Note: Descriptions are shown in the official language in which they were submitted.
A pharmaceutical composition for the treatment of high
blood pressure
It is known that the high blood pressure of patients
with essential hypertension can be reduced using inhi-
bitors of angiotensin converting enzyme (ACE inhibitors),
such as captopril or enalapril (Therapiewoche 29 C1979J
7746; Lancet 2 C1981J 543-546>. However, a certain per-
centage of patients with essential hypertension do not
respond to substances of this type (Drug Devel. Eval. _4
C1980J 82-91).
It has been disclosed that the antihypertensive action
of enalapril or captopril is potentiated by the addition
of diuretically effective amounts of a diuretic of the
thiazide type or analogous compounds (Brunner et al.,
Clin. Exp. Hypertension 2 C1980J 639-657; McGregor et
al., er. Med. J. 284 C1982J 693-696). It is generally
assumed that this effect is based on stimulation by the
diuretic of the renin-angiotensin system via a loss of
salt and volume (P.J.S. thin et al., J. Pharm. Pharmacol.
37 C 1985 J 105 ) .
There is a report in Arzneim.-Forsch./Drug Res. 34 (II)
C1984J 1417-1425 of investigations into the cardio-
vascular action of 2-CN-C(S)-1-carboxy-3-phenylpropylJ-L-
alanylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxy-
lic acid ("ramiprilate"). This entailed animals being
pretreated with furosemide or piretanide for several
days for the purpose of sodium depletion.
We have now found, surprisingly, that ACE inhibitors com
biped with loop diuretics in low dosage effectively lower
blood pressure.
Thus the invention relates to pharmaceutical compositions
containing
a) an angiotensin converting enzyme inhibitor or its ~340'~22
,..
physiologically tolerated salt, and
b) a loop diureltic or its physiologically tolerated
salt.
In a drawing which illustrates an embodiment of the
invention, Figure 1 shows the results of administering
ramipril and piretanide to spontaneously hyperterisive rats.
Examples of loop diuretics included within the meaning
of the present invention are furosemide, bumetanide,
ethacrynic acid, etozolin and piretanide. As is evident
from the name, the main point of attack of these di-
uretics, which have a short but potent effect, is the
loop of Henle (cf. Mutschler, ArzneimittelWirkungen
(Effects of drugs) 4th Edition, Stuttgart 1981, pages
486 and 487>. Compounds of the formula I
R2
R3
R \ \
(I )
HZNOZg ~ COOH
in which
R1 denotes chlorine or phenoxy,
R2 denotes hydrogen, pyrrolidino or n-butylamino, and
R3 denotes hydrogen or 2-furylmethylamino
are particularly suitable examples.
Piretanide (see fora~ula II)
(II)
O
g2p~ ~ COOH
is particularly preferred.
Suitable ACE inhibitors are described in, for example,
US Patent 4,129,!iTl, US Patent 4,154,960, US Patent
4,374,829, European Patent A-79,522, European Patent A-
T9,022, European Patent A-49,658, European Patent
134472
.. ~ 3
_.- A-51,301, US Patent 4,454,292, US Patent .4,374,847,
European Patent A-72,352, US Patent 4,350,704, European
Patent A-50,80~D, European Patent A-46,953, US Patent
4,344,949, European Patent A-84,164, US Patent 4,470,972,
European Patent A-65,301 and European Patent A-52,991.
A large proportion of the ACE inhibitors disclosed in the
abovementioned publications can be described by the gene-
ral formula V,
* *
R800C - 'CFI - N10 C - ~ - NA - CH -'(CIi2)~ RS ( V )
R R ~ R ~OOR
in Which
n is 1 or 2,
R5 denotes Hydrogen,
an optionally
substituted ali-
phatic radic:a.l having 1 - 8 carbon atoms,
an optionally substituted alicyclic radical having
3 - 9 carbon atoms,
an optionally substituted aromatic radical having
6 - 12 carbon atoms,
an optionally substituted araliphatic radical having
7 - 14 carbon atoms,
an optionally substituted alicyclic-aliphatic radical
having 7 - 14 carbon atoms,
a radical ORa or SRa, in which
Ra represents an optionally substituted aliphatic radi-
cal having 1 - 4 carbon atoms, represents an optional-
ly substituted aromatic radical having 6 - 12 carbon
atoms, or an o ptionally substituted heteroaromatic
radical having 5 - 12 ring atoms,
R6 denotes hydrog en, an optionally substituted aliphatic
radical having 1 - 6 carbon atoms,
an optionally substituted alicyclic radical having
3 - 9 carbon a toms,
an optionally substituted alicyclic-aliphatic radical
having 4 - 13 carbon atoms,
an optionally substituted aromatic radical having
~.3~~'~~2
- 4
_.- 6 - 12 carbon atoms,
an optionally substituted araliphatic radical having
7 - 16 carbon atoms,
an optionally substituted heteroaromatic radical hav-
ing 5 - 12 ring atoms, or
the side chain, protected where necessary, of a natu-
rally occurring a-amino acid,
R7 and R8 are identical or different and denote hydrogen,
an optionally substituted aliphatic radical having
1 - 6 carbon atoms,
an optionally substituted alicyclic radical having
3 - 9 carbon atoms,
an optionally substituted aromatic radical having
6 - 12 carbon atoms,
an optionally substituted araliphatic radical having
7 - 16 carbon atoms, and
R9 and R10, together with the atoms carrying them,
form a heterocyclic, mono-, bi- or tricyclic ring sys-
tem having 3 - 15 carbon atoms, particularly suitable
ring systems of this type being those of the following
group:
Tetrahydroisoquinoline (A); decahydroisoquinoline (B>;
octahydroindole (C); octahydrocyclopentaCb7pyrrol <D);
2-azaspiroC4.57decane (E); 2-azaspiroC4.47nonane (F);
spiroC(bicycloC2.2.17heptane)-2,3-pyrrolidine7 (G); spiro-
C(bicycloC2.2.2:loctane)-2,3-pyrrolidine7 (H); 2-azatri-
cycloC4.3Ø16~~i7decane (I); decahydrocycloheptaCb7pyrrol
(J); octahydroisoindole (K); octahydrocyclopentaCc7pyrrol
(L); 2,3,3a,4,5,,7a-hexahydroindole (M); 2-azabicycloC3.1.07-
hexane (N); all of which can optionally be substituted.
However, the unsubstituted systems which have the follow-
ing structural formulae are preferred.
1~44~22
-. -
- / COORS COORS
l-
w I w w ~
_A _B Nl"" COORg
C
N OOR8 8
Nl ' COOK CURB
_D E I _F
I
COOR8 ~COORB COOR8
N
= H I . I I
cooRB N~--cooRB
~rlv ycooRs
I
J K L
COORS \ ~ COOR8
I
M N
For the compounds which have several chiral atoms, all
the possible diastereomers are suitable as racemates or
enantiomers, or mixtures of various diastereomers. The
S configuration of the carbon atoms labelled with an as-
terisk is preferred.
Examples of ver;~ suitable ACE inhibitors of the formula
V are those in which
n is 1 or 2,
1340722
_ 6
R5 denotes hydrogen,
alkyl having 1 - 8 carbon atoms,
alkenyl having 2 - 6 carbon atoms,
cycloalkyl Ihaving 3 - 9 carbon atoms,
aryl which Ihas 6 - 12 carbon atoms and
can be mono-, di- or trisubstituted by (C1-C4)-
alkyl, (C1-C4)-alkoxy, hydroxyl, halogen, vitro,
amino, aminomethyl, (C1-C4>-alkylamino, di-
(C1-C4)-alkylamino, (C1-C4)-alanoylamino,
methylene~dioxy, carboxyl, cyano and/or sulfamoyl,
alkoxy having 1 - 4 carbon atoms,
aryloxy which has 6 - 12 carbon atoms
and can t>e substituted as described above for aryl,
mono- or bic;yclic heteroaryloxy which has 5 - 7 or
8 - 10 ring atoms respectively, 1 to 2 of these ring
atoms being sulfur or oxygen atoms and/or 1 - 4 of
these ring atoms being nitrogen,
and which can be substituted as described above
for aryl,
Amino-(C1-C~,)-alkyl,
(C1-C4)-alkanoylaa~ino-(C1-C4)-alkyl,
(C7-C13)-aroylamino-(C1-C4)-alkyl,
(C1-C4)-alkoxycarbonylamino-(C1-C4)-alkyl,
(C6-C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)-alkyl,
(C6-C12)-aryl-(C1-C4)-alkylsmino-(C1-C4)-alkyl,
(C1-C4)-alkylamino-(C1-C4>-alkyl,
di-(C1-C4)-alkylamino-(C1-C4)-alkyl,
guanidino-(C1-C4)-alkyl,
imidazolyl, indolyl,
(C1-C4)-alkylthio,
(C1-C4)-alkylthio-(C1-C4>-alkyl,
(C6-C12)-arylthio-(C1-C4)-alkyl
which can be substituted in the aryl moeity as des-
cribed above for aryl,
(C6-C12)-aryl-(C1-C4)-alkylthio
which can be substituted in the aryl ~aoeity as des-
cribed above for aryl,
1340722
7
carboxyl-(C1-C4>-alkyl,
carboxyl, carbamoyl,
carbamoyl-(C1-C4)-alkyl,
tC1-C4)-alkoxycarbonyl-(C1-C4>-alkyl,
(C6-C12)-aryloxy-(C1-C4)-alkyl
which can be substituted in the aryl moeity as des-
cribed above for aryl, or
(C6-C12)-aryl-(C1-C4)-alkoxy which can be substi-
tuted in the aryl moeity as described above for aryl,
R6 denotes hydrogen,
alkyl having 1 - b carbon atoms,
alkenyl having 2 - 6 carbon atoms,
alkynyl having 2 - 6 carbon atoms,
cycloalkyl having 3 - 9 carbon atoms,
cycloalkenyl having 5 - 9 carbon atoms,
(C3-Cg>-cycloalkyl-(C1-C4)-alkyl,
(CS-Cg)-cycloalkenyl-(C1-C4)-alkyl,
optionally partially hydrogenated aryl which has 6 - 12
carbon atoms and can be substituted as described above
for R,
(C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)-aroyl-
(C1 or C2)alkyl,
each of which can be substituted as the preceding aryl,
mono- or bicyclic, optionally partially hydrogenated
heteroaryl which has 5 - 7 or 8 - 10 ring atoms respec-
tively, 1 to 2 of these ring atoms being sulfur or oxygen
atoms and/or 1 to 4 of these ring atoms being nitrogen
atoms,
and can be substituted as the preceding aryl, or
the optionally protected side chain of a naturally occur-
ring a-amino acid R6-CH<NH2)-COOH,
R7 and R8 are identical or different and denote hydrogen,
alkyl having 1 - 6 carbon atoms,
alkenyl having 2 - 6 carbon atoms,
di-(C1-C4)-alkylamino-(C1-C4)-alkyl,
(C1-CS)-slkanoyloxy-(C1-C4)-alkyl,
(C1-C6)-alkoxycarbonyloxy-(C1-C4)-alkyl,
1340?22
- 8
(C~-C13)-aro:~loxy-(C1-C4)-alkyl,
..- (C6-C12)-aryloxycarbonyloxy-(C1-C4)-alkyl,
aryl having c5 - 12 carbon atoms,
(C6-C12)-arY~'~-(C1-C4)-alkyl,
(C3-C9)-cycloalkyl or
(C3-Cg)-cycloalkyl-(C1-Ct,)-alkyl and
R9 and R10 have the abovementioned meaning, preferably
those ACE inhibitors of the formula V in which
n is 1 or 2,
R5 denotes (C1-C6>-alkyl, (C2-C6)-alkenyl, (C3-Cg)-
cycloalkyl, amino-(C1-C4>-alkyl, (C2-C5)-acylamino-
lC1-C4)-alkyl., (C7-C13)-aroylamino-(C1-C4)-alkyl,
(C1-C4)-alkoxycarbonylamino-(C1-C4)-alkyl, (C6-C12)-
aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4>-alkyl,
(C6-C12)-aryl. which can be mono-, di- or trisubstituted
by (C1-C4)-alkyl, (C1-C4>-alkoxy, hydroxyl,
halogen, vitro, amino, (C1-C4>-alkylamino, di-(C1-C4)-
alkylamino and/or methylenedioxy or 3-indolyl, in par-
ticular methyl, ethyl, cyclohexyl, tert.-butoxycarbonyl-
amino-(C1-C4)-alkyl, benzoyloxycarbonylamino-(C1-C4>-
alkyl or phenyl which can be mono- or disubstituted,
or in the case of methoxy trisubstituted, by phenyl,
(C1-C2)-alkyl, (C1 or C2)-alkoxy, hydroxyl,
fluorine, chlorine, broa~ine, amino, (C1-C4>-alkyl-
amino, di-(C1-C4)-alkylamino, vitro and/or methy-
lenedioxy,
R6 denotes hydrogen or (C1-C6)-alkyl which can option-
ally be substituted by amino, (C1-C6>-acylamino or
benzoylacnino, (C2-C6)-alkenyl, (C3-C9)-cycloalkyl,
(C5-C9)-cycloalkenyl, (C3-C7)-cycloalkyl-(C1-C4)-
alkyl, (C6-C12)-aryl or partially hydrogenated aryl,
each of which can be substituted by (C1-C4)-alkyl,
(C1 or C2)-alkoxy or halogen, (C6-C12)-aryl-(C1 to
C4)-alkyl or (C7-C13)-aroyl-(C1-C2)-alkyl, both
of which can be substituted in the aryl radical as de-
fined above, a mono- or bicyclic heterocycle radical
1340'22
9
having 5 to 7 or 8 to 10 ring atoms respectively, 1
to 2 of these ring atoms being sulfur or oxygen atoms
and/or 1 to 4 of these ring atoms being nitrogen atoms,
or a side clhain of a naturally occurring, optionally pro-
s tected, ti-amino acid, but in particular hydrogen, (C1-C3)
-alkyl, (C2 or C3)-alkenyl, the optionally protective
side chain of lysine, benzyl, 4-methoxybenzyl, 4-
ethoxybenzyl, phenethyl, 4-aminobutyl or benzoylmethyl,
R7 and R8 denotte identical or different radicals hydrogen,
(C1-C6)-alkyl, (C2-C6)-alkenyl or (C6-C12)_
aryl-(C1-C4:1-alkyl, but in particular hydrogen,
(C1-C4)-alkyl or benzyl, and
R9 and R10 have the abovementioned meaning, in parti-
cular those ACE: inhibitors of the formula V in which n
is 2, RS denotes phenyl, R6 denotes methyl,
R7 and Ra denote identical or different (C1-C6)-alkyl
radicals or (C~-C10)-aralkyl radicals such as benzyl
or nitrobenzyl, and
R9 and R10 together represent a radical of the formula
~~2 ~P
X
~CH2 ~m
in which m denotes 0 or 1, p denotes 0, 1 or 2, and X
denotes -CH2-, -CH2-CH2- or -CH=CH-, it also being poss-
ible for a 6-ring formed with X to be s benzene ring.
Here and hereinafter, aryl is to be understood preferably
to be optionally substituted phenyl, biphenylyl or naph-
thyl. A similar statement applies to radicals derived
from aryl, such as aryloxy and arylthio. Aroyl is parti-
cularly understood to be benzoyl. Aliphatic radicals can
A
:- ~ 1340722
,o
be straight-chain or branched.
A mono- or bicyclic heterocycle radical having 5 to 7 or
8 to 10 ring atoms respectively, 1 to 2 of these ring
atoms being sulfur or oxygen atoms and/or 1 to 4 of these
ring atoms being nitrogen atoms, is understood to be, for
example, thienyl, benzo~b~thienyl, furyl, pyranyl, benzo-
furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimi-
dinyl, pyridazinyl, indazolyl, isoindolyl, indolyl,
purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naph-
thyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, pteri-
dinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl.
It is also possible for the radicals to be partially or
completely hydrogenated.
Naturally occurring a-amino acids are described in, for ex-
ample, Houben-Weyl, Methoden der Organischen Chemie
(Methods of Organic Chemistry), vol. XV/1 and XV/2.
If R1 represents a side chain of a protected naturally
occurring a-amino acid such as, for example, protected
Ser, Thr, Asp, Asn, Glu, Gln, Arg, Lys, Hyl, Cys, Orn,
Cit, Tyr, Trp, His or Hyp, preferred protective groups
are the groups customary in peptide chemistry (cf. Houben-
Weyl, vol. XV/1 and XV/2). In the case where R1 denotes
the protected side chain of lysine, the known amino pro-
tective groups are preferred, but in particular Z, Boc
or (C1-C6)-alkanoyl. 0-protective groups suitable
for tyrosine are preferably (C1-C6>-alkyl, in parti-
cular methyl or ethyl.
ACE inhibitors of the formula V can be prepared by react-
ing together their fragments in a suitable solvent, where
appropriate in the presence of a base and/or of a coupl-
ing auxiliary, where appropriate reducing unsaturated
compounds which are produced as intera~ediates, such as
Schiff's bases, and eliminating protective groups which
have been temporarily introduced for the protection of
reactive groups, and converting the resulting compounds,
A
1340722
11
w where appropriate, into their physiologically tolerated
salts.
It is possible to react compounds of the formula VI with
compounds of the formula VII in the said manner.
R800C~H-N-H HOOC-CH NH~H-(CH ) -RS
R9 R10 ~6 ~R~ 2 n
(vI) (vII)
The reaction of these compounds can be carried out, for
example, in analogy to known peptide coupling processes
in the presence of coupling auxiliaries such as carbodi-
imides (for example dicyclohexylcarbodiimide), diphenyl-
phosphoryl azide, alkanephosphoric anhydrides, dialkyl-
phosphinic anhydrides or N,N-succinimidyl carbonates in
CH3CN,Amino groups in compounds of the formula YI can
be activated with tetraethyl diphosphite. The compounds
of the formula VII can be converted into active esters
(for example with 1-hydroxybenzotriazole), mixed anhyd-
rides (for example with chloroformic esters), azides or
carbodiimide derivatives, and thus be activated (cf.
Schr~der, L~bke, The Peptides, volume 1, New York 1965,
pages 76-136).
It is likevise possible to react compounds of the formula
VII' with compounds of the formula VIII with the form-
ation of compounds of the formula V,
R800C-CH-N C-CH Y1 ~-CH-(CH ) -RS
R9 R10 ~ R6 ~R~ 2 n
(VI.I' ) (VIII)
in which either Y1 represents amino and Y2 represents a
leaving group, or Y1 represents a leaving group and Y2
represents amino. Examples of suitable leaving groups
are Cl, Br, I, alkylsulfonyloxy or arylsulfonyloxy.
134o7.zz
12
_ ' Alkylations of this type are advantageously carried out in
water or in an organic solvent in the presence of a base.
Furthermore, compounds of the formula IX can be condensed
with compounds of the formula X
R800C-CH N-C-C=Ql ~2~-(C'2~~ RS
COOR
R9 R10 O R6
(IX) (X)
in which either Q1 represents amino + hydrogen and Q2
represents oxo, or Q1 represents oxo and Q2 represents
amino + hydrogen. The condensation is advantageously
carried out in water or in an organic solvent such as a
lower alcohol, in the presence of a reducing agent, such
as NaBH3CN, compounds of the formula V being obtained
directly. However, it is also possible to reduce the
Schiff's bases or enamines produced as intermediates,
where appropriate after previous isolation, with the
formation of compounds of the formula V, for example by
hydrogenation in the presence of a transition metal
catalyst.
Finally, reaction of compounds of the formula IX (a1 - H +
NH2) with compounds of the formula XI, or their reaction
vith compounds of the formulae XII and XIII, also result
in compounds of the formula V (n = 2),
R~OOC-CH~CH-CO-R5
(XI)
OCH-COORS R5-CO-CH3
(XII) (XIII)
134022
- 13
_ - the Schiff's bases produced as intermediates being redu-
ced, and a carbonyl group being converted into methylene
by reduction.
In the abovementioned formulae VI - XIII, RS-R10 and n
are as defined in formula V. Protective groups introdu-
ced temporarily to protect reactive groups not involved
in the reaction are eliminated in a manner known per se
after the reaction is complete (cf. Schroder, Lubke, loc.
cit., pages 1 ~- 75 and 246 - 270).
Orally active .ACE inhibitors are advantageous, such as,
for example, r,amipril, enalapril, captopril, lisinopril,
perindopril, cilazapril, RHC 3659, CGS 13945, CGS 13928C,
CGS 14824A, CI~-906, SCH 31846, zofenopril, fosenopril,
alacepril and others. Orally active ACE inhibitors are
described in, 'for example, Brunner et al., J. Cardiovasc.
Pharmacol. 7 (;Suppl. I) C1985J S2-S11.
The ACE inhibitors of the formula III
H
COON
s N ~ (S) ~S~ /~
H ~ ,_ CH - ~ - CH - CHZ - CIi2~ ( I I I
CH (COO ~clR
3
in which
R denotes hydrogen, methyl, ethyl or benzyl,
which are disclosed in European Patent A-79,022 are
preferred, in particular the compound of the formula
III in which R denotes ethyl (ramipril>.
The ACE inhibitors of the formula IV
H
cooH
2 5 (S ) (S
- H - ~ - - ~2 - CHZ ~ (IV)
CH ~OR4
O 3
1340722
14
. in which
R4 denotes hydrogen, (C~-C4)-alkyl or benzyl,
which are disclosed in European Patent A-84,164, are also
preferred, in particular the compound of the formula IV
in which R4 denotes ethyl.
Thus, preferred compositions according to the invention
are those which contain a compound of the formula IV with
R4 = ethyl together with piretanide or furosemide, but in
particular those which contain ramipril together with
piretanide and which contain ramipril together with
furosemide.
The combination of ACE inhibitors and loop diuretics
effects a potent and persistent lowering of blood pres-
sure and can thus be used for the treatment of high blood
pressure of various etiologies. It is a particularly
interesting fact that there is not an additive behavior
of the actions of the two components; on the contrary, a
synergistic effect is observed. In spontaneously hyper-
tensive rats there is a lowering of blood pressure with
the combination even when it contains doses of an ACE
inhibitor, such as ramipril, which alone have no effect,
when they are combined with doses of a loop diuretic,
such as piretanide, which alone have no diuretic effect
(subdiuretic doses). This shows that loop diuretics, in
particular compounds of the abovementioned formula I,
are able to stiimulate the renin-angiotensin system without
showing a diuretic and saluretic effect. No such effect
is achieved with compounds of the hydrochlorothiazide type.
For the reasons mentioned, the composition according to
the invention is superior to the individual components
for the treatment of high blood pressure, since it allows
smaller doses of the components to be administered, and
thus reduces any toxicological problems there may be.
. 1340722
' 15
The invention also relates to a process for the prep-
aration of a composition of this type, which comprises
conversion into a suitable form for administration of
a) an angiotensin converting enzyme inhibitor or its
physiologic<~lly tolerated salt, and
b) a loop diuretic or its physiologically tolerated salt,
together with physiologically acceptable vehicles and,
where appropriate, other auxiliaries or additives.
The invention furthermore relates quite generally to
products containing
a) an angiotensin converting enzyme inhibitor or its
physiologically tolerated salt, and
b) a loop diuretic or its physiologically tolerated
salt, preferably in a subdiuretic dose,
as a combination product for concurrent, separate or
sequential administration for the treatment of high
blood pressure.
The ratio by veight of ACE inhibitor: loop diuretic in
the said compositions and products varies depending on
the activity of the active compounds, preferably between
10 . 1 and 1 : 500. For ramipril (=A) + piretanide
(=B), for example, A . B preferably varies between 4 . 1
and 1 . 10, in particular between 2 . 1 and 1 . 3. In
contrast, with ramipril (=A) + furosemide (=C) the ra-
do A : C is preferably 1 : 1 to 1 . 200, in particular
1 : 4 to 1 : 40i.
By reason of their pKa value the loop diuretics of the
formula I (pKa of furosemide: 3.8) form salts with ACE
inhibitors of the formula V, the compound of the formula
~~~~~z~
16
I being converted into its cation with protonation of the
NH group adjacent to CHR6 in the compound of the formula
V. If the compound of the formula V (R7 and/or R8 = H)
is in the form of a zwitterion, a carboxylate group is
protonated.
Hence the invention also relates to a salt of a loop di-
uretic of the 'formula I with an ACE inhibitor, and to
pharmaceutical compositions and products which contain
such a salt of a compound of the formula V. If necessary,
the said compo:>itions and products can additionally con-
tain a loop diuretic of the formula I in the free form,
or its physiologically tolerated salt, or a ACE inhibitor
in the free form, or its physiologically tolerated salt.
Preferred salts of compounds of the formula I are those
with compounds of the formula III or IV, in particular
those of piretanide or furosemide with ramipril or a com-
pound of the farmula IV with R4 = ethyl.
The salts of campounds of the formula I with compounds of
the formula V are prepared by dissolving stoichiometric
amounts of the reactants in a suitable solvent, and depo-
siting the salts in solid form by concentration, cooling
or addition of another solvent in which they are less
soluble. The salts can be processed to give compositions
or products in the manner described above.
The doses of the ACE inhibitor and of the loop diuretic
in the compositions or products according to the inven-
tion are each preferably selected so that the ACE inhi-
bitor and/or the loop diuretic would alone show no effect
or not a full effect. Thus, a dose of the loop diuretics
which is far below the ED50, for instance at its threshold
diuretic dose, suffices. The sufficient doses of the ACE
inhibitors as components are those which are at approxi-
mately the minimum dose adequate for plasma ACE inhibition
134~'~~~
,7
(for determination, see: Metzger et al., Arzneim.-Forsch./
Drug Res. 34 (:fI), 1402, 1403); thus, they can be below
those which are required for an acute lowering effect on
blood pressure when an ACE inhibitor is used alone.
S For the use according to the invention in mammals, pre-
ferably in humans, for example the doses of an ACE
inhibitor of the abovementioned formula III or IV range,
for example, from 0.05 to 2 mg/kg/day, and those of a
diuretic of the abovementioned formula I range from 0.2
to 25 mg/kg/day.
The compositions or products according to the invention
can be administered parenterally or orally. The oral
administration form is preferred.
The pharmacologically utilizable combinations of the pre-
sent invention and their salts can be used for the prep-
aration of pharmaceutical products which contain an ef-
fective amount of the active substances together with
vehicles, and which are suitable for enteral and paren-
teral administration. Use is preferably a~ade of tablets
or gelatin capsules which contain the active compounds
together with dliluents, for example lactose, dextrose,
sucrose, mannitol, sorbitol, cellulose and/or glycine,
and lubricants such as diatomaceous earth, talc, stearic
acid or its salts, such as magnesium or calcium stearate,
and/or polyethylene glycol. Tablets likewise contain
binders, such as magnesium aluminum silicate, starch,
gelatin, tragacanth, methylcellulose, sodium carboxymethyl-
cellulose and/or polyvinylpyrrolidone, and, if necessary,
pigment, flavorings and sweeteners.
Injectable solutions are preferably isotonic aqueous
solutions or suspensions which can be sterilized and may
contain auxiliaries such as preservatives, stabilizing
agents, wetting and/or emulsifying agents, solubilizers,
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18
salts to regulate the osmotic pressure and/or buffer
substances.
The pharmaceutical products according to the invention,
which may contain, if desired, further pharmacologically
valuable substances, are prepared by, for example,
conventional mixing, granulating and coating processes,
and contain 0.1% to about 75%, preferably about 1% to
about 50%, of the active compounds.
This entails the active compounds being mixed or dissol-
ved together with the abovementioned auxiliaries and addi-
tives in a mixing device at 5 - 50°C and then, for ex-
ample, compressed to form tablets or dispensed into gela-
tin capsules or ampoules.
The examples which follow serve to illustrate the present
invention without the latter being restricted to them.
Example 1
Effect of the combination of ramipril (=A) and piretanide
(=B) on the spantaneously hypertensive rat
10 spontaneously hypertensive rats (Wistar-Kyoto) are
attached to instruments and kept in metabolism cages
during the tests. Ramipril (=A> (1 mg/kg) and piretan-
ide (=B) (1.2 and 16 mg/kg) are administered orally in
Tylose using a stomach tube. The control group received
only Tylose. The amount of urine excreted after 5 hours,
the sodium excretion after 5 hours and the mean arterial
pressure were determined.
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19
Table 1 Excretion of urine over 5 hours
Amount of urine (ul/100g.5h)
Tylose (1ml/kg) 46065
A (1mg/kg) 760+185
B (1mg/kg) 900+180
B (2mg/kg) 1470+140
B (16mg/kg) 3520+405
A (1 mg/kg> + B (1 mg/kg) 1100+145
A (1 mg/kg) + B (2 mg/kg) 1545+130
A (1 mg/kg) + a (16 mg/kg) 3590285
Table 2 Excretion of sodium over 5 hours
mNa(X+SD+SEM) (mmol/150g.5h)
Tylose (1ml/kg) 0.0210.00090.003
A (1mg/kg> 0.080+0.049 +0.016
B (1mg/kg) 0.082+0.057 +0.021
B (2mg/kg) 0.156+0.063 +0.022
B (1bmg/kg) 0.462+0.146 +0.052
A (1 mg/kg) + B (1 mg/kg) 0.1570.050 0.321
A (1 mg/kg) + B (2 mg/kg> 0.1580.033 0.012
A (1 mg/kg) + B (1b mg/kg) 0.513+0.07b +0.031
The change in the mean blood pressure (MBPt) ss a X of
the initial blood pressure (MBPO> with time is shown in
Figure 1. The individual lines in this figure have
the following meanings:
;... , 1340722
Tylose (1 mg/kg): line h
A (1 mg/kg>: line a
B (1 mg/kg>: line b
B (2 mg/kg): line c
5 B (16 mg/kg): line d
A (1 mg/kg) + 8 (1 mg/kg): line g
A (1 mg/kg) + a (2 mg/kg>: line f
A (1 mg/kg) + B (16 mg/kg): line a
Example 2
10 Preparation of an oral combination product from ramipril
(=A) and piretanide (=B)
1,000 tablets containing 1 mg of each of A and a were
prepared using the following auxiliaries:
A 1 g
15 8 1 g
Corn starch 140 g
Gelatin 7.5 g
Microcrystalline cellulose 2.5 g
Magnesium stearate 2.5 g
20 A and B are mixed with an aqueous solution of gelatin.
The mixture is dried snd milled to form granules. Micro-
crystalline cellulose and magnesium stearate together with
corn starch are mixed with the granules. The resulting
granules are compressed to form 1,000 tablets, each tab-
let containing 1 mg of each of A and B.
Example 3
Preparation of a psrenteral combination product of rami-
pril (=A) and piretanide <=B)
134~72~
' 21
The preparation of an injection solution for the treat-
ment of hypertension is described below:
A 0.25 g
B 0.25 g
Methylparaben 5 g
Propylparaben 1 g
Sodium chloride 25 g
Water for injections 5 l
A, B, the preservatives and sodium chloride are dissolved
in water for injection and made up to 5 l with water for
injections. The solution is sterilized by filtration and
dispensed under aseptic conditions into pre-sterilized
bottles which are closed with sterilized rubber caps.
Each bottle contains 5 ml of solution.
Example 4
Preparation of an oral combination product of ramipril
(=A) and furosemide (=C)
1000 tablets which contain 5 mg of A and 20 mg of C were
prepared with l:he following auxiliaries:
A 5 g
C 20 g
Corn starch 140 g
Gelatin 7.5 g
Microcrystalline cellulose 2.5 g
Magnesium stearate 2.5 g.
A and C are mixed with an aqueous gelatin solution. The
mixture is dried and milled to form granules. hicrocrys-
talline cellulase and magnesium stearate together pith
corn starch sre mixed with the granules. The resulting
I
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22
_.~ granules are compressed to form 1000 tablets, each tablet
containing 5 mg of A and 20 mg of C.
Example 5
Preparation of an oral combination product of enalapril
(=D) and furosemide (=C)
1000 tablets containing 10 mg of D and 20 mg of C are
prepared with the following auxiliaries:
D 10 g
C 20 g
Corn starch 140 g
Gelatin 7.5 g
Microcrystalline cellulose 2.5 g
Magnesium stearate 2.5 g
D and C are mixed with an aqueous gelatin solution. The
mixture is dried and milled to form granules. Microcrys-
talline cellulose and magnesium stearate together with
corn starch are mixed with the granules. The resulting
granules are compressed to form 1000 tablets, each tablet
containing 10 mg of D and 20 mg of C.
Example 6
In analogy to Example 2, tablets containing 4 mg of rami-
pril and 1 mg of piretanide per tablet are prepared.
Example 7
In analogy to Example 2, tablets containing 0.5 mg of
ramipril and 5 mg of piretanide per tablet are prepared.
''~ ' 1340'22
23
Example 8
In analogy to Example 4, tablets containing 25 mg of rami-
pril and 30 mg of furosemide per tablet are prepared.
Example 9
In analogy to Example 4, tablets containing 1 mg of rami
pril and 25 mg of furosemide per tablet are prepared.
r
