The invention provides a pharmaceutical composition containing
a somatostatin analogue, and its use in the treatment of breast
cancer. The pharmaceutical composition preferably contains lactic
acid in addition to the somatostatin analogue and is better tolerated
when administered by injection.
What is claimed is:
1. A pharmaceutical composition consisting of octreotide acetate
and 88% lactic acid, in the ratio of 1 part of octreotide to 5 parts
of lactic acid, up to 1 part of octreotide to 60 parts of lactic
acid, and with sodium hydrogen-carbonate to pH 4 to 4.5, and mannitol
in isotonic sterile water, for parenteral administration.
2. The pharmaceutical composition of claim 1, in which the ratio
of octreotide acetate to lactic acid is 1 to 5 up to 1 to 40.
3. The pharmaceutical composition of claim 1, in which the octreotide
acetate is present at from 0.05 to 1 mg per ml, and the lactic acid
is present at 3 mg per ml.
4. The pharmaceutical composition of claim 1, in which the pH is
5. A method of treating breast cancer in a subject which comprises
administering a therapeutically effective amount of the composition
of claim 1 to a subject in need of such treatment.
6. A method of claim 5 in which the composition in co-administered
with a dopamine agonist.
The present invention relates to a pharmaceutical composition comprising
a somatostatin analogue, and to its use in the treatment of breast
Somatostatin is a tetradecapeptide incorporating a cyclic dodecapeptide
having the structure: ##STR1## and has the properties of inhibiting
the release of growth hormone, inhibiting the release of insulin
and glucagon and reducing gastric secretions. Its effect is short
and, to solve this problem of short duration, somatostatin analogues
which are long acting have been made. These compounds still have
to be administered by injection, which can be painful especially
in repeated administration.
It has now been found that parenteral compositions of somatostatin
analogues, especially octreotide and derivatives thereof, show particularly
interesting properties, e.g. they may be better tolerated if lactic
acid is present in the pharmaceutical composition.
In a first aspect the present invention provides a pharmaceutical
composition comprising a somatostatin analogue and lactic acid.
By the term "analogue" as used herein is meant any straight-chain
or cyclic polypeptide derived from that of the naturally occurring
tetra-decapeptide somatostatin wherein one or more amino acid units
have been omitted and/or replaced by one or more other amino radical(s)
and/or wherein one or more functional groups have been replaced
by one or several other isosteric groups. The term "analogue"
includes also the corresponding derivatives bearing a sugar residue.
In general, the term covers all modified derivatives of a biologically
active peptide which exhibit a qualitatively similar effect to that
of the unmodified somatostatin peptide. Hereinafter these compounds
are referred to as compounds of the invention.
Cyclic, bridge cyclic and straight-chain somatostatin analogues
are known compounds. Such compounds and their preparation are described
in U.S. Pat. No. 4,310,518 and 4,235,886, in European Patent Specifications
EP-A-1295; 70,021; 113,209; 215,171; 203,031; 214,872; 143,307 and
in Belgian Patent Specification BE-A-900,089.
When the compounds of the invention bear a sugar residue, this
is preferably coupled to a N-terminal amino group and/or to at least
one amino group present in a peptide side chain, more preferably
to a N-terminal amino group. Such compounds and their preparation
are disclosed e.g. in WO 88/02756.
Preferred compounds of the invention are:
A. Compounds of formulae I to III ##STR2## wherein W is S or (CH.sub.2).sub.s
where s is 0, 1 or 2;
one of X and Z is S and the other is S or CH.sub.2 ;
Y is S or (CH.sub.2).sub.t where t is 0, 1 or 2;
each of R.sub.1 and R.sub.2 independently of the other, is C.sub.1-5
alkyl, benzyl, benzyl having one or two C.sub.1-5 alkyl, halogen,
hydroxy, amino, nitro, and/or C.sub.1-5 alkoxy substituents, or
C.sub.1-5 alkyl substituted with a 5- or 6- membered heterocyclic
R.sub.3 is 3-indolylmethyl, either unsubstituted or having C.sub.1-5
alkyl, C.sub.1-5 alkoxy or halogen substitution;
R.sub.4 is C.sub.1-5 alkyl, C.sub.1-5 hydroxyalkyl, benzyl, carboxy-(C.sub.1-5
alkyl), amino (C.sub.1-5 alkyl) or benzyl having a C.sub.1-5 alkyl,
halogen, hydroxy, amino, nitro and/or C.sub.1-5 alkoxy substituent;
R.sub.5 is C.sub.1-5 alkyl, benzyl, or benzyl having a C.sub.1-5
alkyl, halogen, hydroxy, amino, nitro, and/or C.sub.1-5 alkoxy substituent.
Examples of C.sub.1-5 alkyl groups are methyl, ethyl, propyl, iso-propyl,
butyl, sec-butyl and pentyl; examples of C.sub.1-5 alkoxy groups
are methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and
pentoxy; halogens are fluorine, chlorine, bromine, or iodine: and
the term "5- or 6-membered heterocyclic ring" represents
such rings with one or two oxygen, nitrogen and/or suphur heteroatoms,
e.g. imidazole, furan, thiazole, pyrazole and pyridine.
In the compounds of Formulae I, II and III, there are several asymmetric
centres which lead to the existence of optical isomers for such
compounds. For each of the asymmetric centres of the various amino
acids which make up these cyclic hexapeptides, both the D and L
configurations are included.
The following are representative cyclic hexapeptide analogues of
somatostatin of Formulae I, II and III: ##STR3##
Preferred Formula I compounds are:
Preferred Formula II compounds are:
Preferred Formula III compounds are: ##STR4##
B. Compounds of formula IV ##STR5## wherein A is C.sub.1-12 alkyl,
C.sub.7-10 phenylalkyl or a group of formula RCO--, whereby
i) R is hydrogen, C.sub.1-11 alkyl, phenyl or C.sub.7-10 phenylalkyl,
ii) RCO-- is
a) an L- or D-phenylalanine residue optionally ring-substituted
by F, Cl, Br, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3
b) the residue of a natural .alpha.-amino acid other than defined
under a) above or of a corresponding D-amino acid, or
c) a dipeptide residue in which the individual amino acid residues
are the same or different and are selected from those defined under
a) and/or b) above, the .alpha.-amino group of amino acid residues
a) and b) and the N-terminal amino group of dipeptide residues c)
being optionally mono-or di-C.sub.1-12 alkylated,
A' is hydrogen or, when A is C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl,
also C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl,
Y.sub.1 and Y2 represent together a direct bond or each of Y.sub.1
and Y.sub.2 is independently hydrogen or a radical of formulae (1)
to (5) ##STR6## wherein R.sub.a is methyl or ethyl
R.sub.b is hydrogen, methyl or ethyl
m is a whole number from 1 to 4
n is a whole number from 1 to 5
R.sub.c is (C.sub.1-6)alkyl
R.sub.d represents the substituent attached to the .alpha.-carbon
atom of a natural .alpha.-amino acid (including hydrogen)
R.sub.e is (C.sub.1-5)alkyl
R.sub.a ' and R.sub.b ' are independently hydrogen, methyl or ethyl,
R.sub.8 and R.sub.9 are independently hydrogen, halogen, (C.sub.1-3)alkyl
p is 0 or 1,
q is 0 or 1, and
r is 0, 1 or 2,
B is -Phe- optionally ring-substituted by halogen, NO.sub.2, NH.sub.2,
OH, C.sub.1-3 alkyl and /or C.sub.1-3 alkoxy, or naphthylalanine
C is (L)-Trp- or (D)-Trp- optionally .alpha.-N-methylated and optionally
benzene-ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3
alkyl and/or C.sub.1-3 alkoxy,
D is -Lys-, ThiaLys, .gamma.F-Lys, .delta.F-Lys or Orn, optionally
.alpha.-N-methylated, or a 4-aminocyclohexylAla or 4-aminocyclohexylGly
E is Thr, Ser, Val, Phe, Ile or an aminoisobutyric acid residue
F is a group of formula --COOR.sub.7, --CH.sub.2 OR.sub.10, ##STR7##
wherein R.sub.7 is hydrogen or C.sub.1-3 alkyl,
R.sub.10 is hydrogen or the residue of a physiologically acceptable,
physiologically hydrolysable ester,
R.sub.11 is hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenyl-alkyl,
R.sub.12 is hydrogen, C.sub.1-3 alkyl or a group of formula --CH(R.sub.13)--X.sub.1,
R.sub.13 is --CH.sub.2 OH, --(CH.sub.2).sub.2 --OH, --(CH.sub.2).sub.3
--OH, or --CH(CH.sub.3)OH or represents the substituent attached
to the .alpha.-carbon atom of a natural .alpha.-amino acid (including
X.sub.1 is a group of formula --COOR.sub.7, --CH.sub.2 OR.sub.10
or ##STR8## wherein R.sub.7 and R.sub.10 have the meanings given
R.sub.14 is hydrogen or C.sub.1-3 alkyl and
R.sub.15 is hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenylalkyl,
R.sub.16 is hydrogen or hydroxy,
with the proviso that when R.sub.12 is --CH(R.sub.13)--X.sub.1
then R.sub.11 is hydrogen or methyl,
wherein the residues B, D and E have the L-configuration, and the
residues in the 2-and 7-position and any residues Y.sub.1 4) and
Y.sub.2 4) each independently have the (L)- or (D)- configuration.
In the compounds of formula IV, the following significances or
combinations thereof are preferred.
1. A is C.sub.7-10 phenylalkyl, especially phenethyl, or a group
of formula RCO. Preferably A is a group of formula RCO.
1.1. Preferably R is C.sub.1-11 alkyl or C.sub.7-10 phenylalkyl,
especially C.sub.7-10 phenylalkyl, more especially phenethyl, or
RCO has the meanings a), b) or c).
1.2. When RCO has the meanings a), b) or c), the .alpha.-amino
group of amino acid residues a) and b) and the N-terminal amino
group of dipeptide residues c) is preferably non-alkylated or mono-C.sub.1-12
alkylated, especially --C.sub.1-8 alkylated, more especially -methylated.
Most preferably the N-terminal is non-alkylated.
1.3. When RCO has the meaning a) this is preferably a') an L- or
D-phenylalanine or -tyrosine residue optionally mono-N-C.sub.1-12
alkylated. More preferably a') is an L- or D-phenylalanine residue
or an L- or D-N-(C.sub.1-8 -alkyl)-phenylalanine residue. Most preferably
a') is a D-phenylalanine or D-N-(C.sub.1-8 alkyl)-phenylalanine
residue, especially a D-phenylalanine or D-(N-methyl)-phenylalanine
1.4. When RCO has the meaning b) or c) the defined residue is preferably
lipophilic. Preferred residues b) are thus b') .alpha.-amino acid
residues having a hydrocarbon side chain, e.g. leucine and norleucine
residues, said residues having the L- or D-configuration, and preferred
residues c) are dipeptide residues in which the individual amino
acid residues are the same or different and are selected from those
defined under a') and b') above.
1.5. Most preferably RCO has the meaning a) especially the meaning
2. B is B', where B' is Phe or Tyr
3. C is C', where C' is -(D)Trp-
4. D is D', where D' is -Lys-, -MeLys- or -Lys(.epsilon.-Me)-,
5. E is E', where E' is the residue of a natural .alpha.-amino
acid other than Val, especially -Thr-.
6. F is F', where F' is a group of formula ##STR9## especially
a group of formula ##STR10## (in which case R.sub.11 =H or CH.sub.3).
In the latter case the moiety --CH(R.sub.13)--X.sub.1 preferably
has the L-configuration. Preferably F' is other than -ThrNH.sub.2
when E' is Thr.
6.1. R.sub.11 is preferably hydrogen.
6.2. As the substituent attached to the .alpha.-carbon atom of
a natural amino acid (i.e. of formula H.sub.2 N--CH(R.sub.13)--COOH),
R.sub.13 is preferably --CH.sub.2 OH, --CH(CH.sub.3)--OH, isobutyl
or benzyl, or R.sub.13 is --(CH.sub.2).sub.2 --OH or --(CH.sub.2).sub.3
--OH. It is especially --CH.sub.2 OH or --CH(CH.sub.3)OH.
6.3. X.sub.1 is preferably a group of formula ##STR11## or --CH.sub.2
--OR.sub.10, especially of formula --CH.sub.2 --OR.sub.10 and R.sub.10
is preferably hydrogen or has the meaning given under 7 below. Most
preferably it is hydrogen.
7. As the residue of a physiologically acceptable, physiologically
hydrolysable ester R.sub.10 is preferably HCO, C.sub.2-12 alkylcarbonyl,
C.sub.8-12 phenylalkylcarbonyl or benzoyl.
8. Preferably the residues in the 2- and 7-positions have the L-configuration.
9. Preferably Y.sub.1 and Y2 together represent a direct bond.
Most preferred compound of formula IV is the compound IVa ##STR12##
also known as octreotide.
C. Compounds of formulae V to VIII ##STR13## [see Vale et al.,
Metabolism, 27, Supp. 1, 139, (1978)] ##STR14## [see European Patent
Publication No 1295 and Application No. 78 100 994.9] ##STR15##
[see Veber et al., Life Sciences, 34, 1371-1378 (1984) and European
Patent Application No. 82106205.6 (published as No. 70 021)] also
known as cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe). ##STR16## [see
R. F. Nutt et al. Klin. Wochenschr. (1986) 64 (Suppl. VII) 71-73.
The contents of all the above publications including the specific
compounds are specifically incorporated herein by reference.
The compounds of the invention may exist e.g. in free form, salt
form or in the form of complexes thereof. Acid addition salts may
be formed with e.g. organic acids, polymeric acids and inorganic
acids. Such acid addition salt forms include e.g. the hydrochlorides
and acetates. Complexes are e.g. formed from compounds of the invention
on addition of inorganic substances, e.g. inorganic salts or hydroxides
such as Ca- and Zn-salts, and/or an addition of polymeric organic
The compounds of the invention may be prepared in accordance with
conventional methods. They are conveniently used in the form of
an acetate hydrate. Typical peptide concentrations are from 85 to
According to the invention, in addition to the lactic acid and
the compound of the invention, the pharmaceutical composition preferably
contains also a basic compound selected in such a way that the pharmaceutical
composition is buffered to a pH of 4 to 4.5, preferably 4.2.
Preferably the basic compound is selected from sodium hydroxide
and sodium hydrogen-carbonate. Such a compound is preferably added
in such an amount that the resulting pharmaceutical composition
has a pH buffered as indicated above.
Preferably the pharmaceutical composition of the invention is water
based. It may be used in the same way as for known compositions
based on e.g. acetic acid and sodium acetate. Conveniently it is
used for parenteral administration, e.g. subcutaneously. Typical
doses for s.c. administration are from 0.05 to 1 mg compound of
the invention per ml, particularly 0.1 to 1 mg/ml, preferably given
twice or once a day or by continous infusion. The composition may
be administered at the same doses and in the same way as for other
known compositions containing the same active agent.
The ratio of lactic acid to compound of the invention is preferably
from about 1:1 to about 40:1, particularly 5:1 to 40:1. The lactic
acid is conveniently used as a hydrate, e.g. 88% pure.
Typically the pharmaceutical composition of the invention may contain
per ml from 0.05 to 1 mg of a compound of the invention, from about
2 to 4 mg lactic acid, particularly as a hydrate (88% pure), sufficient
sodium hydrogencarbonate or sodium hydroxide to pH 4.2 and sterile
The composition of the invention may contain further ingredients,
e.g. a preserving agent, for example phenol, and/or an agent for
adjusting isotonicity, for example mannitol or sodium chloride.
Preferably, phenol is added to the composition when it is formulated
as multidose vials.
When mannitol is used for adjusting the isotonicity of the pharmaceutical
composition of the invention, the amount of mannitol preferably
does not exceed 5.5% by weight of the composition. Conveniently
mannitol is present in a ratio mannitol to lactic acid of about
10:1 to 20:1.
When sodium chloride is used for adjusting the isotonicity, it
is preferably present in a ratio to lactic acid of about 1:1 to
20:1, more preferably 2:1 to 10:1.
The composition of the invention may be produced according to conventional
methods, e.g. by mixing a somatostatin analogue with lactic acid
and optionally the other ingredients as mentioned in the desired
amount. Preferably the somatostatin analogue is first dissolved
in water (for injection). The composition of the invention is advantageously
prepared under sterile and aseptic conditions; the compounds of
the invention may also be produced under sterile conditions. The
composition of the invention being intended for parenteral administration,
particularly for injections, it is conveniently filled up in ampoules
or vials under aseptic conditions. The pharmaceutical composition
may be packed under carbon dioxide or other inert gas to prevent
degradation, preferably under carbon dioxide.
After injection, the composition of the invention is locally much
better tolerated than one containing acetic acid and sodium acetate,
e.g. known compositions of the compound IVa. Particularly the parenteral
administration of a composition of the invention, e.g subcutaneous
injection, is less painful.
In addition to the improved local tolerance after injection, the
composition of the invention which basically contains a polypeptide
as somatostatin analogue, exhibits good stability characteristics.
The pharmaceutical composition of the invention is particularly
indicated for use in the treatment of breast cancer.
Breast carcinoma is the most common type of tumours in women over
40 years age and a leading cause of deaths. The invention may be
of value for tumours which are hormone-dependent, e.g. estrogen-dependent,
or hormone-independent. Breast cancer is a disease for which an
important effort has still to be invested to find any sort of alleviation.
It has been found that the compounds of formulae I to III, the
compounds of formula IV wherein B is B', C is C', D is D', E is
E' and F is F', especially the compound IVa, and their derivatives
bearing a sugar residue, particularly the derivatives preparable
by an Amadori or Heyns rearrangement from a natural or a synthetically
accessible mono-, di- or oligosaccharide, and the compounds of formulae
V to VIII, as defined above, have a beneficial effect on patients
with breast cancer, e.g. in arresting progress of the disease, as
indicated by e.g. extent and duration of the response.
Preferred somatostatin analogues bearing a sugar residue are those
disclosed in WO 88/02756, the contents of which being incorporated
herein by reference.
A particularly preferred compound is ##STR17## (referred to as
The beneficial effect on patients with breast cancer with the somatostatin
analogues as mentioned above may be shown in the following clinical
In a first clinical trial, 5 patients suffering from metastatic
breast carcinoma are studied, who had no previous systemic treatment
of metastasis (adjuvant treatment is ignored) and had easy access
to their veins. The patients had PS 0 or 1 and could be post-menopausal.
The compounds of the invention may be continuously administered
parenterally, e.g. s.c. by means of a pump at the rate of e.g. 0.5
to 2 mg per 24 hours, over at least 3 days.
The growth factor IGF profile is determined and the levels found
to be reduced.
A second clinical trial may be effected as follows:
In a second trial the compounds of the invention are administered
to at least 14 patients having breast cancer and the extent and
duration of the response determined.
Patients are included who have breast cancer as evidenced by histological
biopsy (glandular analysis-EOA). They present a metastatic illness
and/or loco-regional localisation which is measurable and evaluable.
If desired patients are included who are resistant to other treatment
to conventional therapy such as surgery, radiotherapy, other chemotherapy
and/or hormone therapy.
The patients present at least one target, on X-ray analysis, which
is measurable or evaluable such as a primitive metastatic tumour
which is cutaneous or sub-cutaneous. It may be gangliar or visceral.
Preferably the patients have lesions which have progressed within
the month preceding the trial and have an estimated survival time
of at least 3 month.
Preferably the trial excludes:
patients in which the sole criteria for diagnosing breast cancer
are biological modifications,
patients administered with an embroynic carcinoma antigen pathology,
patients with ascitis, a pleural effusion, a pulmonary carcinoma
lymphangitis, or an osseous localisation as sole metastatic manifestation,
patients treated on a unique tumoural target by radiotherapy less
than eight weeks before inclusion in the study (they are eligible
however if evidence of progression during this time),
patients with a unique cerebral localisation,
patients presenting another malignant tumour with the exception
of a carcinoma in situ in the cervix uteri or a spino- or basocellular
skin cancer, and
patients not able to attend regular consultations.
With these exclusions the efficacy of the compounds may be followed
more clearly. The compounds may be used in the method of treatment
at the invention however in treating patients falling in the above
The compounds of the invention may be administered at the same
dosage as or at a lower dosage than in the first trial, but preferably
in two doses, one in the morning and one in the evening. The treatment
is for at least 3 months or until complete remission. The response
may be followed by conventional methodology, e.g. according to IUCC
response criteria, e.g. progression, stabilization, partial or complete
remission. The evaluation is effected e.g. on day 0, 15, 45, 60
A third clinical trial may be effected as follows:
Patients with advanced breast cancer are included. In addition
their breast cancers are analysed with autoradiography on adjacent
tissue sections using as radioligand e.g. either .sup.125 I-[Leu.sup.8,
D-Trp.sup.22, Tyr.sup.25 ]-somatostatin-28 or a .sup.125 I-Tyr.sup.3
analogue of the compound IVa, for their content in somatostatin
receptors. The patients have progressive disease and measurable
and/or evaluable parameters according to criteria of the IUCC (i.e.
appearance of new lesions or growth of existing metastatic lesions)
not responding to primary hormonal and/or cytotoxic therapy. As
in the above indicated second clinical trial, the third trial preferably
also excludes patients with previous or concurrent malignancies
at other sites, with the exception of cone biopsied in situ carcinoma
of the cervix uteri and adequately treated basal or squamous cell
carcinoma of the skin.
The compounds of the invention may be administered at the same
dosage as or at a lower dosage than in the second trial. Preferably
the compounds of the invention are administered parenterally, e.g.
subcutaneous, particularly in a continuous subcutaneous way by means
of a portable syringe pump (infusion pump). Treatment is for at
least 2 months or until complete remission. The response may be
followed by conventional methodology e.g. according to IUCC response
criteria. The evaluation is effected e.g. on day 0,30 and 60. All
lesions are measured at each assessment or when multiple lesions
are present, a representative number of 5 lesions may be selected
for measurement. Regression of the lesions is the sum of the products
of the diameters of each individual lesion or those selected for
study, which decreases by 50% or more.
The compounds of the invention, e.g. octreotide, is administered,
e.g. parenterally, e.g. sub-cutaneously, or orally. The appropriate
dosage will vary depending upon, for example, the somatostatin analogue
employed, the host, the mode of administration and the severity
of the condition being treated. Doses may be in the range used to
treat gastro-enteropancreatic endocrine (GI) tumours such as vipomas,
or acromegaly, to about 10 times that dose. Preferred ranges are
e.g. from about 4 to 10 times the GI-tumour or acromegaly dose.
Thus for octreotide, GI tumours may be treated initially with 0.05
mg once or twice a day by sub-cutaneous injection. Dosage can be
increased to 0.2 mg three times daily. For acromegaly daily doses
of from 100 to 300 .mu.g s.c. may be used. Octreotide is tolerated
at least to 1 mg.
Indicated daily doses for octreotide in the use of the invention
are from 0.1 to 1 mg s.c., preferably 0.2 to 1 mg s.c.. Octreotide
is preferably administered parenterally in the form of a formulation
based on lactic acid as disclosed above. The compound IVb (octreotide
with a sugar residue) is preferably administered in an oral form,
e.g. at a dosage of 2 .mu.g to 20 mg p.o., preferably 300 to 5000
.mu.g p.o.. Oral unit dosages may contain for example from about
0.5 .mu.g to about 10 mg of compound IVb.
Preferably a dopamine agonist is also administered in the treatment
of breast cancer. The preferred dopamine agonist is bromocriptine,
preferably used as the mesylate.
Further examples include:
ro-6-hydroxyl-1-propyl-3-benzo[quinolinyl] sulfamide, also known
as CV, preferably used as the hydrochloride.
Preferred compounds are low molecular weight ergot derivatives,
i.e. compounds which do not have a peptide moiety in the 8 position,
i.e. not ergopeptides. They may have for example an amino group,
e.g. an acylamino, ureidio or sulphamino moiety or thiomethyl moiety
in the 8 position which may be substituted by for example one or
if desired two (C.sub.1-4)alkyl groups. Conveniently these have
a single bond in the 9,10 position of the ergoline nucleus.
The preferred compounds are 8.alpha.-sulphamoylamino ergolines.
These may be based on the formula: ##STR18## wherein R.sub.1.sup.a
inter alia is (C.sub.1-4)alkyl,
R.sub.2.sup.a inter alia is H or (C.sub.1-4)alkyl,
R.sub.3.sup..alpha. inter alia is --NHSO.sub.2 N[(C.sub.1-4)alkyl].sub.2
The preferred Examples include:
(also known as Mesulergine hereinafter compound B);
used as the hydrochloride, also known as CQP, (hereinafter compound
preferably used as the hydrochloride, (hereinafter compound D).
The most preferred example is (b), i.e. compound C.
Other preferred compounds include:
(also known as Lisuride preferably used as the hydrogen maleate);
ii) 6-n-propyl-8.alpha.-methylmercaptomethyl-ergoline-I (also known
as Pergolide preferably used as the mesylate);
iii) Transhydrolisuride also known as terguride having the chemical
name 3-(6-methyl-ergolin-8.alpha.-yl)-1,1-diethyl-urea, published
e.g. in DOS 3135305 and 3124714.
iv) 6-n-propyldihydro-lisuride also known as proterguride having
the chemical name 3-(6-n-propyl-ergolin-8.alpha.-yl)-1,1-diethyl-urea.
v) 6-and 2-substituted, e.g. 6-n-propyl and/or 2-methyl or bromo
derivatives of terguride, lisuride and proterguride e.g. as published
in European Patent Publication No. 21206 (A.1) and 160842 (A.1)
the contents of which especially the examples and pharmacological
data thereof, are incorporated herein by reference. Examples include
2-bromerguride, also known as 2- bromolisuride, preferably used
in the form of the hydrochloride.
vi) Metergoline, also known as (+)-N-(carboxy)-1-methyl-9,10-dihydrolysergamine
vii) dosergoside, also known as N-(1S,2R,3E)-2-hydroxy-1-(hydroxymethyl)-3-heptadecanyl)-6-methylergoline-
viii) FCE-21336 also known as 1-ethyl-3-(3'-dimethylaminopropyl)-3-(6-alkyl-ergoline-8'-beta-carbonyl)-u
rea preferably used as the diphosphate.
ix) GYKI-32887 also known as 6-methyl-8-(N-mesyl-N-2-azidoethyl)
ergolene preferably used as the bimaleate, e.g. as disclosed in
U.S. Pat. No. 4,299,836.
Groups of compounds include compounds of formula (I') ##STR19##
wherein R.sub.1 ' is hydrogen or C.sub.1-4 alkyl,
R.sub.2 ' is hydrogen, chlorine, bromine or methyl,
R.sub.3 ' is C.sub.1-5 alkyl or C.sub.3-5 alkenyl in which the
double bond is not at the carbon atom adjacent to the nitrogen atom,
R.sub.4 ' is C.sub.3-7 alkyl; C.sub.3-7 cycloalkyl; adamantyl;
phenyl; phenyl substituted by one or more members selected from
the group consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkylthio, trifluoromethyl, hydroxy, nitro, amino and mono- and
di-(C.sub.1-3 alkyl)-amino; or phenyl bearing a condensed non-aromatic,
heterocyclic ring having 5- or 6-ring members including 1 or 2 hetero
atoms selected from the group consisting of oxygen and sulphur,
published in GB 2,152,507 A, the contents of which especially the
examples and pharmacological data thereof are incorporated herein
by reference, e.g.
compound E) preferably used as the hydrochloride, and the 2-chloro
Other examples include a compound of formula I" ##STR20##
wherein R.sub.1 " is hydrogen or C.sub.1-4 alkyl,
R.sub.2 " is hydrogen, chlorine, bromine or methyl,
R.sub.3 " is C.sub.1-5 alkyl or C.sub.3-5 alkenyl in which
the double bond is not at the carbon atom adjacent to the nitrogen
R.sub.4 " is C.sub.1-7 alkyl; C.sub.3-7 cycloalkyl; adamantyl;
phenyl; phenyl substituted by one or more members selected from
the group consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3
alkylthio, tri-fluoromethy, hydroxy, nitro, amino and mono- and
di-(C.sub.1-3 -alkyl)-amino; or phenyl fused with a non-aromatic,
heterocyclic ring having 5- or 6-ring members including 1 or 2 hetero
atoms selected from the group consisting of oxygen and/or sulphur,
with the proviso that when R.sub.2 " is hydrogen, neither R.sub.3"
nor R.sub.4 " is methyl,
e.g. the compounds wherein R.sub.1 "=H R.sub.2 "=Br or
especially CH.sub.3 ", R.sub.3 "=CH.sub.3 and R.sub.4"
=tert butyl, filed off German Application P 3447383.1 filed 24 Dec
1984 as English application No. 8531420, now published as G.B.Application
2169291 A and also in other countries, the contents of which including
all the examples thereof are incorporated herein by reference.
These dopamine agonists may be used for example in free base form
or in pharmaceutically acceptable acid addition salt form, e.g.
the hydrochloride, maleate or mesylate.
The compounds may be administered in the second clinical trial
in association with the compounds of the invention. The compounds
are administered at daily doses used to lower prolactin levels.
For example bromocriptine is administered at a daily dose of 5 mg
p.o. twice a day.
The present invention accordingly in one aspect provides:
a) Use of a somatostatin analogue of formulae I to III, of formula
IV wherein B is B', C is C', D is D', E is E', F is F'and A, A',
Y.sub.1, and Y.sub.2 are as defined above, and their derivatives
bearing a sugar residue, preferably their derivatives preparable
by an Amadori or Heyns rearrangement from a natural or synthetically
accessible mono-, di- or oligosaccharide, or of formulae V to VIII
in free form or a pharmaceutically acceptable salt form or complex
form, in the treatment of breast cancer, e.g. hormone-dependent
or hormone-independent breast tumours and/or somatostatin receptor
positive breast tumours, and/or
b) Use of a somatostatin analogue as mentioned in a) above in the
manufacture of a medicament suitable for the treatment of breast
cancer, particularly a parenteral or oral composition, e.g. a composition
for subcutaneous administration, and/or
c) A method of treating breast cancer in a subject which comprises
administering a therapeutically effective amount of a somatostatin
analogue as mentioned in a) above to a subject in need of such a
d) A method of co-administering a somatosatin analogue as mentioned
in a) above and a dopamine agonist in the treatment of breast cancer
to a subject in need of such a treatment.
The pharmaceutical compostition of the invention is particularly
useful in the treatment of breast cancer when the somatostatin analogue
is administered s.c.,e.g. by continuous infusion. The administration
can be effected continuously over 24 hours with an acceptable tolerance
for the patient.