DERIVES DE PROSTAGLANDINE E1 A TITRE D'AGENTS AYANT UNE ACTIVITE PHARMACOLOGIQUE ET COMPOSITIONS PHARMACEUTIQUES CONTENANT CES COMPOSES, EN PARTICULIER POUR L'ADMINISTRATION PERCUTANEE

PROSTAGLANDIN EL DERIVATIVES AS PHARMACOLOGICALLY ACTIVE AGENTS, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS, ESPECIALLY FOR TRANSCUTANEOUS ADMINISTRATION

Abrégé anglais

Abstract:
The invention describes prostaglandin E1 derivatives as
pharmacologically active agents, and pharmaceutical compositions
containing these compounds, especially for transcutaneous
administration. The derivatives have the general formula:
<IMG> (I)
in which R1 is a hydrogen atom and R2 is a C1-4 alkyl residue.

Revendications

Claims:
1. A transdermal pharmaceutical composition comprising:
prostaglandin E1 derivative of general formula I,
<IMG> (I)
in which R1 is hydrogen, or R1 and the hydrogen atom gem
thereto are replaced by a carbonyl oxygen atom, and R2 is a C1-4
alkyl residue; and, wherein said derivative is present in a
transdermally deliverable amount in combination with a
transdermally effective carrier.
2. The transdermal pharmaceutical composition of claim 1
wherein R2 is an ethyl group.
3. The composition of claim 1 wherein the transdermally
effective carrier comprises a substance selected from the
group consisting of gels, ointments and liquid vehicles.
4. The composition of Claim 1 wherein the transdermally
effective carrier comprises plaster.
5. The composition of claim 1 for the treatment of
circulatory insufficiencies.
6. Use of prostaglandin E1 derivatives of general formula I,
<IMG> (I)
in which R1 is a hydrogen atom or a carbonyl oxygen atom and R2
is a C1-4 alkyl residue, for the preparation of a pharma-
ceutical composition to be administered transcutaneously.
7. The use according to claim 6, wherein R2 is an ethyl
group.

8. The use according to claim 6 or 7, wherein the
pharmaceutical composition is for the treatment of circulatory
insufficiencies, of impotence, for the inhibition of platelet
aggregation, for the treatment of bronchial asthma, of
gastrointestinal ulcers and ulcers of the skin, of haematomas,
of impaired hair growth or of rejections following
transplantations of an organ.
9. The use of prostaglandin E1 derivatives of general
formula I,
<IMG> (I)
in which R1 is a hydrogen atom or a carbonyl oxygen atom and R2
is a C1-4 alkyl residue, for the treatment of a disorder by
transcutaneous application, said disorder being selected from
the group consisting of circulatory insufficiencies,
impotence, platelet aggregation, bronchial asthma,
gastrointestinal ulcers, ulcers of the skin, haematomas,
impair hair growth and rejection following transplantation or
an organ.
10. The use according to claim 9 wherein R2 is an ethyl group.
11. Process for the preparation of a pharmaceutical
composition for transcutaneous administration containing a
prostaglandin E1 derivative of general formula I
<IMG> (I)
in which R1 is a hydrogen atom or a carbonyl oxygen atom and R2
is a C14 alkyl residue, characterized in that a prostaglandin
E1 derivative of general formula I is combined with a carrier
substance or adjuvant suitable for transcutaneous
administration.

12. A process according to claim 11, wherein R2 is the ethyl
group.
13. A process according to claim 11 or 12, wherein the
pharmaceutical composition for transcutaneous administration
is determined for the treatment of circulatory
insufficiencies, of impotence, for the inhibition of platelet
aggregation, for the treatment of bronchial asthma, of
gastrointestinal ulcers and ulcers of the skin, of haematomas,
of impaired hair growth or of rejections following
transplantations of an organ.

Description

132735~
"Prostaglandin El Derivatives as Pharmacologically Active Agents,
and Pharmaceutical Compositions Containing These Compounds,
E~pecially ~or Transcutaneous Administration"
BACKGROUND OF THE INVENTION
The invention relates to prostaglandin E1 derivatives (PGE1
derivatives) as pharmacologically active agents and to
pharmaceutical compositions - especially for transcutaneous
application - which contain a PGEl derivative.
DE-A-27 53 986 published on July 6, 1978 to Upjohn Company
and the corresponding US-A-4,205,178 issued on May 27, 1980
assigned to upjohn Company disclose 6-keto prostaglandin E1
derivatives, especially the 6-keto PGE1 methyl ester.
- A number of biological and pharmacological effects are
described for these compounds. Various routes of administration
are indicated for the various kinds of illnesses to be treated,
e.g. oral, intravenous, subcutaneous, intra-arterial, buccal,
rectal and intra-vaginal administration. Topical administration
is described in connection with skin injuries or skin diseases
at or near the site of the injury or disease.
A

13273~9
6-keto prostaglandin El derivatives are also described in
DE-A-28 40 032 published on March 29, 1979 to Ono Pharmaceutical
Company, in which the authors also refer to various fo:rms of
pharmacological activity and administration.
Prostaglandin E1 (PGEl) and 6-keto prostaglandin El (6-k
PGE1) can be used for the treatment of several diseases. These
diseases include peripheral occlusive diseases, complications in
arteriosclerosis such as Meniere's disease or acute loss o~
hearing, acute myocardial infarctation, unstable angina pectoris,
acute ischaemic strokes, impotence, bronchial asthma, impaired
hair growth and rejection following kidney transplants; see H.
Sinzinger and W. Rogatti, Prostaglandin El in atherosclerosis,
Springer Verlag Berlin - Heidelberg - New York, 1986 S. Schrey,
PGE1, Therapie der arteriellen VerschluBkrankheit,
Universitatsdruckerei and Verlag Dr. C~ Wolf und Sohn, Munich,
; 1985. PGEl is used for the treatment of chronic arterial
occlusive diseases in phase III and IV. This condition calls for
intra-arterial or intravenous infusion which results in a severe
limitation in the use of PGEl, as the infusion iq not~only a
strain on the patient, but also involves a certain risk o~
arterial haemorrhage. Neither route of administration (i.a. and
i.v.) is suitable for continuous therapy in ambulatory patient
care. However, long-term administration would be most
appropriate for these diseases. The oral administration of PGEl
is always problematic as either the very low bio-availability
rule~ out such administration, or the typical undesired effects
(nauRea, vomiting, diarrhoea) are prohibitive due to the high
concentration of the drug in the gastrointestinal track when
orally a~ministered.
SUMMARY OF_THE INVENTION
The object underlying the invention is to provide P&E1 and
PGE1 derivatives as pharmaceutical compositions or pharma-
cologically active agents. The PGE1 derivatives, which

( 13273~9
were especially developed as pharmacologically active agents
; for transcutaneous adminstration, are absorbed by the skin and
subsequently split by hydrolases into prostaglandin E1 or 6-
keto PGBl and alcohol. The PGEl derivatives thus fulfill the
. requirements of the "Pro-Drug" concept and avoid the
; disadvantages of PGEl and 6-keto PGE1 when adminstered
arterially, intravenously or orally.
` The subject matter of the invention is therefore prosta-
glandin E1 derivatives of the general formula I
.~,, O Rl
,~~ COOR2 tI)
' ~
HO O'H
in which R1 is a hydrogen atom and R2 is a Cl_4 alkyl residue,
~;~ as pharmacologically active agents.
i
A further subject matter of the invention is a pharmaceu-
tical composition containing a prostaglandin E1 derivative ac-
~; cording to formula I.
,.:
~' Still a further subject matter of the invention is the
use of prostaglandin El derivatives of general formula I,
O Rl
,~ ~,~~ COOR2
` ~ (I~
HO
in which R1 is a hydrogen atom (PGE1) or a carbonyl oxygenatom (6-k-PGE1) and R2 is a C1_4 alkyl residue for the
preparation of a pharmaceutical composition to be administered
transcutaneously.

` 13273~9
BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 shows the absorption rate of PGE1 and PGEl ethyl
-ester which has been determined as the cumulative urinary
excretion following transcutaneous administration.
DETAILED DESCRI TION
'
Specific examples of alkyl residues are the methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertiary
butyl group.
Due to the non-toxicity of the fragments, the preferred
group R2 is the ethyl group.
-The preparation of the compounds of general formula I is
carried out according to methods known per se via esterifica-
tion of PGEl and 6-k PGEl. The methyl and ethyl ester, for in-
stance, are pr~pared by reacting the same with diazomethane or
diazoethane; also see Ch. J. Sih et al., J. Am. Chem. Soc.,
Vol. 97 (1975), pp. 857 to 865.
;
The compounds of general formula I can be used to treat
circulatory insufficiencies, for instance of the brain, the
heart and the extremities, to inhibit platelet aggregation
(~hrombocyte aggregation), impotence and to treat allergic
reactions such as bronchial asthma, rejection following
transplantations and impaired hair growth. Typical examples of
deficiencies in the cerebral blood supply are transitory
cerebral ischaemia, acute loss of hearing, vertigo cauæed by
circulatory insufficiencies and ischaemic strokes. Typical
examples of deficiencies in the myocardial blood supply are
angina pectoris and myocardial infarction. Typical examples of
deficiencies in the blood supply of the extremities are

1~73~
periphal arterial circulatory insufficiencies in
arteriosclerosis and Raynaud's disease and Raynaud's syndrom.
.,
The compounds of general formula I can also be used to
treat gastrointestinal ulcers and ulcers o~ the skin. Typical
examples of gastrointestinal ulcers are ulcus ventriculi, duo-
denal ulcers and ulcerative colitis (Crohn's disease). A typi-
cal example of a skin ulcer is ulcus cruris. The compounds of
general formula I have a cyto-protective effect. The cells ex-
hibit increased resistance to noxious stimuli.
The compounds of general formula I can further be used to
treat haematomas, especially surface haematomas.
In addition to transcutaneous administration, the com-
pounds of general formula I can also be administered by
inhalation, intravenously and intra-arterially and in each
case incorporated into microsomes.
The preparation of pharmaceutical compositions is carried
out according to conventional methods. For the preparation of
pharmaceutical compositions to be administered transcu-
taneously, the compounds of general formula I can be mixed
with a gel, ointment or liquid vehicle either with or without
various solvents and stabilizers. The packages used are
sprays, tubes, ampules and individual doses. Once applied to
the skin either with or without an additional occlusive
dressing, the active agent is absorbed.
The compounds of general formula I can also be placed
either with or without stabilizers and solvents onto a plaster
and can then be applied as such.
The conversion of the ethyl ester to PGEl in the human
body was demonstrated in the following way: an isotopically
labelled P&El e~hyl ester was applied in the manner described
abo~e. The isotopically labelled urinary metabolites were

13273~9
.
separated with HPLC and compared with the retention time of
the main metabolite of PGEl (7~-hydroxy-5,11-diketo-
tetranorprosta-1,20-dioic acid). It was found that after
administration of the PGEl ethyl ester, the main metabolite
was identical to the main meta~olite after administration of
PGE1. This proves that the PGE1 ethyl ester is a pro-drug of
PGE1.
The following examples illustrate the invention.
E X A M P L E
The preparation of prostaglandin El ethylester.
Excess diazoethane in diethyl ether ~17 mg/ml; 0.3 mmol)
is added to 500 ~g PGEl (1.31 ~mol) in 500 ~1 ethanol under
stirring and cooling. The reaction mixture is taken out of the
cooler and is stirred until it reaches room temperature.
Stirring is then continued for a further 30 minutes. The
excess diazoethane and the ethanol are removed at room
temperature by a stream of nitrogen. The product is purified
by high-pressure liquid chromatography (RP 18).
In the same manner and with excess diazoethane, 500 ~g of
6-keto PGEl in 500 ~1 of ethanol are reacted and processed in
diethyl ether. The ester is purified by high-pressure liquid
chromatography (RP 18).
~ X A ~ P L E 2
250 ~g of prostaglandin El ethyl ester together with an
isotopically labelled PGEl-ethyl-ester in 250 ~1 of ethanol
were worked into 2 g of a gel vehicle of the composition as
indicated below. The gel was applied to the upper arm and

1327~9
rubbed in for 1 minute. The application area was covered with
a plastic foil.
.~
.~One week later, 250 ~g of prostaglandin El together with
an isotopically labelled PGEl in 250 ~1 of ethanol were mixed
with 2 g of a gel vehicle of the composition as indicated
below. It, too, was applied to the upper arm and rubbbed in
for 1 minute.
Measurement of the absorbed quantity was carried out by
determining the isotopically labelled prostaglandin
metabolites in the urine. For this, the total urine was
-collected in portions from the beginning of the application
onwards. Four hours after the application, the plastic film
was removed and the excess gel wiped off. As can be seen in
Fig. 1, the absorption rate of PGE1 ethyl ester (23 %) was
clearly better than that of PGE1 (approx. 4 ~).
:.
The gel vehicle was prepared according to the following
recipe:
;
Isopropanol 40.0 g
Diisopropyl adipate0.5 g
Carbopol ~40 2.0 g
j Trometamol 1.91 g
~ Purified waterad 100.0 g
`~The isopropanol can also be exchanged for ethanol.
The water, alcohol and diisopropyl adipate are mixed, the
carbopol is dispersed in this mixture and left to swell. The
gel is neutralized with the aqueous trometamol-solution.