NO863583L - PHARMACEUTICAL PREPARATION FOR TREATMENT OF HIGH BLOOD PRESSURE - Google Patents

Abstract

The preparation contains an angiotensin converting enzyme inhibitor and a loop diuretic.

Description

As is known, with inhibitors of Angiotensin-Converting

the enzyme (ACE inhibitors), such as captopril or enalapril,

high blood pressure is lowered in essential hypertensives (Therapie-woche 29 /1979/ 7746, Lancet 2 /1981/ 543-546). However, a certain percentage of essential hypertensives do not respond to such substances (Drug Devel. Eval. 4 /1980/ 82-91).

It is known that the antihypertensive effect of enalapril

or captopril is enhanced by the addition of diuretically effective amounts of a diuretic of the thiazide type or analogous compounds (Brunner et al., Clin. Exp. Hypertension 2

/1980/ 639-657, McGregor et al., Br. with. J. 284 /1982?

693-696). As a reason for this effect, it is usually assumed that the diuretic over a salt and volume loss stimulates the renin-angiotensin system (P. J. S. Chin et al., J. Pharm.

Pharmacol. 37 /1985/ 105).

In Arzneim.-Forsch./Drug Res. 34 (II) /1984/ 1417-1425 reports on investigations into the cardiovascular effect of 2-/N-/Ts)-l-carboxy-3-phenylpropyl/-L-alanyl/-(IS, 3S, 5S)-2- azabicyclo-/3 . 3. 0_7octane-3-carboxylic acid ("Ramiprilat") . Thereby, the animals were pre-treated for several days with furosemide or piretanide for reasons of sodium depletion. '"'*

It has now surprisingly been found that ACE inhibitors in combina-

treatment with loop diuretics in low doses is effective in lowering blood pressure.

The invention therefore relates to pharmaceutical preparations containing a) an Angiotensin-Converting-enzyme inhibitor or its physiologically tolerable salt and

b) a loop diuretic or its physiologically tolerable salt.

Loop diuretics within the scope of the invention include, for example

show furosemide. bumetanide, ethacrynic acid, etozolin and piretanide. As their names indicate, the main point of attack of these short but intensely effective diuretics is at the loop of Henle (compare Mutschler, Arzneimittelwirkungen, 4th edition, Stuttgart 1981, pages 486 and 487). As such, compounds of formula I come into particular consideration

in which

R"'" means chlorine or phenoxy,

R 2 means hydrogen, pyrrolidemo or n-butylamino and R 2 means hydrogen or 2-furylmethylamino.

Particularly preferred is piretanide (see formula II).

Suitable ACE inhibitors are, for example, described in US patents

4,129,571, 4,154,960, 4,374,829, EP-A-79522, 79022, 49658, 51301, US Patents 4,454,292, 4,374,847, EP-A-72352, US Patent 4,350,704, EP- A-50800, 46953, US Patent 4,344,949, EP-A-84164, US Patent 4,470,972, EP-A-65301 and 52991.

A large part of the ACE inhibitors known from the above-mentioned publications can be described by the general formula V

in which

n means 1 or 2,

R~* means hydrogen,

an optionally substituted aliphatic residue with 1-8 C atoms, an optionally substituted alicyclic residue with 3-9 C atoms, an optionally substituted aromatic residue with 6-12 C atoms, an optionally substituted aliphatic residue with 7-14 C atoms atoms, an optionally substituted alicyclic-aliphatic residue with

7-14 C atoms,

a residue OR cl or SR cl, wherein

Ra means an optionally substituted aliphatic residue with 1-4 C atoms, an optionally substituted aromatic residue with 6-12 C atoms, or an optionally substituted heteroaromatic residue with 5-12 ring atoms,

R^ means hydrogen,

an optionally substituted aliphatic residue with 1-6 C atoms, an optionally substituted alicyclic residue with 3-9 C atoms, an optionally substituted alicyclic-aliphatic residue with 4-13 C atoms,

an optionally substituted aromatic residue with 6-12 C atoms, an optionally substituted araliphatic residue with 7-16 C atoms, an optionally substituted heteroaromatic residue with 5-12 ring atoms or

the if necessary protected side chain of a natural

occurring ^-amino acid,

R 7 and R 8 are the same or different and mean hydrogen,

an optionally substituted alicyclic residue with 1-6 C atoms, an optionally substituted alicyclic residue with 3-9 C atoms, an optionally substituted aromatic residue with 6-12 C atoms, an optionally substituted araliphatic residue with 7-16 C- atoms, and

9 10

R and R, together with the atoms that carry them, form a heterocyclic, mono-, bi- or tricyclic ring system with 3-15 C atoms, as such ring systems particularly those of the following group come into consideration:

Tetrahydroisoquinoline (A), decahydroisoquinoline (B), octahydro-indole (C), octahydrocyclopenta/b/ (D), 2-azaspiro/4.5/decane (E), 2-azaspiro/4.4/nonane (F), spiro/Tbicyclo /2.2.1/heptane)-2,3-pyrrolidine/ (G), spiro/Tbicyclo/2 . 2. 2_7octane)-2,3-pyrrolidine/ (H), 2-azatricyclo/4.3.0.1 '_/decane (I), decahydrocyclo-hepta/b/pyrrole (J), octahydroisoindole (K), octahydrocyclo-penta/ c/pyrrole (L), 2,3,3a,4,5,7a-hexahydroindole (M), 2-aza-bicyclo/3.1.O/hexane (N), all of which may optionally be substituted. However, the unsubstituted systems which have the following structural formulas are preferred:

For the compounds which have several chiral atoms, all possible diastereomers such as racemates or enantiomers or mixtures of different diastereomers are taken into account. The S configuration of the C atoms marked with an asterisk is preferred.

Well suited are e.g. ACE inhibitors of formula V, wherein

n means 1 or 2,

R means hydrogen,

alkyl with 1-8 C atoms,

alkenyl with 2-6 C atoms,

cycloalkyl with 3-9 C atoms,

aryl with 6-12 C atoms,

which may be mono-, di- or tri-substituted with (C^-C^)-alkyl, (C^-C^)- alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C-^-C^ )- alkylamino. Di-(C-^-C^ )-alkylamino, (C-^-C^ )-alkanoylamino, methylenedioxy, carboxy, cyano and/or sulfamoyl,

alkoxy with 1-4 C atoms,

aryloxy with 6-12 C atoms,

which may be substituted as described above by aryl, mono- or bicyclic heteroaryloxy with 5-7 resp. 8-10 ring atoms, of which 1 to 2 ring atoms mean sulphur-

or oxygen atoms and/or 1 to 4 ring atoms means nitrogen,

which may be substituted as described above by aryl, amino-(C1~C4)-alkyl,

(C]_~C4 )-alkanoylamino-(C^-C^ )alkyl,

(C7~C]_3 )-aroylamino-(C-^-C^ )-alkyl,

(C-^-C^ )-Alkoxycarbonylamino-(C-^-C^ )-alkyl, (Cg-C12)-aryl-(C1~C4)-Alkoxycarbonylamino-(C1~C4)-alkyl, (C1 -C4)-alkylamino-(C1-C4)-alkyl,

Di-(C1~C4 )-alkylamino-(Cj^-C^^ )-alkyl,

guanidino-(C1~C4)-alkyl,

imidazolyl, indolyl,

(C1-C4)-alkylthio,

(C1~C4 J"alkYltio_(c1"c4)-alkyl,

■(C1-C4)-alkylthio-(C1-C4 )-alkyl,

(<C8-C>12)-arylthio-(C1-C4)-alkyl,

which may be substituted in the aryl part as described above by aryl,

(C 8 -C 12 )-aryl-(C 1 -C 4 )-alkylthio,

which in the aryl part may be substituted as described above by aryl,

carboxy-(C 1 -C 4 )alkyl,

carboxy, carbamoyl,

carbamoyl-(C-^-C4 )-alkyl,

(C1~C4)-Alkoxycarbonyl-(C1~C4)-Alkyl, (C8-C12)-Aryloxy-(C1-C4)-Alkenyl,

which in the aryl part may be substituted as described above by aryl, or

(C 8 -C 12 )-aryl-(C 1 -C 4 )-alkoxy,

which in the aryl part may be substituted as described above by aryl,

R means hydrogen,

alkyl with 1-6 C atoms,

alkenyl with 2-6 C atoms,

alkynyl with 2-6 C atoms,

cycloalkyl with 3-9 C atoms, e .:. cycloalkenyl with 5-9 C atoms,

(C3-C8)-cycloalkyl-(C1-C4)-alkyl,

(C5-C9)-cycloalkenyl-(C1~C4)-alkyl,

optionally partially hydrogenated aryl with 6-12 C atoms,

which may be substituted as described above by R, (<C>6<-C>12)-aryl-(C1-C4)-alkyl or (C7-C13)-aroyl-or C2)alkyl,

both of which can be substituted as the above-mentioned aryl, mono- or bicyclic, optionally partially hydrogenated hetero-aryl with 5-7 resp. 8-10 ring atoms, of which 1 to 2 ring atoms mean sulfur or oxygen atoms and/or 1 to 4 ring atoms mean nitrogen atoms,

which may be substituted as the above-mentioned aryl or the optionally protected side chain of a naturally occurring α-amino acid R<6->(CH(NH^)-COOH,

R 7 and R 8 are the same or different and mean

hydrogen,

alkyl with 1-6 C atoms,

alkenyl with 2-6 C atoms,

Di - (C1~C4 ) -alkylamino-(C-L~C4 ) -alkyl,

(C1-C5)-alkanoyloxy-(C1~C4)-alkyl,

(C^-Cg )-Alkoxy-Carbonyloxy-(C-^-C^ )-Alkyl, (C7~C13)-Aroyloxy-(C1-C4)-Alkyl,

(C 8 -C 4 )-aryloxycarbonyloxy (C-^-C 4 )-alkyl,

aryl with 6-12 C atoms,

(C 8 -C 12 )-aryl-(C 1 -C 4 )-alkyl,

(C3~C8)-cycloalkyl or

(C3-C8)-cycloalkyl-(C1-C4)-alkyl

and

9 10

R and R have the above meaning, preferably such ACE inhibitors of formula V, wherein

n means 1 or 2,

R<5> denotes (C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl, (C 3 -C 8 )-cycloalkyl,

amino-(C1-C4 )-alkyl, (C2~C5 )-acylamino-( C-^- C^ )-alkyl, (C7~C13)-aroylamino-(C1-C4)-alkyl, ( C^ C^ )-Alkoxy-carbonylamino-(C1-C4 )-alkyl, (c6-c12)-aryl-(C-^-C^ )-Alkoxycarbonylamino-(C^-C^)-alkyl, (cg"c12 ^~ ary ^ >

which can be mono-, di- or tri-substituted with (C^-C^)-alkyl, (C^-C4)-alkyloxy, hydroxy, halogen, nitro, amino, (C-^-C4 )-alkylamino, Di- (C 1 -C 4 )-alkylamino and/or methylenedioxy or means 3-indolyl, especially methyl, ethyl, cyclohexyl, tert. butoxycarbonylamino-(C^-C4)-alkyl, benzoyloxycarbonylamino-(C^-C4)-alkyl or phenyl,

which may be mono- or disubstituted by phenyl, (C^-C2)-alkyl, (C^-or C2)-aloxy, hydroxy, fluorine, chlorine, bromine, amino, (C^-C4)-alkylamino, Di-( C 1 -C 4 )alkylamino, nitro and/or methylenedioxy or in the case of methoxy,

may be trisubstituted,

R means hydrogen or (C-^-Cg-alkyl, which may optionally be substituted with amino, (C-^-Cg)-acylamino or benzoyl-amino or means (C2-Cg)-alkenyl, (-Cg)-cycloalkyl , (C5-C9)-cycloalkenyl, (C3-C?)-cycloalkyl-(C^-C^ )-alkyl, (Cg-C.^2)-aryl or partially hydrogenated aryl, which may respectively be substituted with (C 3 -C 4 )-alkyl, (C 3 or C 2 )-alkoxy or halogen or means (C 8 -C 3 -C 2 )-aryl-(C 3 to C 4 )-alkyl or (C 3 -C 4 )-aroyl -(C 1 -C 2 )-alkyl, both of which may be substituted as defined above in the aryl radical, a mono- or bicyclic heterocycle radical with 5 to 7 or 8 to 10 ring atoms, of which 1 to 2 ring atoms mean sulfur or oxygen atoms and /or 1 to 4 ring atoms means nitrogen atoms or means a side chain of a naturally occurring, optionally protected α-amino acid, in particular however hydrogen, (C 1 -C 3 )-alkyl, (C 2 or C 3 )-alkenyl, the optionally protected side chain of lysine, benzyl, 4-methoxybenzyk, 4-ethoxybenzyl, phenethyl, 4-amino-butyl or benzoylmethyl,

R 7 and R 8 are the same or different residues and mean hydrogen,

(C 1 -C 8 )-alkyl, (C 2 -C 8 )-alkenyl or (C 8 -C 12 )-aryl-(C 1 -C 4 )-alkyl, especially however hydrogen, (C 1 -C 4 )-alkyl or benzyl, and 9 10 R and R have the above meaning, especially such ACE inhibitors of formula V, in which n means 2, R^ means phenyl,

g

R means methyl,

R 7 and R 8 mean the same or different (C 1 -C 8 -alkyl radicals or (C 1 -C 2 -aralkyl radicals such as benzyl or nitrobenzyl, and

9 10

R and R together mean a residue with formula

where m = 0 or 1, p = 0, 1 or 2, and X = -C^-,

-CH2-CH2- or -CH=CH-, one with X also forming a 6-ring

may be a benzene ring.

By aryl, here as in the following, it is preferably understood to mean optionally substituted phenyl, biphenylyl or naphthyl. The same applies to residues derived from aryl such as aryloxy, arylthio. By aroyl is meant in particular benzoyl. Aliphatic residues can be straight or branched.

With a mono or bicyclic heterocyclene residue with 5 to 7 resp. 8 to 10 ring atoms, of which 1 to 2 ring atoms mean sulfur or oxygen atoms and/or of which 1 to 4 ring atoms mean nitrogen atoms, for example thienyl, benzo/b/thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinoli-nyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, quinolinyl, fteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. These residues can also be partially or completely hydrogenated.

Naturally occurring «-amino acids are e.g. described in Houben-Weyl, Methoden der Organischen Chemie, volumes XV/1 and XV/2 .

If R"'" means a side chain of a protected naturally occurring ct-amino acid, such as e.g. protected Ser, Thr, Asp, Asn, Glu, Gin, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp,

as protective groups, the groups common in peptide chemistry are preferred (compare Houben-Weyl, volumes XV/1 and XV/2).

In the case that R"<*>" means the protected lysine side chain, the known amino protecting groups are preferred, especially however Z, Boe or (C1,-Cb r )-alkanoyl. The O-protecting group for tyrosine is preferably (C 1 -C 8 )-alkyl, especially methyl or ethyl.

ACE inhibitors of formula V can be prepared by reacting their fragments with each other in a suitable solvent, possibly in the presence of a base and/or a coupling aid, possibly reducing intermediately formed unsaturated compounds, such as Schiff's bases and for the protection of reactive groups temporarily cleaves off inserted protecting groups and transfers the formed compounds optionally in their physiologically tolerable salts.

Compounds with formula VI can be converted in the aforementioned manner

with compounds of formula VII.

The conversion of these compounds can, for example, be carried out analogously to known peptide coupling methods in the presence of coupling aids, such as carbodiimides (e.g. dicyclohexylcarbodiimide), diphenylphosphoroylazide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or N,N-succinimidyl carbonates in CH^CN. Amino groups in compounds of formula VI can be activated with tetraethyl diphosphite" The compounds of formula VII can be transferred to active esters (e.g. with 1-hydroxybenzotriazole), mixed anhydrides (e.g.

with chloroformate esters), azides or carbodiimide derivatives and are thus activated (compare Schroder, Liibke, The Peptides, vol. 1, New York 1965, pages 76-136).

Likewise, it is also possible to react compounds of formula VII<1> with compounds of formula VIII to form compounds of formula V in which either Y 1 means amino and Y 2 a cleavable group or Y 1 means a cleavable group and Y 2 means amino. Suitable cleavable groups are e.g. Cl, Br, J, alkylsulfonyloxy or arylsulfonyloxy.

Alkylations of this type are conveniently carried out in water or an organic solvent in the presence of a base.

Furthermore, compounds of formula IX can be condensed with compounds of formula X

1 2

wherein either Q means amino + hydrogen and Q means oxo or Q 1 means oxo and Q 2 means amino + hydrogen. The condensation is conveniently carried out in water or an organic solvent, such as a lower alcohol, in the presence of a reducing agent, such as NaBH^CN, as compounds of formula V are directly obtained. However, the Schiff's bases formed as intermediates can also be reduced or anamines optionally after previous isolation to form compounds of formula V, for example by hydrogenation in the presence of a transition metal catalyst.

Finally, the reaction of compounds of formula IX (Q<1>= H + NH2) with compounds of formula XI or their reaction with compounds of formula XII and XIII also leads

to compounds of formula V (n=2).

as intermediately formed Schiff bases are reduced and a carbonyl group is reductively transferred into the methylene. In the above-mentioned formulas VI - XIII, R^-R"^ and n are as defined for formula V. Protective groups introduced temporarily to protect reactive groups not participating in the reaction are cleaved off after completion of the reaction in a manner known per se (compare Schroder, Lubke , see above, pages 1-75 and 246-270). Orally active ACE inhibitors such as ramipril, enalapril, captopril, lisinopril, perindopril, cilazapril, RHC 3659, CGS 13945, CGS 13928C, CGS 14824A are advantageous. , CI-906, SCH 31846, sofenopril, fosenopril, alacepril and others. Orally active ACE inhibitors are discussed, for example, in Brunner et al., J. Cardiovasc. Pharmacol. 7 (suppl. I) (1985) pp. 2-11 ............ Preferred are the ACE inhibitors of formula III known from EP-A-79022

in which

R means hydrogen, methyl, ethyl or benzyl,

especially the compound of formula III, wherein R=ethyl (ramipril).

Further preferred are the ACE inhibitors of formula IV known from EP-A-84164

in which

R 4 means hydrogen, (C 1 -C 1 )-alkyl or benzyl, in particular

the compound of formula IV, in which R 4=ethyl.

Preferred preparations according to the invention are thus those which contain a compound of formula IV with R 4 = ethyl together with piretanide or furosemide, especially those which contain ramipril together with piretanide and ramipril together with furosemide.

The combination of ACE inhibitors and loop diuretics has a strong and persistent blood pressure-lowering effect and can therefore be used to treat high blood pressure of various origins.

Of particular interest is the fact that the effects of the two components are not additive, rather a synergistic effect has been observed. In the spontaneously hypertensive rat, the combination of doses of an ACE inhibitor such as ramipril already leads to a lowering of blood pressure, which alone has no effect, when combined with doses of a loop diuretic such as pyretanide, which alone has no diuretic effect (subdiuretic dose). This shows that loop diuretics, especially compounds of the above-mentioned formula I, which manage to stimulate the renin-angiotensin system, without showing a diuretic and saluretic effect. Such an effect is not achieved with compounds of the hydrochlorothiazide type.

For the aforementioned reasons, the preparation according to the invention is superior to the individual components in the treatment of high blood pressure, as they make it possible to add smaller doses of the components and thus reduce any toxicological problems.

The invention also relates to a method for producing such a preparation, the method being characterized by

a) an angiotensin-converting-enzyme inhibitor or its physiologically tolerable salt and b) a loop diuretic or its physiologically tolerable salt, are brought together with physiologically tolerable carriers and possibly further auxiliaries or additives in a suitable administration form. The invention also generally relates to products containing a) an angiotensin-converting enzyme inhibitor or its physiologically tolerable salt and b) a loop diuretic or the physiologically tolerable salt, preferably in a subdiuretic dose,

as a combination preparation for simultaneous, separate or temporally staggered use in the treatment of high blood pressure.

The weight ratio of ACE inhibitor:loop diuretic in the aforementioned preparations and products varies according to the activity of the active substance, preferably between 10:1 and 1:500. For ramipril (=A) + piretanide (=B) e.g. A:B preferably ranges between 4:1 and 1:10, especially between 2:1 and 1:3. In contrast, with ramipril (=A) + furosemide (=C), the A:C ratio is preferably 1:1 to 1:200, especially 1:4 to 1:40.

Loop diuretics of formula I formed due to its pK a value (pKa of furosemide: 3.8) salts with ACE inhibitors of formula V, the compound of formula I passing into its cation during protonation of the NH- adjacent to CHR function in the compound of formula V. If the compound with

7 8

formula V (R and/or R = H) exists as a zwitterion, a carboxylate function is protonated.

The invention therefore also relates to a salt of a loop diuretic of formula I with an ACE inhibitor as well as pharmaceutical preparations and products containing such a salt of a compound of formula V. If necessary, the said preparations and products can additionally contain a loop diuretic with formula I in free form or its physiologically tolerable salt or an ACE inhibitor in free form or its physiologically tolerable salt.

Preferred are salts of compounds of formula I with for r bonds of formula III or IV, especially those of piretanide or furosemide with ramipril or a compound of

4

formula IV with R=ethyl.

The salts of the compounds of formula I are prepared with compounds of formula V, by dissolving stoichiometric amounts of the reaction participants in a suitable solvent and by evaporation, cooling or the addition of a further solvent, in which the salts are less soluble, these are separated in solid form . The salts can be processed into preparations or products in the above-mentioned manner.

The doses of the ACE inhibitor and the loop diuretic in the preparations resp. the products according to the invention are preferably chosen respectively so that the ACE inhibitor and/or the loop diuretic alone would not yet show any or no full effect. Thus, with loop diuretics, a dose that is far below the ED^Q value is already sufficient, e.g. at its diuretic threshold dose. The ACE inhibitors as components can already be used in doses such as e.g. lies at the minimal dose for a sufficient plasma ACE inhibition (determine see: Metzger et al., Arnzeim.-Forsch./Drug Res. 34 (II), 1402, 1403), they may thus lie below such

which alone are necessary for an acute blood pressure-lowering effect

ning when using an ACE inhibitor.

In the application according to the invention in mammals, preferably

show in humans, for example, the doses of an ACE inhibitor

tor of the above-mentioned formula III or IV in the range of 0.05 to 2 mg/kg/day and of a loop diuretic of the above formula I in the range of 0.2 to 25 mg/kg/day.

The preparations resp. the products according to the invention can be administered parenterally or orally. The oral application form is preferred.

The pharmacologically applicable combinations of the present invention and their salts can be used for the production of pharmaceutical preparations which contain an effective amount of the active substances together with carriers and which are suitable for enteral and parenteral administration. Preferably used

tablets or gelatin capsules, which contain the active substances together with diluents, e.g. lactose, dex-

trose, cane sugar, mannitol, sorbitol, cullulose and/or glycine and lubricants such as silica, talc, stearic acid or its salts, such as magnesium or calcium stearate and/or polyethylene glycol. Tablets also contain binders such as magnesium aluminum silicates, starch,

gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and, if necessary, colouring, flavorings and sweeteners.

Injectable solutions are preferably isotonic aqueous solutions or suspensions, which may be sterilized and may contain auxiliary substances such as preservatives, stabilisers, wetting agents and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffer substances.

The pharmaceutical preparations according to the invention which, if desired, can contain further pharmacologically valuable substances, are prepared, e.g. using common mixing, granulating and coating methods and containing 0.1% to approx. 75%, preferably approx. 1% to approx. 50% of the active substance.

Thereby, the active substances are mixed or dissolved together with the above-mentioned auxiliaries and additives in a mixing device at 5-50°C and then pressed, for example, into tablets or filled into gelatin capsules or ampoules.

The invention will be explained in more detail with the help of some examples.

Example_l

Effect of the combination of ramipril (=A) and piretanide

(=B) on the spontaneously hypertensive rat.

10 spontaneously hypertensive rats (Wistar-Kyoto) were instrumented and kept in metabolic cages during the experiment. Ramipril (=A) (1 mg/kg) and piretanide (=B) (1.2 and 16 mg/kg) are administered in tylose orally by stomach tube. The control group only receives tylose. The amount of urine excreted after 5 hours, the sodium excretion after 5 hours and the mean arterial pressure were determined.

The figure shows the time course of the average blood pressure (MBP) in % of the initial blood pressure (MBP). Thereby, the individual curves have the following meanings:

Eczema Gel_2_

Preparation of an oral combination preparation of ramipril (=A) and piretanide (=B).

1000 tablets, each containing 1 mg A and B, are prepared with the following aids:

A and B are mixed with an aqueous gelatin solution. The mixture is dried and ground into a granule. Microcrystalline cellulose and magnesium stearate as well as corn starch are mixed with the granulate. The formed granules are pressed into 100 tablets, each tablet containing 1 mg of A and B each.

Example_el_3

Preparation of a parenteral combination preparation of ramipril (A) and piretanide (=B).

The preparation of an injection solution for the treatment of hypertension is described in the following:

A, B, the preservatives and sodium chloride are dissolved in water for injection and filled with water for injection to 5 1. The solution is sterile filtered and aseptically filled in pre-sterilized bottles that are closed with sterilized rubber stoppers. Each bottle contains 5 ml of solution.

Example<p>el_4

Preparation of an oral combination preparation of ramipril (=A) and furosemide (=B).

1000 tablets containing 5 mg A and 20 mg C were prepared with the following aids:

A and C are mixed with an aqueous gelatin solution. The mixture is dried and ground into a granule. Microcrystalline cellulose and magnesium stearate as well as corn starch are mixed with the granulate. The formed granules are pressed into 1000 tablets, each tablet containing 5 mg A and 20 mg C.

Example_el_5

Preparation of an oral combination preparation of enalapril (=D) and furosemide (=C).

1000 tablets containing 10 mg D and 20 mg C are prepared with the following aids:

D and C are mixed with an aqueous gelatin solution. The mixture is dried and ground into a granule. Microcrystalline cellulose and magnesium stearate as well as corn starch are mixed with the granulate. The formed granules are pressed into 1000 tablets, each tablet containing 10 mg D and 20 mg C.

Example_el_6

Analogously to example 2, tablets are produced, which per

tablet contains 4 mg ramipril and 1 mg piretanide.

Example_7

Analogously to example 2, tablets are produced, which per

tablet contains 0.5 mg ramipril and 5 mg piretanide.

Example_el_8

Analogously to example 4, tablets are produced, which per

tablet contains 25 mg ramipril and 30 mg furosemide.

Example_el_9

Analogously to example 4, tablets are prepared, which contain 1 mg ramipril and 25 mg furosemide per tablet.

Claims (10)

1. Process for the production of a pharmaceutical preparation containing a) an Angiotensin-Converting-enzyme inhibitor or its physiologically tolerable salt and b) a loop diuretic or its physiologically tolerable salt, characterized by a) an Angiotensin-Converting-enzyme inhibitor or its salt and b) a loop diuretic or its salt is brought together with a physiologically acceptable carrier and possibly further auxiliaries or additives into a suitable administration form. 2. Method according to claim 1, characterized in that a subdiuretic dose of the loop diuretic or its salt is added. 3. Method according to claim 1 or 2, characterized in that a preparation containing a loop diuretic of formula I in which R means chlorine or phenoxy, R 2 means hydrogen, pyrrolidino or n-butylamino and R 3 means hydrogen or 2-furylmethylamino. 4. Method according to one of claims 1-3, characterized in that a preparation containing a loop diuretic of formula II or II' is prepared 5. Method according to one of claims 1-4, characterized in that a preparation containing an Angiotensin-Converting enzyme inhibitor of formula III is produced in which R means hydrogen, methyl, ethyl or benzyl, or containing an Angiotensin-Converting Enzyme Inhibitor of Formula IV in which R 4 means hydrogen, (C 1 -C 4 )-alkyl or benzyl. 6. Method according to one of claims 1-5, characterized in that a preparation containing an Angiotensin-Converting enzyme inhibitor of formula III or IV or its physiologically tolerable salt is prepared, wherein R resp. R 4 means ethyl. 7. Process for the preparation of a product containing a) an Angiotensin-Converting-enzyme inhibitor or its tolerable salt and b) a loop diuretic or its physiologically tolerable salt as a combination preparation for simultaneous, separate or temporally staggered use in the treatment of high blood pressure, characterized in that the two components are respectively brought together with a physiologically acceptable carrier and possibly further auxiliaries or additives in a suitable administration form. 8. Method according to claim 7, characterized in that the loop diuretic or its salt is added in a subdiuretic dose. 9. Method according to claim 7 or 8, characterized in that it is carried out with components that are defined as in one of claims 3-6. 10. Process for the preparation of a salt of a) an Angiotensin-Converting-enzyme inhibitor and b) a loop diuretic of formula I, wherein R 1 , R 2 and R 3 has the meaning specified in claim 3, characterized in that an Angiotensin-Converting-enzyme inhibitor is reacted with a loop diuretic of formula I.