Use of a combination of an angiotensin-creating enzyme inhibitor and calcium antagonist for application at albuminuria

(54) Use of a combination of an angiotensin enzyme inhibitor and a calcium antagonist for administration to proteinuria

The invention relates to the use of an angiotensin enzyme (ACE-inhibitor) in combination with a calcium antagonist for the prevention and therapy of proteinuria.

JUDr. Miloš VŠETEČKA attorney

115 From PRAGUE 1, Žitná 25

<img file="CS9103587A3_D0001.tif" />

<img file="CS9103587A3_D0002.tif" />

Use of a combination of an angiotensin-forming enzyme inhibitor and a calcium antagonist for administration in proteinuria

Technical field

The invention relates to the prevention and therapy of proteinuria (urinary excretion of proteins) by the combined dosing of an angiotensin-converting enzyme inhibitor (Angiotensin-Converting-Snzyme-Inhibitor = ACE-inhibitor) and a calcium antagonist.

BACKGROUND OF THE INVENTION

Angiotensin-forming enzyme inhibitors (ACE-inhibitors) are compounds that suppress the conversion of Angiotensin I to the presorically active angiotensin II. Such compounds are described, for example, in the following patent publications or published patent applications:

US Pat. No. 4,350,633, U.S. Pat. No. 4,344,949, US Pat. No. 4,294,832, U.S. Pat. EP-A 31 741

EP-A 51,020, EP-A 49,658, EP-A 29,488, EP-A 46,953, EP-A 52,870, US Pat. No. 4,129,571, U.S. Pat. No. 4,154,960, U.S. Pat. No. 4,374,829, EP-A 79 522, EP-A 79 022,

EP-A 51 301, U.S. Pat. No. 4'454 292, US Pat. C.

374 847, EP-A 72 352, EP-A 84 164, U.S. Pat. C.

470 972, EP-A 65 301 and EP-A 52 991. Their blood pressure lowering effects are well documented.

Calcium antagonists are such compounds, ι

- 2 which affect the supply of calcium ions to cells, especially smooth muscle cells. Such compounds, as well as their blood pressure lowering effects, have been documented in a large number of publications and patents.

Combinations of ACE inhibitors and calcium antagonists and their use at high blood pressure are known, for example, from EP-A 180 7S5 and EP-A 265 685.

Urinary protein excretion occurs especially in diseases of kidney tissue (nephritis, nephrosis, renal contraction) and kidney filling due to insufficient heart function. In addition to albumins, globulins and white blood cells also enter the urine. The highest levels of proteinuria occur in nephrosis and amyloidosis. Constant proteinuria in diabetes melitus points to the development of intercapillary sclerosis (glomerulosclerosis, Kimmelstiel-Wilson syndrome).

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that the combination of an angiotensin-forming enzyme inhibitor (ACE-inhibitor) and a calcium antagonist is suitable for the prevention and therapy of proteinuria, which may typically occur in diabetes mellitus and kidney weight loss (donor kidney), but also as a consequence glomerulosclerosis (intercapillary sclerosis) due to glomerular hyperfusion. Orally active ACE inhibitors are preferred, such as Rampiril, enalapril, Captopril, Alacepril, Benazepril, Ceranapril, Cilazapril, Delapril, Posinopril, Imidapril, Libenzapril, Lisinopril, Moexipril, Moveltipril, Perindopril, Quilapril, Quinapril, Quinapril, Quinapril, Quinapril, CS 622, 36378, PPL 63547,

- 3 S 9650 and others. Orally active ACE inhibitors are described, for example, in Pharmacology of Antihypertensive Theaperutics / Eds. D. Ganten, PJ Mutrow / Springer Verlag, Berlin 1990, pp. 377-480.

Suitable ACE inhibitors are the following compounds of the formula I or their physiologically acceptable salts:.

C + - CH-NC-CH-NH-CH- / CH_O/ - R / 1 /

II II II

R⁴ R⁵ 0 R¹ C00R² where n is 1 or 2,

R is a hydrogen atom optionally substituted aliphatic radical of 1 to 8 carbon atoms, optionally substituted alicyclic radical of 3 to 9 carbon atoms, optionally substituted aromatic radical of 6 to 12 carbon atoms, optionally substituted araliphatic radical of 7 to 14 carbon atoms, optionally substituted alicyclic a sucammac aliphatic radical having 7 to 14 carbon atoms, or an OR group^and or SR^and , whereas

R^and denotes an optionally substituted aliphatic radical having 1 to 4 carbon atoms or an optionally substituted aromatic radical

- 4 to 6 to 12 carbon atoms or an optionally substituted 5 to 12 ring heteroaromatic radical,

R¹ a hydrogen atom, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 3 to 9 carbon atoms, an optionally substituted alicyclic aliphatic radical having 4 to 13 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, optionally substituted an araliphatic radical having 7 to 16 carbon atoms, an optionally substituted heteroaromatic radical having 5 to 12 ring atoms, or optionally a protected side chain of a naturally occurring alpha-amino acid,

3

R and R^J which are the same or different, a hydrogen atom, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 3 to 9 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, an optionally substituted araliphatic radical having 7 to 16 carbon atoms carbon atoms and

R 1 and R 2 together with the carrier atoms are a heterocyclic monocyclic, bicyclic or tricyclic ring system of 3 to 15 carbon atoms, the following being particularly suitable as ring systems:

tetrahydroisoquinoline (A), halohydroisoquinoline (Β), octahydroindole (0), octahydrocyclopenta (b) pyrrole (D), 2-azaspiro (4,5) decane (E), 2-azaspiro [4.4] nonane (P), spiro) bicyclo / 2,2 / heptane / -2,3 "pyrrolidine / G /, spiro / bicyclo / 2,2,2 / octane / -2,3-pyrrolidine / H /, 2-azatricyclo / 4,3» 0 » 16'9 (decane / 1), decahydrocyclohepta (b) pyrrole (J), octahydroisoindole (K), octahydrocyclopehta (c) pyrrole (L), 2,3,3a, 4 »5,7a-hexahydroindole (Μ), 2-azabicyclo [3.1.1.0] hexane (N), hexahydrocyclopenta (b) pyrrole (0), pyrrolidine (R), thiazolidine (Q), all of which may be optionally substituted. However, unsubstituted systems having the following structures are preferred:

COOR³

I / A /

R

<img file="CS9103587A3_D0003.tif" />

<img file="CS9103587A3_D0004.tif" />

<img file="CS9103587A3_D0005.tif" />

/ D /

<img file="CS9103587A3_D0006.tif" />

<img file="CS9103587A3_D0007.tif" />

/ G / 1 /

<img file="CS9103587A3_D0008.tif" />

COOR '/ J /

<img file="CS9103587A3_D0009.tif" />

<img file="CS9103587A3_D0010.tif" />

/ Μ /

<img file="CS9103587A3_D0011.tif" />

/ Ν /

<img file="CS9103587A3_D0012.tif" />

<img file="CS9103587A3_D0013.tif" />

For compounds having chiral atoms, all possible diastereoisomers, such as racemates or enantiomers, or various mixtures of different diastereoisomers are contemplated. The S-configuration of the carbon atoms marked with a cross in formula (1) is preferred.

Preferred are AEC inhibitors of formula I wherein n is 1 or 2,

R is hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 9 carbon atoms, aryl of 6 to 12 carbon atoms, which may be monosubstituted, disubstituted or trisubstituted with an alkyl group (C 1 -C 4) -alkoxy, (C 1 -C 4) -alkoxy, hydroxy, halogen, nitro, amino, amino-ethyl, (C 1 -C 4) alkylamino, further (C 1 -C 4) alkoxy, (C 6 -C 12) aryloxy, which may also be substituted as above, monocyclic or bicyclic heteroaryloxy (C 5 -C 7), optionally 8 up to 10 ring atoms, wherein 1 to 2 ring atoms denote sulfur or oxygen atoms and / or 1 to 4 ring atoms denote a nitrogen atom, wherein the aryl group may be substituted as above, (C 1 -C 4) aminoalkyl, (C 1 -C 4) alkanoylaminoalkyl (C 1 -C 4) alkanoyl and alkyl, (C 1 -C 4) aroyl (C 1 -C 4) aroyl and (C 1 -C 4) alkyl, (C 1 -C 4) alkoxycarbonylaminoalkyl

- 11 to 4 carbon atoms in both the alkoxy and alkyl moieties, arylalkoxyctohonylaminoalkyl group having 6 to 12 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in both the alkoxy moiety and the alkyl moiety, an alkylaminoalkyl group having 1 to 4 carbon atoms in both alkyl moieties, dialkylaminoalkyl of 1 to 4 carbon atoms in all alkyl moieties, guanidinoalkyl of 1 to 4 carbon atoms in the alkyl moiety, imidazolyl group, indolyl, alkylthio of 1 to 4 carbon atoms, alkylthioalkyl of both alkyl moieties, arylthioalkyl of 6 to 12 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the alkyl moiety, wherein the aryl moiety may be substituted as above, arylalkylthio having from 6 to 12 carbon atoms in the aryl moiety of about 4 to 4 carbon atoms in the alkyl moiety, wherein the aryl moiety may be substituted as described above, (C 1 -C 4) carboxyalkyl, carboxyl, carbamoyl, (C 1 -C 4) carbamoylalkyl, (C 1 -C 4) alkoxycarbonylalkyl, aryl group, aryl a (C6 -C12) alkoxy alkyl group having from 1 to 4 carbon atoms in the alkyl moiety, wherein the aryl moiety may be substituted as described above, arylalkoxy of 6 to 12 carbon atoms in the aryl moiety and of 1 to 4 carbon atoms in the alkyl moiety, wherein the aryl moiety may be substituted as above, a hydrogen atom, an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms atoms, C 2 -C 6 alkynyl, C 3 -C 9 cycloalkyl, C 5 -C 9 cycloalkenyl, C 3 -C 9 cycloalkylalkyl having 1 to 4 carbon atoms in the alkyl moiety, C 5 -C 9 cycloalkenylalkyl having 1 to 4 carbon atoms in the alkyl moiety, C 6 -C 12 aryl groups optionally partially hydrolyzed, which may be substituted as described above for R, (C 6 -C 12) arylalkyl having 1 to 4 carbon atoms in the alkyl moiety, wherein the aryl moiety may be substituted as described above, (arylalkyl) having 7 to 13 carbon atoms in the aroyl moiety and having 1 to 5 carbon atoms; or 2 carbon atoms in the alkyl moiety, wherein the aryl moiety may be substituted as above, with a monocyclic, optionally bicyclic, optionally partially hydrogenated C 5 -C 7 heteroaryl group, optionally with 3 to 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and / or 1 to 4 ring atoms are nitrogen atoms, and may be substituted as above for an aryl group, or optionally protected lateral chain of naturally occurring alpha-amino acids r¹-ch / nh₂/ -cooh,

R1 and R2⁵ which are the same or different, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a dialkylamino group having 1 to 4 carbon atoms in all alkyl moieties, and an acanoyloxyalkyl group having 1 to 5 carbon atoms in alkanoyl C 1 -C 4 alkyl moieties, C 1 -C 4 alkoxycarbonyloxyalkyl, both in the alkoxy group and in the alkyl group, (C až-C 12) aryl-Cal-Cry aryl, (C až-C 4) aryloxycarbonyloxyalkyl (C až-C 4 4) aryl group, C až-C 12ry (Cry-Cry) aryl group , arylalkyl having 6 to 12 carbon atoms in the aryl portion and 1 to 4 carbon atoms in the alkyl portion, cycloalkyl of 3 to 9 carbon atoms, or cycloalkylalkyl of 3 to 9 carbon atoms in the cycloalkyl moiety and 1 to 4 carbon atoms in the alkyl moiety;

R * and R6 are as defined above.

Particularly preferred are compounds of formula I wherein n is 1 or 2,

R (C 1 -C 4) alkyl, (C 2 -C 6) alkenyl, (C 3 -C 9) cycloalkyl, (C 1 -C 4) aminoalkyl, (C 2 -C 5) acyl amino group; up to 4 carbon atoms in the alkyl moiety, an aroylaminoalkyl group having 1 to 13 carbon atoms in the aroyl moiety and 1 to 4 carbon atoms in the alkyl moiety, (C 1 -C 4) alkoxycarbonylaminoalkyl group having 1 to 4 carbon atoms in the alkyl moiety, a (C 6 -C 12) aryl alkoxycarbonylaminoalkyl group having 1 to 4 carbon atoms in the alkoxycarbonyl and alkyl moieties, a (C 6 -C 6) aryl group 12 carbon atoms which may be monosubstituted, disubstituted or trisubstituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl, halogen, nitro, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino and / or methylenedioxy, or 3-indolyl, in particular methyl, ethyl, cyclohexyl, a tert-butoxycarbonylaminoalkyl group having 1 to 4 carbon atoms in the alkyl moiety, a benzoyloxycarbonylaminoalkyl group having 1 to 4 carbon atoms in the alkyl moiety, or a phenyl group which may be monosubstituted or disubstituted with phenyl, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, hydroxyl, fluoro, chloro, bromo, amino, C 1 -C 4 alkylamino, dialkylamino in each case having 1 to 4 carbon atoms, nitro and / or methylenedioxy or, in the case of methylenedioxy, also trisubstituted,

R @ 4 is hydrogen, C1 -C4 alkyl optionally substituted by amino, C1 -C8 acylamino or benzoylamino, C2 -C8 alkenyl, C3 -C9 cycloalkyl, (C 5 -C 9) cycloalkenyl, (C 3 -C 7) cycloalkylalkyl, and C 1 -C 4 alkyl, (C až-C 12) aryl or partially hydrogenated (C být-Cryry) aryl group which may be substituted by C až-C alky alky alkyl, C nebo-C 2 (C alko nebo) alkoxy or halogen, C až-C 12 12 (C až-Cryry) aryl group and having 1 to 4 carbon atoms in the al16 keel or an aroylalkyl group having 7 to 13 carbon atoms in the aroyl moiety and 1 to 2 carbon atoms in the alkyl moiety, both of the above aryl radicals may be substituted as mentioned above, a monocyclic or bicyclic heterocyclic radical having 5 to 7 carbon atoms or 8 to 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen and / or 1; up to 4 ring atoms denote nitrogen atoms or a side chain of naturally occurring, optionally protected amino acids, in particular a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, alkenyl of 2 or 3 carbon atoms, optionally protected lysine side chain, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenylethyl, 4-aminobutyl or benzoylmethyl,

R² and R ^ are the same or different from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms or arylalkyl of 6 to 12 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the alkyl Parts, in particular hydrogen, C1-C4alkyl or benzyl; _and the above meaning.

Preferably R ^ and R ^ together denote the remainder of the patternWWW β »%

-fr

- 17 - /

<img file="CS9103587A3_D0014.tif" />

- / CH₂/ m in which m denotes zero or one xsfcaxdxisgdaa p denotes zero, one or two, and

X is -CHg-, -CHg-Cl-, or -CH = CH-, wherein the six-membered ring formed by X is a benzene ring.

As used herein, the term "aryl" refers in particular to an optionally substituted phenyl, biphenyl or naphthyl group. This applies correspondingly to residues derived from an aryl group such as aryloxy, arylthio. Aroyl is especially understood to mean benzoyl. The aliphatic residues may be straight or branched.

Monocyclic or bicyclic heterocyclic radicals are those having 5 to 7 carbon atoms or 8 to 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen and / or 1 to 4 ring atoms are nitrogen atom means, for example, thienyl, benzo (b) thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imida18 zolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquininyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridyl, isoxazyl, oxazolyl or an isothiazolyl group. Said residues may also be partially or completely hydrogenated. For example, naturally occurring alpha-amino acids are described in Houben-7 / yl, Methoden der Organischen Chemie, Vol. XV / 1 and XV / 2.

If R^2- denotes the pxx side chain of protected naturally occurring alpha-amino acids, such as protected Ser, Thr, Asp, Asn, Glu, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp, as protecting groups preferred groups common in peptide chemistry (see Houben-Weyl, Vol. XV / 1 and XV / 2).

In case R² is a protected side chain of lysine, known amino protecting groups, in particular Z, Boc or C1-C6-alkyl, in particular methyl or ethyl, are suitable.

Particularly preferred are 2- (N- (1-Sephoxycarbonyl-3-phenylpropyl) -5-alanyl) - (1-S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3- acid compounds. carboxylic acid (Rampiril), 1- (N) -1-S-ethoxycarbonyl-3-phenylpropyl (-S-alanyl) - (2S, SaR, 7aS) -octahydro (1H) indole-2-carboxylic acid (Trandolapril), acid 2- (N- (L-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl) -1,2,3,4-tetrahydroisoquinoline-3-S-carboxylic acid (Quinapril), ΤΤ'- 19 1-Ν - (1-S-ethoxycarbones of 1-3-phenylpropyl) -S-alanyl-S-proline (Enalapril),

1- (N- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-lysyl) -S-proline (Lisinopril), 1- (N- (1-S-thoxycarbonyl-n-butyl) -S-) - alanyl] - (2S, 3aS, 7aS) -octahydro (1H) indole-2-carboxylic acid (Perindopril) as well as the corresponding dicarboxylic acids. Orally active ACE-inhibitors are preferred, such as Rampiril, Enalapril, Captopril, Alacepril, Benzazepril, Ceranapril, Cilazapril, Delapril, Posinapril, Imdapril, Libenzapril, Lisinopril, Moexipratl, Moveltipril, Perindopril, Qu35april, Qu35april, Qu35april, Qu35april .

For example, compounds of formula I may be prepared by reacting a compound of formula V with a compound of formula VI

R³OOC-CH / R⁴/ - NHR⁵ /IN/

HOOC-CH / R¹/ - NH - CH / COOR²/ - / CH₂/_n - R / VI /.

For example, the reaction of these compounds may be carried out analogously to known coupling procedures in peptide chemistry in an organic solvent such as dimethylformamide, dichloromethane or DMA in the presence of a coupling agent such as carbodiimides (e.g. dicyclohexylcarbodiimide), diphenylphospharylazide, alkanephosphonic anhydrides or Ν, Ν-succinimidyl carbonates, in a solvent such as CH 2 CN. The amino groups in the compounds of formula (V) may be activated by tetra (O).

B »

777etiyldifosfi tem. Compounds of formula (VI) may be converted to the active ester (e.g. with 1-hydroxybenzotriazole), mixed anhydrides (e.g. with esters (chloroformic acid), azides or carbodiimide derivatives).

In '· /' du to activate / see for example Schrdder, Ltlbke,

The Peptides, Volume 1, New York 1965, pp. 76-136].

The reaction is preferably carried out at a temperature in the range of -20 ° C and the boiling point of the reaction mixture.

Compounds of formula VII can also be reacted with compounds of formula VIII to form compounds of formula I,

R³OOC-CH / R⁴/ - N / R⁵/ - CO - CH / R¹/ - Y¹ / VII /

Y² - CH / COOR²/ - / CH₂/_n - R / VIII /, _in τ 2 wherein either Y is amino and Y is cleavable

2 or Y represents a leaving group and Y represents an amino group. Suitable leaving groups are, for example, chlorine, bromine, iodine, alkylsulfonyloxy or arylsulfonyloxy.

Alkylation of this kind is conveniently carried out in water or in an organic solvent such as aliphatic alcohols (such as ethyl alcohol), benzyl alcohol, acetonitrile, nitromethane or glycol ether at a temperature ranging from -20 ° C to the boiling point of the reaction mixture in the presence of a base such as an alkali metal hydroxide or an organic amine.

Further, a compound of formula IX can be condensed with a compound of formula X

R³OOC-CH / R⁴/ - N / R⁵/ - CO - C / R¹/ - Q¹ / IX /

Q² = C / COOR²/ - / CH₂/_n - R (X), wherein Q represents either an amino group + a hydrogen atom and

1 z P

Q is oxo, or Q is oxo and Q is amino + hydrogen.

The condensation is preferably carried out in water or in an organic solvent, such as a lower aliphatic alcohol, at a temperature in the range of 20 ° C to the boiling point of the reaction mixture in the presence of a reducing agent such as HaBH 4 CN. . However, they can also be reduced as intermediates resulting from Schiff bases or enamines, optionally after prior isolation, to form compounds of formula II, for example by hydrogenation in the presence of a transition metal catalyst.

Finally, the reaction of the compounds of formula IX / Q also leads¹ = H + NH₂with compounds of formula XI or their reaction with compounds of formulas XII and XIII conveniently in the presence of a base such as sodium alcoholate in an organic solvent such as a lower alcohol at a temperature between 10 ° C and the boiling point of the reaction mixture, to compounds of formula II (n = 2)

R²00C-CH = CH-COR / XI /

OCH - COOR² / XII /

R = CO-CH₃ (XIII), wherein the intermediate Schiff bases are reduced as described above and the carbonyl group is reductively converted (for example using a complex hydride) to methylene.

<img file="CS9103587A3_D0015.tif" />

In the above formulas V to XIII, the symbols R to R-⁷ and m is as defined for formula (I). Protective groups introduced temporarily to protect non-reactive reactive groups are cleaved off in a manner known per se following completion of the reaction (see Schrdder, Lilke, loc. Cit.). 1 to 75 and 246 to 270; Greene, Protective Groups in Organic Synthesis ”, New York 1981].

Suitable calcium antagonists are compounds of formula II

<img file="CS9103587A3_D0016.tif" />

23, 4 wherein R is methyl, ethyl or isopropyl, and

R is methoxycarbonyl, ethoxycarbonyl or 1,2,4oxadiazol-3-yl, and their physiologically acceptable salts.

«

Other suitable calcium antagonists are 5- [3,4,4-dimethoxyphenylthyl] -methylamino] -2- (3,4-dimethoxyphenyl) -2-isopropylvaleronitrile (Verapamil).

<img file="CS9103587A3_D0017.tif" />

(2 S is) -3- (ae-ethoxy) -5- (2-) dimethylamino / ethyl) -2,3-dihydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine-4 / 5H /-he

- 24 OCH.

<img file="CS9103587A3_D0018.tif" />

ch₂ch₂n / ch₃/₂ (Diltiazem) and 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -3,5-pyridinedindicarboxylic acid dimethyl ester (Nif edipine)

<img file="CS9103587A3_D0019.tif" />

2% R, n-r-ϊ. 'i.VÁx? ι ί.ϊΛ * ;.' $

fyž fa · '·

In addition to the last three calcium antagonists, they are particularly preferred

4- (2,3-dichlorophenyl) -2,6-dimethyl-3-methoxycarbonyl-5-ethoxycarbonyl-1,4-dihydropyridine (Felodipine) and 4- (2,3-dichlorophenyl) -2,6-dimethyl-3 - (1,2,4-Oxadiazol-3-yl) -5-isopropylcarbonyl-1,4-dihydropyridine, as well as their physiologically acceptable salts with acids.

Of particular interest are the following combinations:

Rampiril + Felodipin

Rampiril + 4- (2,3-dichlorophenyl) -2,5-dimethyl-3- (1,2,4-oxadiazol-5-yl) -5-isopropoxycarbonyl-1,4-dihydropyridine, Trandolapril + Felodipine,

Trandolapril + 4- (2,3-dichlorophenyl) -2,6-dimethyl-3- (1,2,4-oxadiazol-3-yl) -5-isopropoxycarbonyl-1,4-dihydropyridine,

Trandolapril + Verapamil,

Quinapril + Felodipine or

Quinapril + 4- (2,3-dichlorophenyl) -2,6-dimethyl-3- (1,2,4-oxadiazol-5-yl) -5-isopropoxycarbonyl-1,4-dihydropyridine, and the physiologically acceptable salts thereof the individual components, if such salts are formed.

In addition to the use of said combinations, the present invention also relates to the simultaneous, separate or timed use of ACE inhibitors and calcium antagonists when applied to proteinuria.

For example, the pharmaceutical preparations can be prepared by either intimately mixing the individual components in powder form or by dissolving the individual components in a suitable solvent, such as a lower alcohol, and then removing the solvent.

The ratio of active ingredients in the combination according to the invention is preferably 1 to 15 parts by weight of an ACE inhibitor to 15 to 1 part by weight of a calcium antagonist. The combinations and preparations according to the invention contain in total preferably 0.5 to 99.5% by weight, in particular 4 to 96% by weight, of this active ingredient.

<img file="CS9103587A3_D0020.tif" />

For use in the present invention in mammals, especially humans, the dose of the ACE-inhibitor of the above formula is between 0.05 and 100 mg / kg / day and the calcium antagonist is between 0.05 and 200 mg / kg / day. .

The compositions or products of the present invention may be administered parenterally or orally, but oral dosage forms are preferred.

The parmacologically usable combinations of the present invention and salts thereof can be used to produce pharmaceutical compositions comprising an effective amount of the active ingredient together with a carrier and suitable for enteral and parenteral administration. In particular, tablets or gelatin capsules are used which contain the active substances together with diluents, such as lactose, dextrose, cane sugar, mannitol, sorbol, cellulose and / or glycerin, and lubricants such as diatomaceous earth, talc, acid. stearate or salts thereof, such as magnesium or calcium stearate and / or propylene glycol. The tablets also contain binders such as magnesium salicilate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if necessary, colorants, flavors and sweeteners.

AND.¹

Suitable injectable solutions are, in particular, isotonic aqueous solutions or suspensions which may be sterilized.

Suitable salts of the abovementioned compounds are, depending on the acidic or basic nature of the compounds, alkali metal or alkaline earth metal salts or salts with physiologically acceptable amines, or salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid , sulfuric acid, maleic acid, fumaric acid, tartaric acid or citric acid.

DETAILED DESCRIPTION OF THE INVENTION

Prevention of progressive proteinuria in rats with renal remainder

1. Method

In mature male Sprague-Dawley rats, 2/3 of the right kidney is first infarced by ligature and, at one week interval, the contralateral kidney is removed. The animals received the chow preparation immediately after 8 weeks. The consumption of food shows that group II (n: 17) received 58 mg / kg of Pelodipine (EE), group III / n: 10 / 1.6 mg / kg of Ramipril (RA) and group

IV / ml / 41 mg / kg of Pelodipine and 1.4 mg / kg of Ramipril. Control group I received normal food. Urine was collected 24 hours prior to surgery and then for 1, 3, 5 and 7 weeks. Blood samples were taken from the retro-orbital plexus under light pentobarbital anesthesia each day before the end of the study after measuring the blood pressure in A. Kardtas under final pentobarbital anesthesia.

2. Results

The mean blood pressure is 160 * 7 mra Hg in control group I, 122 * 3 mm Hg with FE, 117 ¹ 7 mm Hg for RA and 108-4 mm Hg for FE and RA. Proteinuria, which is less than 20 mh / 24 hpdin before surgery, increases continuously in the control group to 105-28 mg / 24 h at week 7. The increase in proteinuria slows down by two weeks when applied with FE, but finally, with a 114 T value of 28 mg / 24 h, similar results are obtained. At 48-15 mg / 24 h, protein excretion was significantly lower with RA. This protein excretion has been reduced to only 31 - 4. mg / 24 h with RA + FE; Plasma creatinine levels doubled after surgery in all groups from an average of 42 to 73 mol / l, but were not further affected after application. Plasma CE activity was reduced by 80% on average with and without FE, while FE alone had no effect. »

In Figures 1 and 2, the experimental times in weeks are shown under the symbol T; left values ​​without number are pre-operation values. The values ​​indicated as A in Figures 1-4 are measured after the dose of 58 mg / kg Felodipine, the values ​​referred to as B are measured after the dose of 1.6 mg / kg Ramipril and the values ​​referred to as G are measured after the combination 1.4 mg / kg of Ramipril and 41 mg / kg of Felodipine. D values ​​represent control.

Figure 1 shows the ratio of protein secretion to creatinine secretion P / C in mg / µmol.

Figure 2 shows total protein excretion Ρηρ / mg / over 24 hours.

Figure 3 shows the percentage exclusion

7 * *** vwrTi-TtMn ^ -.

- 29 protein counting (% P) within 24 hours versus experiment duration.

In Fig. 4, blood pressure (BP - mm Hg) is shown, wherein * indicates mean blood pressure, indicates systolic blood pressure, and indicates diastolic blood pressure.

•

3. Discussion

The results of experiments in rats show that calcium antagonists and ACS-inhibitors, despite the same effect on systemic blood pressure, differ in their effect on renal impairment due to nephron loss.

Tests have also shown that while controlling the systemic blood pressure with a calcium antagonist, the onset of proteinuria is delayed, but is ultimately due to the accelerated loss of renal function. This undesirable process can be suppressed by co-administration of an ACE-inhibitor.

The following examples serve to illustrate the present invention in greater detail, without restricting it.

Example 1

Production of oral combination preparation from Pamipril and Pelodipine

1000 tablets containing 2 mg Ramipril and 6 mg Pelodipine are prepared as follows:

<td>Ramipril</td><td>2 g</td>

<td>Pelodipin</td><td>6 g</td>

<td>cornstarch</td><td>140 g</td>

<td>gelatine</td><td> 7,5</td>

<td>microcrystalline cellulose</td><td> 2,5</td>

<td>magnesium stearate</td><td> 2,5</td>

The two active compounds are mixed in an aqueous solution

gelatin. The resulting mixture is dried and ground to a granulate.

i fab. Microcrystalline cellulose and magnesium stearate are mixed with the granulate. The granules thus produced are processed into 1000 tablets, each containing 10 tablets;

2 mg of Ramipril and 6 mg of Pelodipine.

Example2

Production of oral combination preparation from Trandolapril and Verapamil

1000 tablets containing 3 mg Trandolapril and 50 mg Verapamil are prepared as follows:

Trandolapril Verapamil Maize starch Gelatin Microcrystalline cellulose Magnesium stearate

The two active compounds are mixed with an aqueous gelatin solution. The mixture is dried and ground to a granulate, followed by mixing the obtained granulate with magnesium stearate and microcrystalline cellulose. 1000 tablets are compressed from the granulate, each tablet containing 3 mg Trandolapril and 50 mg Verapamil.

g 50 g 130 g é

gg

<img file="CS9103587A3_D0021.tif" />

KS Example 3

Production of oral combination preparation from Quinapril and Pelodipine

1000 tablets containing 2.5 mg of Quinapril and 6 mg of Pelodipine are prepared as follows:

Quinapril

Pelodipine corn starch Gelatin Microcrystalline cellulose Magnesium stearate

2.5 g 5 g

150 G

7.5 g

2.5 g 2.5 g

The two active compounds are mixed with an aqueous gelatin solution. The resulting mixture is dried and ground to a granulate, then mixed with microcrystalline cellulose and magnesium stearate. 1000 tablets are compressed from the granules so produced, each tablet containing 2.5 mg of Quinapril and 5 mg of Pelodipine.

eWr. KM VETECKA attorney

11604 PRAGUE 1, Žitná26

<img file="CS9103587A3_D0022.tif" />

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