Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1~717()
; . O.Z. 0050/033446
R`etinic acid N~carboxy)-phenylamides and 7,8-dehydro-
retinic acid N-(carboxy)-phenylamides, their preparation,
and pharmaceutical formulations containing these com-
pounds
The present invention relates to all-E- and 13-Z-
retinic acid compounds of the formulaeI and II
CO 2H
~ ~Co2lI
where the broken line is a chemical bond or two hydrogen
atoms and the carboxyl group in the aromatic ring may
be in the ortho-, meta- or para-position, the preparation
of these compounds, pharmaceutical formulations containing
these compounds,-and their use as drugs.
German Laid-Open Application DOS 2,102,586 dis-
closes that retinic acid amides which, for example, are
10 substituted by a benzyl or phenyl group at the amide
nitrogen, exhibit a pharmacPlogical action, It states
that these compounds may be used for the topical and sys-
temic therapy of pre-cancerous conditions and carcinomas,
and for the topical and systemic prophylaxis of carcin-
omas. They may also be employed for the therapy of
acne, psoriasis and other dermatological disorders
accompanied by intensified or pathologically modified
keratinization, and in cases of eczema and of disorders
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of the mucous membranes, Examples of specific
compounds mentioned, inter alia, in German Laid-Open
Application DOS 2,102,586 are retinic acid N-ethylamide,
retinic acid N-benzylamide and retinic acid N-phenylamide.
German Laid-Open Application DOS 2,300,107 dis-
closes retinic acid amides, especially with substituted
phenyl radicals, for roughly the same applications.
Examples of specific compounds described are retinic
acid (p-ethoxy)-anilide and retinic acid N-(p-ethoxy-
carbonyl)-phenylamide.
A disadvantage of these known retinic acid amides
is their narrow therapeutic range. The substances
either exhibit a relatively low activity, or are toxic
even at relatively low doses. For example, retinic
acid N-ethylamide can reverse keratinization of hamster
tracheal tissue, induced by vit min A hypovitaminosis,
at molar concentrations of as low as 2 x lO 9. The
relevant methods are described by G.H. Clamon et al.,
Nature 250 (1974), 64-66 and M.B. Sporn et al., Nature
~53 (1975), 47-50. The keratinization is regarded as
a pre-cancerous process. Retinic acid N-ethylamide
however has a toxic effect on hamster tracheal carti-
lage tissue in a culture at a molar concentration o~ as
little as 9 x lO 7, as described by M.B. Sporn et al.,
Nature 263 (1976), 110-113. On the other hand,
retinic acid N-(p-ethoxycarbonyl)-phenylamide has a low
cellular toxicity, but requires a molar concentration of
10 8 to heal the keratinization of hamster tracheal
tissue.
,7~
We have found that the all-E- and 13-Z-retinic
acid N-(carboxy)-phenylamides of the formulae I and II
exhibit particularly valuable pharmacological properties,
since they have a substantially higher therapeutic index.
For example, all-E-retinic acid N-(p-carboxy)-
phenylamide exhibits as low a toxicity as the corresponding
ethyl ester. However, in the prophylaxis of precancerous
conditions of keratinized hamster tracheal tissue the free
acid is still active at a molar concentration of 10 and
is thus substantially more active than the ethyl ester.
Similar results were obtained with all-E-retinic acid N-(m-
carboxy)-phenylamide, all-E-retinic acid N-(o-carboxy)-phenyl-
amide, all-E-7,8-dehydro-retinic acid N-(p-carboxy)-phenylamide,
all E-7,8-dehydro-retinic acid N-(m-carboxy)-phenylamide, all-
E-7,8-dehydro-retinic acid N-(o-carboxy)-phenylamide, 13-Z-
retinic acid N-(p-carboxy)-phenylamide, 13-Z-retinic acid
N-(m-carboxy)-phenylamide and 13-Z-retinic acid N-(o-carboxy)-
phenylamide.
Amongst the compounds according to the invention,
all-E~retinic acid N-(p-carboxy)-phenylamide, all-E-7,8-
dehydro-retinic acid N-~p-carboxy)-phenylamide and 13-Z-
retlnic acid N-(p-carboxy)-phenylamide, and in particular
all-E-retirlic acid N-(o-carboxy)-phenylamide are preferred~
The compounds according to the invention are
prepared in the conventional manner by reacting a reactive
acid derivative of all-E- or 13-Z-retinic acid or all-E- or
13-Z-7,8-dehydroxy-retinic acid with ortho-, meta- or
para-aminobenzoic acid or one of its acid derivatives, the
resulting derivative, in the latter case, being subsequently
hydrolyzed to the acid in the conventional manner.
The reactive acid derivatives of all-E- or 13-Z-
retinic acid or o~ all-E- or 13-Z-7,8-dehydro-retinic acid
Bi
are in particular the esters or acid halides, preferably
the acid chlorides. Derivatives of ortho-, meta- or para-
aminobenzoic acid which may be employed are in particular
the corresponding esters, for example ethyl esters. The
retinic acid N-~alkoxycarbonyl)-phenylamide first produced on
reacting the retinic acid chloride with the aminobenzoic acid
esters càn be converted to the phenylcarboxylic acid in the
conventional manner by alkali-catalyzed hydrolysis of the
ester groups.
The preparation of the retinic acld chlorides,
and their further reaction with an aminobenzoic acid or
one of its esters, is preferably carried out in an inert
organic solvent, such as a dialkyl ether or an aliphatic
chlorohydrocarbon, eg. diethyl ether or methylene chloride, or
in a mixture of these solvents, in the presence of a base
at from -25 to +25C.
Preferably, ther eaction is carried out in diethyl
ether or in a solvent mixture, using from one to two moles
of pyridine, per mole of reactant, as the base. The reaction
is advantageously carried out in the abs~nce of oxygen and
moisture, for example under nitrogen as a blanketing gas.
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_ 5 _ o.z. oOSo/033446
The end product is worked up in the conventional
manner. However, a preferred method of purification
is recrystallization.
By virtue of the pharmacological properties
mentioned, the compounds according to the invention can
be employed in the topical and systemic therapy and pro-
phylaxis of pre-cancerous conditions and carcinomas of
the skin, mucous membranes and internal organs, and in
the topical and systemic therapy of acne, psoriasis and
other dermatological disorders accompanied by pathologic-
ally modified keratinization.
A preferred indication is the prophyl-
actic and therapeutic treatment of pre-cancerous con-
ditions and tumors of the bladder, the mammary gland,
the skin and the mucous membranes.
The compounds according to the invention have
significant tumor-inhibiting action. Growth control may
be observed in cells cultivated in vitro and may be de-
tected by the method described by R. Lotan et al in Jour-
nal of the National Cancer Institute 60, pages 1035-1041.
The compounds also lnhibit the prolireration of spontane-
ous chemioally or virally transformed cells in tlssue culture,
the pre~erred culture being S 91 melanoma cells.
Accordingly, the invention also relates to
pharmaceutical formulations which contain a c.ompound of
the formula I or II as the active co~pound , in addition
to conventional carriers or diluents, with or without
pharmaceutical excipients , and to the use of a compound
of the formula I or II for the preparation of a drug.
The present invention ~lso embraces the prepara-
_ 6 -- O.Z. 0050/03~4~a6
tion of therapeutic agents or formulations
which are obtained in the c~nventional manner, in parti-
cular by mixing a dose of the active compound approp-
riate for the part cular application with conventiona
carriers or diluents, with or withcut conventional
pharmaceutical excipients , in accord~nce wi~h the
desired route of administration.
For t~cal application the therapeutic agents
contain the compounds, to be used according to the inven-
lo tion, at a concentration of from 0.001 to 1.0%, prefer-
ably from 0.01 to 0.1%, whilst for systemic administra-
- tion a single dose is preferably from 0.1 to 5 mg.
Suitable daily dosages are from 5 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, powders, gran-
ules, solutions or suspensions. For external use,
- suitable forms are in particular pastes, olntments,jell;es,
creams, lotions, powders, solutions or emulsions and sprays.
The drugs according to the invention may be employed
eith~r intel~lally or externally~ Preferably, they
are administered orally or applied topically.
Examples of conventional pharmaceutical auxili-
aries for t~cal application are alcohols, eg. isoprcpanol,
oxye~hylated castor oil or oxyethylated hydr~genated
castor oil, polyacrylic acid, glycerol monosteara+e,
pa~;affin oil, vaseline, wool grease, polyethylene glycol
400, polyethylene glycol 400 stearate and oxyethylated
7~7~)
_ 7 _ o.z. 0050/033446
fatty alcohols, whilst examples for systemic administra-
tion are sucrose, lactose, propylene glycol, ethanol,
starch, talc and polyvinylpyrrolidone.
EXamples of further conventional additives are
preservatives, antioxidants, flavorings, stabilizers,
emulsifiers, lubri.cants, wetting agents and the like.
It is a precondition that ali materials used in the
preparation of pharmaceutical formulatiolls should be
non-toxic and compatible with the active compounds
employed (cf. L.G Goodman and A. ~ilman, The Pharma-
cological Basis of Therapeutics).
EXAMPLE 1 '.
all-E-Retinic acid N-(p-carboxy)-phenylamide:
75 parts by weight of retinic acid are suspended
in 1,000 parts by volume of diethyl ether, 21.9 parts by
weight of pyridine are added and a solution of 33 parts
by weight of thionyl chloride in 150 parts by volume of
diethyl ether is introduced dropwise at 0C. Stirring
is continued for 2 hours at 0C, the crystalline
pyridinium hydrochloride is separated off by filtration,
and the filtrate is run into a suspension of 34 parts by
volume of p-aminobenzoic acid in 41.8 parts by weight of
pyridine, 250 parts by volume of diethyl ether and 250
parts by volume of methylene chloride at a rate such
that the reaction temperature does not exceed -20C.
The mixture is then stirred for 2 hours at about 25C
To obtain the product, the reaction mixture is
washed with 250 parts by volume of ice-cold 1 N hydro-
chloric acid and with 250 parts by volume of saturated
sodium chloride solution and worked up in the convention-
1~L27~7~
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al manner, and the residue is recrystallized from 1,200
parts by volume of acetone After drying at 50C
and 0.1 mm Hg for 5 hours, 75 parts by weight of all-E-
retinic acid N-(p-carboxy)-phenylamide, melting point
199 to 201C, are obtained.
EXAMPLES 2 T0 9
By working in accordance with the instructions
given in Example 1, the following compounds are obtained
in comparable yields:
all-E-Retinic acid N-(m-carboxy)-phenylamide,
o melting point 193-194C after recrystallization from
acetone.
all-E-Retinic acid N-(o-carboxy)-phenylamide,
melting point 172-173C after recrystallization from
acetonitrile.
13-Z-Retinic acid N-(p-carboxy)-phenylamide,
melting point 165-166C after recrystallization from
ethyl acetate,
13-Z-Retinic acid N-(m-carboxy)-phenylamide,
melting point 152-154C after recrystallization from
; 20 ethyl acetate.
13-Z-Retinic acid N-(o-carboxy)-phenylamide,
melting point 144-146C after recrystallization from
ethyl acetate.
all-E-7,8-Dehydro-retinic acid N-(p-aarboxy)-
phenylamide, melting point 235-237C after recrystalliza-
tion from acetonitrile/methanol.
all-E-7,8-Dehydro-retinic acid N-(m-carboxy)-
phenylamide, melting point 211-213C after recrystalliza-
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- 9 - o.Z. 0050/033446
tion from acetonitrile/methanol.
all--E-7,8-Dehydro-retinic acil N-(o-carboxy)-
phenylamide, melting point 202-205C after recrystalliza-
tion from acetonitrile/methanol.
The isomer purity of the compounds prepared can
be determined by high pressure liquid chromatography and
is as a rule > 960/o. The structure ascribed is based
on H-NMR spectroscopy.
Examples of suitable pharmaceutical f~rmulations
or drug compositions for external application are:
EXAMPLE 1
Solution
all-E-retinic acid N-(p-carboxy)-phenylamide 0.25 g
oxyethylated hydrogenated castor oil 35.0 g
tCremophor RH 40, from BASF AG,
Ludwigshafen)
Polyethylene glycol 400 35.0 g
oxyethylated castor oil (Softigen 767, 10.0 g
from Chemische Werke Witte~
deionized water to give 100.0 g
The Cremophor RH 40 and Softigen 767 are mixed
and the mixture is heated to 70C. The active com-
pound is dissolved therein whilst stirring and the poly-
ethylene glycol 400 is added. The solutian is then
c~oled to 40C and water at 40C is added slcwly, whilst
stirring. The finished solution is filtered and
packaged in, for example, 100 ml flasks.
EXAMPLE 2
Cream
ail-E-7,8-dehydro-retinic acid N-(p-carboxy~- 0.1 g
phenylamide
butylhydrox~toluene 0.1 g
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glycerol monostearate 11.0 g
polyethylene glycol 400 stearate 6.o g
oxyethylated fatty alcohol 4,0 g
paraffin oil . . - .10.0 g
p-hydroxybenzoic acid ester (Nipasteril,
. from Nipalaboratorium Hamburg) 0.2 g
perfume oil 0.1 g
deionized water . to giye 100.0 g
The fats are melted and the very finely pulverized
lo active compound and butylhydroxytoluene are dispersed
therein whilst stirring at 65C (~olution 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 temperature, whilst stirring. The
finished cream is packaged i~ tubes carrying an inte~1al
protective coating.
:~ EXAMP$E 3
20 Jelly
13-Z-retinic acid.N-(p-carboxy)-phenylamide 0.01 g
butylhydroxytoluenc 0.1 g
oxyethylated castor oil ~Cremophor EL,
from BASF AG, Ludwigshafen) 35.0 g
isopropanol 20.0 g
polyacrylic acid (Carbopol, from
Goodrich Hamburg) 1.5 g
triethanolamine 0.002 g
p-hydroxybenzoic acid ester (Nipasteril,
30 from Nipalaboratorium Hamburg) 0.2 g
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deionized water to give 100.0 g
The Cremophor EL is heated to 60C, the active
compound and the butylhydroxytoluene are dissolved
therein, whilst stirring, and the isopropanol, in which
the Nipasteril has
been dissolved are admixed (solution I). The Carbo-
pol is dispersed in the water, with vigorous s~irring
tSolution II). Solution II is added, a little at a
- time, to solution I, with thorough stirring. The pH
o~ the mixture is brought to 4.5 with triethanola~ine.
The finished jelly is packaged in tubes carrying an
- internal protective coating.
Examples of formulations or drug
compositions particuIarly suitable for systemic use
are the following:
EXAMPLE 4
Drops
a~1-E-retinic-acid N-(p-carboxy)-phenylamide 0.1 g
propylene glycol 25.0 g
ethyl alcohol to give 50.0 g
The ethyl alcohol and propylene glycol are mixed
.~
and the active compound is dissolved in the mixture by
heating at 35C and stirring. After filtration, the
solution is packaged in dark-colored drop bottles.
B AMP$E 5
Hard gelatin capsules
13-Z-retinic acid N-(p-carboxy)-phenylamide 1 mg
lactose to give 0.25 g
The constituents are sieved, mixed and used to
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fill hard gelatin capsules of size 2 on a suitable cap-
sule filling and sealing machine.
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