventi.onal manner, in parti-
cular by mixing a dose of the active compGund approp-
riate for the particular application with conventional
carriers or diluents, with or without conventional
pharmaceutical excipients, in accordance with the
desired route of administration~
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For topical application the therapeutic formula-
tions contain the compounds, to be used according to the
invention, at a concentration of from 0.001 to 1.0%, pre-
ferably from 0.01 to 0.1%, whilst for systemic administra-
tion a single dose is pre~erably from 0.1 to 5 mg Suit-
able daily dosages are from 50 to 100 mg, and can vary in
accordance with the nature and severity of the disorder,
the formulation used, and the route of administration.
The conventional galenical formulations are
employed, for example, for oral administration, tablets,
film tablets, dragees, capsules, pills, ~owders, gran-
ules, solutions or suspensions For external use,
suitable forms are in particular pastes, ointments,je1lies,
creams, lotions, powders, sol1tions or ernulsions and sprays.
~he drugs according to the invention may be employed
either internally or externally. Preferably, they
are adminis-tered orally or applied topically.
Examples of conventional pharmaceutical auxili-
ariesfortopical application are alcohols, eg. isoPropanol,
oxyethylated castor oil or oxyethylated hydrogenated
castor oil, polyacrylic acid, glycerol monostearate,
paraffin oil, vaseline, wool grease, polyethylene glycol
400, polyethylene glycol 400 stearate and oxyethylated
fatty alcohols, whilst examples for systemic administra-
tion are lactose, sucrose, propylene glycol, ethanol,
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starch, talc and polyvinylpyrrolidone.
Examples of further conventional additives are
preservatives~ antioxidants, flavorings, stabilizers,
emulsifiers, lubricants, wetting agents and the like.
It is a precondition that all materials used in the
preparation of pharmaceutical formulations should be
non-toxic and compatible with the active compounds
employed (cf. L.G. Goodman and A. Gilman, The Pharmaco-
logical Basis of Therapeutics).
EXAMPLE 1
N-(E-3-Formyl-but-2-en-1-yl)-phthali,mide:
210 parts by weight of 4-chloro-2-methyl-but-2-
enal-diethylacetal are added dropwise to a solution of
343.2 parts by weight of,ethyl orthoformate in 151
parts by weight of ethanol. The solution is stirred
for 1 hour at 40C and is concentrated on a rotary
evaporator at 16 mm Hg/40C. 400 parts by weight of
dimethylformamide and 300 parts by weight of potassium
phthalimide are added, and the mixture is heated for 1
hour at 120C)C and filtered after it has cooled. The fil-
trate is concentrated on a rotary evaporator at 50C ~nder2 mm Hg and the residue is taken up in 1,500 parts by
volume of diisopropyl ether and 200 parts by volume of
ethanol. At about 0C, 172 parts by wei.ght of N-(E-
4,4-diethoxy-3-methyl-but-2-en-1-yl)-phthalimide
crystallize out overnight and are filtered off and dried
in a stream of nitrogen. The crystals are then
taken up in 1,500 parts by volume of 80% strength aqueous
methanol, about 8 parts by volume of concentrated
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_ ~ _ O.Z. 0050/033447
sulfuric acid are added (resulting in pH 2) and the mix-
ture is stirred for 30 minutes at 50C. It is then
worked up in the conventional manner by partition between
methylene chloride and water, and recrystallization of
the residue from diisopropyl ketone gives 102 parts by
weight of N-(E-3-formyl-but-2-en-1-yl)-phthalimide,
melting point 112C.
EXAMPLE 2
N-all-E-Retinyl-phthalimide:
142.6 parts by weight of N-(E-3-formylbut-2-en-
l-yl)-phthalimide are added to 1,1~0 parts by volume of
a 30% strength by weight solution of ~-ionylidene-ethyl~
triphenyl-phosphonium bisulfate in dimethylformamide,
and ammonia is passed into the mixture at -20C until
saturation is reached. The mixture is allowed to
come to about 25C, 1,500 parts by volume of n~hexane are
added and the batch is washed with three times 650 parts
by volume of 60% strength aqueous methanol. The n-
hexane solution is concentrated to about 700 parts by
volume. After it has cooled in an ice bath, 115
parts by weight of N-all-E-retinyl-phthalimide precipi-
tate as crystals of melting point 103.5C. A further
88 parts by weight can be obtained, after isomerization,
from the mother liquor.
EXAMPLE 3
N-Benzoyl-all-E-retinylamine:
16.8 parts by weight of N-all-E-retinyl-phthali-
mide and 6.2 parts by volume of hydrazine hydrate are
dissolved in 234 parts by volume of methanol, the solu-
;:
11;~76i~5~10 _ O.Z. 0050J033447
tion is refluxed for 2 hours, and 78 parts by volume of
2 N hydrochloric acid are subsequently added at 0C
The phthalic acid hydrazide whichhas precipitated is fil-
tered off, 1,500 parts by volume of water are added to
the filtrate, the mixture is extracted twice with 250
parts by volume of ether, and 80 parts by volume of con-
centrated ammonia are then added to the aqueous phase.
The resulting aqueous alkali phase is extracted with
four times 250 parts by volume of ether. Convention-
al working up of the ether phase gives 11 parts byweight of crude all-E-retinylamine as a red oil.
The crude retinylamine is dissolved in 50 parts
by volume of pyridine at -20C and 5 parts by weight of
benzoyl chloride are added dropwise. The mixture is
allowed to come to 20C, 80 parts by weight of ice are
added, and the batch is extracted with five times 80
parts by volume of methylene chloride. Conventional
working up gives 16.8 parts by weight of a red viscous
oil which is taken up in 50 parts by volume of diiso-
propyl ether, 5,5 parts by welght of N-benzoyl-all-
E-retinylamine, melting point 105.5C, crystallize at
-10C. The mother liquor is concentrated (11 parts
by weight) and chromatographed over 300 parts by weight
of silica gel The fractions which are pure accord-
ing to analysis by thin layer chromatography are
crystallized from ~5 parts by volume of diisopropyl
ether, to give a further 3 ~ parts by weight of pure
product; melting point 104C.
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EXAMPLE 4
Following instructions similar to those in
Example 3, with p-toluyl chloride as the starting
material, N-p-toluyl-all-E-retinylamine, melting point
ll9.5C, is obtained.
Examples of suitable pharmaceutical formulations
or drug compositions for external application are the
following:
EXAMPLE 1
Solution
N-Benzoyl-all-E-retinylamine 0.25 g
oxyethylate~ hydrogenated castor oil35.0 g
(Cremophor RH 40, from ~ASF AG,
Ludwigshafen)
Polyethylene glycol 400 35.0 g
oxyethylated castor oil (Softigen 767,lO.0 g
from Chemische Wer:~e ~tten)
deionized water to give lO0.0 g
The Cremophor r~H 40 and Softiger. 767 are mixed
and the mixture is heated to 70C, The active com-
pound is dissol~ed therein whilst stirring and the poly-
ethylene glycol 400 i5 added, The solution is then
cooled to 40C and water at 40C is added slowly, whilst
stirring. The fin.ished solution .is filtered and
packaged in, for example, lO0 ml flask.s.
EXAMPLE 2
Cream
N-p-Toluyl-all-E-retinylamine O.l g
butylhydroxytoluene O.l g
glycerol monostearate ll.0 g
polyethylene glycol 400 stearate 6.o g
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oxyethylated fatty alcohol 4.0 g
paraffin oil lO.0 g
p-hydroxybenzoic acid ester (Nipasteril,
from Nipalaboratorium Hamburg) 0.2 g
perfume oil O.l g
deionized water to gi~e lO0.0 g
The fats are melted and the very finely pulverized
active compound and butylhydroxytoluene are dispersed
therein whilst stirring at 65C (solution I). The
water is boiled up with the Nipasteril
and then cooled to 65C (solution II). Solution II
is then emulsified, a little at a time, in solution I,
with thorough stirring. After the mixture has cooled
to 45C, the perfume oil is added and the emulsion is
cooled to room ~emperature, whilst stirring. The
finished cream is packaged in tubes carrying an internal
protective coating.
EXA~LE 3
Jelly
N-Benzoyl~all-E-retlnylamine O.Ol g
butylhydroxytoluene O.l g
oxyethylated castor oil (Cremophor EL,
from BASF AG, Ludwigshafen) 35.0 g
isopropanol , 20.0 g
polyacrylic acid (Carbopol, from
Goodrich Hamburg) l,5 g
triethanolamine 0.002 g
p-hydroxybenzoic acid ester (Nipasteril,
from Nipalaboratorium Hamburg) 0,2 g
deionized water to give lO0.0 g
The Cremophor EL is heated to 60C, the active
I r~lerr a Y ~
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compound and the butylhydroxytoluene are dissolved therein, whilst
stirring, and the isopropanol, in which the Nipaesters have been
dissolved are admixed (solution I). The Carbo-
pol~is dispersed in the water, with vigorous stirring
(solution II) Solution II is added, a little at a
time, to solution I, with thorough stirring. The pH
of the mixture is brought to 4.5 with triethanolamine.
The finished jelly is packaged in tubes carrying an
internal protective coating.
Examples of formulations or drug compositions
particularly suitable for systemic use are the .
following:
~XAMPLE 4
Drops
N-Benzoyl-all-E-retinylamine 0.1 g
propylene glycol 25 0 g
ethyl alcohol to give 50.0 g
The ethyl alcohol and propylene glycol are mixed
and the active compound is dissolved in the mixture by
heating at ~5C and stirring After filtration, the
solution is packaged in dark-colored drop bottles.
EXAMPLE 5
Hard gelatin capsules
N-p-Toluyl-all-E-retinylamine 1 mg
lactose to give 0.25 g
The constituents are sieved, mixed and used to
fill hard gelatin capsules of size 2 on a suitable cap-
sule filling and sealing machine
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