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Details for Patent: 5,098,910

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Details for Patent: 5,098,910

Title: Combination of angiotensin-converting enzyme inhibitors with calcium antagonists as well as their use in drugs
Abstract:The invention relates to combinations of angiotensin-converting enzyme inhibitors with calcium antagonists, processes for their preparation and their use as medicaments.
Inventor(s): Becker; Reinhard (Wiesbaden, DE), Henning; Rainer (Hattersheim am Main, DE), Ruger; Wolfgang (Kelkheim, DE), Teetz; Volker (Hofheim am Taunus, DE), Urbach; Hansjorg (Kronberg/Taunus, DE)
Assignee: Hoechst Aktiengesellschaft (Frankfurt am Main, DE)
Filing Date:May 30, 1989
Application Number:07/358,427
Claims:1. A pharmaceutical composition, comprising pharmaceutically synergistically effective amounts of

a) an angiotensin-converting enzyme inhibitor (ACE inhibitor) of the formula I ##STR14## in which n=1 or 2,

R=hydrogen,

an optionally substituted aliphatic radical with 1-8 carbon atoms,

an optionally substituted alicyclic radical with 3-9 carbon atoms,

an optionally substituted aromatic radical with 6-12 carbon atoms,

an optionally substituted araliphatic radical with 7-14 carbon atoms,

an optionally substituted alicyclic-aliphatic radical with 7-14 carbon atoms,

a radical OR.sup.1 or SR.sup.1, wherein

R.sup.1 represents an optionally substituted aliphatic radical with 1-4 carbon atoms, an optionally substituted aromatic radical with 6-12 carbon atoms or an optionally substituted heteroaromatic radical with 5-12 ring atoms,

R.sup.1 is hydrogen,

an optionally substituted aliphatic radical with 1-6 carbon atoms,

an optionally substituted alicyclic radical with 3-9 carbon atoms,

an optionally substituted alicyclic-aliphatic radical with 4-13 carbon atoms,

an optionally substituted aromatic radical with 6-12 carbon atoms,

an optionally substituted araliphatic radical with 7-16 carbon atoms,

an optionally substituted heteroaromatic radical with 5-12 ring atoms or

the side chain, protected if necessary, of a naturally occurring .alpha.-amino acid,

R.sup.2 and R.sup.3 are the same or different and are hydrogen,

an optionally substituted aliphatic radical with 1-6 carbon atoms,

an optionally substituted alicyclic radical with 3-9 carbon atoms,

an optionally substituted aromatic radical with 6-12 carbon atoms, or

an optionally substituted araliphatic radical with 7-16 carbon atoms and

R.sup.4 and R.sup.5 together with the atoms carrying them form an optionally substituted octahydrocyclopenta pyrrole ring system, or a physiologically acceptable salt thereof, and

b) a calcium antagonist or a physiologically acceptable salt thereof.

2. A composition as claimed in claim 1, in which in the ACE inhibitor of the formula I

n=1 or 2

R is hydrogen,

alkyl with 1-8 carbon atoms,

alkenyl with 2-6 carbon atoms,

cycloalkyl with 3-9 carbon atoms,

aryl with 6-12 carbon atoms,

which can be mono-, di- or trisubstituted by (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, hydroxy, halogen, nitro, amino aminomethyl, (C.sub.1 -C.sub.4)-alkylamino, di-(C.sub.1 -C.sub.4)-alkylamino, (C.sub.1 -C.sub.4)-alkanoylamino, methylenedioxy, cyano and/or sulfamoyl,

alkoxy with 1-4 carbon atoms,

aryloxy with 6-12 carbon atoms,

which can be substituted as described above for aryl,

mono- or bicyclic heteroaryloxy with 5-7 or 8-10 ring atoms respectively, of which 1 to 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen,

which can be substituted as described above for aryl,

amino-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.4)-alkanoylamino-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.7 -C.sub.13)-aroylamino-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.4)alkoxy-carbonylamino-(C.sub.1 -C.sub.4)alkyl,

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkoxycarbonylamino-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkylamino-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.4)-alkylamino-(C.sub.1 -C.sub.4)-alkyl,

di-(C.sub.1 -C.sub.4)-alkylamino-(C.sub.1 -C.sub.4)-alkyl,

guanidino-(C.sub.1 -C.sub.4)-alkyl,

imidazolyl, indolyl,

(C.sub.1 -C.sub.4)-alkylthio,

(C.sub.1 -C.sub.4)-alkylthio-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.6 -C.sub.12)-arylthio-(C.sub.1 -C.sub.4)-alkyl,

which can be substituted in the aryl part as described above for aryl,

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkylthio,

which can be substituted in the aryl part as described above for aryl,

carboxy-(C.sub.1 -C.sub.4)-alkyl,

carboxy, carbamoyl,

carbamoyl-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.4)-alkoxy-carbonyl-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.6 -C.sub.12)-aryloxy-(C.sub.1 -C.sub.4)-alkyl,

which can be substituted in the aryl part as described above for aryl, or

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkoxy,

which can be substituted in the aryl part as described above for aryl,

R.sup.1 is hydrogen,

alkyl with 1-6 carbon atoms,

alkenyl with 2-6 carbon atoms,

alkynyl with 2-6 carbon atoms,

cycloalkyl with 3-9 carbon atoms,

cycloalkenyl with 5-9 carbon atoms,

(C.sub.3 -C.sub.9)-cycloalkyl-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.5 -C.sub.9)-cycloalkenyl-(C.sub.1 -C.sub.4)-alkyl,

optionally partially hydrogenated aryl with 6-12 carbon atoms, which can be substituted as described above for R,

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl or (C.sub.7 -C.sub.13)-aroyl-(C.sub.1 or C.sub.2)-alkyl

both of which can be substituted as the previous aryl,

mono- or bicyclic, optionally partially hydrogenated heteroaryl with 5-7 or 8-10 ring atoms respectively, of which 1 to 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms,

which can be substituted as the previous aryl, or

the optionally protected side chain of a naturally occurring .alpha.-amino acid R.sup.1 --CH(NH.sub.2)--COOH,

R.sup.2 and R.sup.3 are the same or different and are hydrogen,

alkyl with 1-6 carbon atoms,

alkenyl with 2-6 carbon atoms,

di-(C.sub.1 -C.sub.4)-alkylamino-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.5)-alkanoyloxy-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.1 -C.sub.6)-alkoxy-carbonyloxy-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.7 -C.sub.13)-aroyloxy-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.6 -C.sub.12)-aryloxycarbonyloxy-(C.sub.1 -C.sub.4)-alkyl,

aryl with 6-12 carbon atoms,

(C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl,

(C.sub.3 -C.sub.9)-cycloalkyl or

(C.sub.3 -C.sub.9)-cycloalkyl-(C.sub.1 -C.sub.4)-alkyl and

R.sup.4 and R.sup.5 have the meaning given in claim 1.

3. A composition as claimed in claim 1, in which in the ACE inhibitor of the formula I

n=1 or 2,

R is (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl, (C.sub.3 -C.sub.9)-cycloalkyl, amino-(C.sub.1 -C.sub.4)-alkyl, (C.sub.2 -C.sub.5)-acylamino-(C.sub.1 -C.sub.4)alkyl, (C.sub.7 -C.sub.13)-aroylamino-(C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy-carbonylamino-(C.sub.1 -C.sub.4)-alkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkoxycarbonylamino-(C.sub.1 -C.sub.4)-alkyl, (C.sub.6 -C.sub.12)-aryl, which can be mono-, di- or trisubstituted by (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, hydroxy, halogen, nitro, amino, (C.sub.1 -C.sub.4)-alkylamino, di-(C.sub.1 -C.sub.4)-alkylamino and/or methylenedioxy, or 3-indolyl,

R.sup.1 is hydrogen or (C.sub.1 14 C.sub.6)-alkyl, which can be optionally substituted by amino, (C.sub.1 -C.sub.6)-acylamino or benzoylamino, (C.sub.2 -C.sub.6)-alkenyl, (C.sub.3 -C.sub.9)-cycloalkyl, (C.sub.5 -C.sub.9)-cycloalkenyl, (C.sub.3 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.4)-alkyl, (C.sub.6 -C.sub.12)-aryl or partially hydrogenated aryl, which can each be substituted by (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 or C.sub.2)-alkoxy or halogen, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 to C.sub.4)-alkyl or (C.sub.7 -C.sub.13)-aroyl-(C.sub.1 -C.sub.2)-alkyl, which can both be substituted as defined previously in the aryl radical, a mono- or bicyclic heterocyclic radical with 5 to 7 or 8 to 10 ring atoms respectively, of which 1 to 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring, optionally protected .alpha.-amino acid,

R.sup.2 and R.sup.3 are the same or different and are hydrogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.6 -C.sub.12)aryl-(C.sub.1 -C.sub.4)-alkyl, and

R.sup.4 and R.sup.5 have the meaning given in claim 1.

4. A composition as claimed in claim 1, wherein said ACE inhibitor comprises 1-[N-(1-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-3aS,6aS)-octahy drocyclopenta[b]pyrol-2-S-carboxylic acid or a physiologically tolerated salt thereof.

5. A composition as claimed in claim 1, wherein said calcium antagonist comprises a calcium antagonist of the formula II ##STR15## in which R.sup.6 is methyl, ethyl or isopropyl and

R.sup.7 is methoxycarbonyl, ethoxycarbonyl or 1,2,4-oxadiazol-3-yl,

or a physiologically acceptable salt thereof.

6. A composition as claimed in claim 1, wherein said calcium antagonist comprises 4-(2,3-dichlorophenyl)-2,6-dimethyl-3-methoxycarbonyl-5-ethoxycarbonyl-1,4 -dihydropyridine or a physiologically acceptable salt thereof.

7. A composition as claimed in claim 1, wherein said calcium antagonist comprises 4-(2,3-dichlorophenyl)-2,6-dimethyl-3-(1,2,4-oxadiazol-3-yl)-5-isopropoxyc arbonyl-1,4-dihydropyridine or a physiologically acceptable salt thereof.

8. A composition as claimed in claim 1, comprising ramipril and felodipine or the physiologically acceptable salts of the above single components, in as far as these form salts.

9. The pharmaceutical composition of claim 1 wherein the amounts of said ACE inhibitor, or salt thereof, and calcium antagonist, or salt thereof, in combination are synergistically effective for simultaneous, separate or periodic regulated use in the treatment of high blood pressure.

10. A method for the treatment of high blood pressure, which comprises administering a pharmaceutical composition as claimed in claim 1.

11. A composition as claimed in claim 1, wherein the amounts of said ACE inhibitor, or salt thereof and calcium antagonist, or salt thereof in said composition are synergistically effective as a medicament in the treatment of cardiac insufficiency.

12. A composition as claimed in claim 1, wherein the amounts of said ACE inhibitor, or salt thereof, and calcium antagonist, or salt thereof, in said composition are synergistically effective as a medicament in the treatment of coronary heart disease.

13. A pharmaceutical composition, as claimed in claim 1, comprising:

a) a compound of the formula I in which

n-32 1 or 2,

R is (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl, C.sub.3 -C.sub.9)-cycloalkyl, amino-(C.sub.1 -C.sub.4)-alkyl, (C.sub.2 -C.sub.5)-acylamino-(C.sub.1 -C.sub.4)-alkyl, (C.sub.7 -C.sub.13)-aroylamino-(C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy-carbonylamino-(C.sub.1 -C.sub.4)-alkyl, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkoxycarbonylamino-(C.sub.1 -C.sub.4)-alkyl, (C.sub.6 -C.sub.12)-aryl, which can be mono-, di- or trisubstituted by (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, hydroxy, halogen, nitro, amino, (C.sub.1 -C.sub.4)-alkylamino, di-(C.sub.1 -C.sub.4)-alkylamino and/or methylenedioxy, or 3-indolyl,

is hydrogen or (C.sub.1 -C.sub.6)-alkyl, which can be optionally substituted by amino, (C.sub.1 -C.sub.6)-acylamino or benzoylamino, (C.sub.2 -C.sub.6)-alkenyl, (C.sub.3 -C.sub.9)-cycloalkyl, (C.sub.5 -C.sub.9)-cycloalkenyl, (C.sub.3 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.4)-alkyl, (C.sub.6 -C.sub.12)-aryl or partially hydrogenated aryl, which can each be substituted by (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 or C.sub.2)-alkoxy or halogen, (C.sub.6 -C.sub.12)-aryl-(C.sub.1 to C.sub.4)-alkyl or (C.sub.7 -C.sub.13)-aroyl-(C.sub.1 -C.sub.2)-alkyl, which can both be substituted as defined previously in the aryl radical, a mono- or bicyclic heterocyclic radical with 5 to 7 or 8 to 10 ring atoms respectively, of which 1 to 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring, optionally protected .alpha.-amino acid,

R.sup.2 and R.sup.3 are the same or different and are hydrogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl, and

R.sup.4 and R.sup.5 together with the atoms carrying them form an octahydrocyclopenta[b]pyrrole ring system, or a physiologically acceptable salt thereof; and

b) a compound of the formula II ##STR16## in which R.sup.6 is methyl, ethyl or isopropyl and

R.sup.7 is methoxycarbonyl, ethoxycarbonyl or 1,2,4-oxadiazol-3-yl,

or a physiologically acceptable salt thereof.

14. A composition as claimed in claim 13, wherein said ACE inhibitor comprises 1-[N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-3aS,6aS)-octahydrocyclo penta[b]pyrol-2-S-carboxylic acid or a physiologically tolerated salt thereof.

15. A composition as claimed in claim 13, wherein said calcium antagonist comprises 4(2,3-dichlorophenyl)-2,6-dimethyl-3-methoxycarbonyl-5-ethoxycarbonyl-1,4- dihydropyridine or a physiologically acceptable salt thereof.

16. A composition as claimed in claim 13 comprising 1-[N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-3aS,6aS)-octahydrocyclo penta[b]pyrol-2-S-carboxylic acid or a physiologically tolerated salt thereof in combination with 4-(2,3-dichlorophenyl)-2,6-dimethyl-3-methoxycarbonyl-5-ethoxycarbonyl-1,4 -dihydropyridine or a physiologically acceptable salt thereof.

17. A method of using the composition as claimed in claim 1, wherein said composition is employed as a medicament in the treatment of cardiac insufficiency.

18. A method of using the composition as claimed in claim 1, wherein said composition is employed as a medicament in the treatment of coronary heart disease.

19. A composition as claimed in claim 1, in which in the ACE inhibitor of the formula I

R is methyl, ethyl, cyclohexyl, tert.-butoxycarbonylamino-(C.sub.1 -C.sub.4)-alkyl, benzolyloxycarbonyl-amino-(C.sub.1 -C.sub.4)-alkyl or phenyl, which can be mono- or disubstituted or, in the case of methoxy, trisubstituted by phenyl, (C.sub.1 -C.sub.2)-alkyl, (C.sub.1 or C.sub.2)-alkoxy, hydroxy, fluoro, chloro, bromo, amino, (C.sub.1 -C.sub.4)-alkylamino, di-(C.sub.1 -C.sub.4)-alkylamino, nitro and/or methylenedioxy,

R.sup.1 is hydrogen, (C.sub.1 -C.sub.3)-alkyl, (C.sub.2 or C.sub.3)-alkenyl, the optionally protected side chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyl or benzoylmethyl, and

R.sup.2 and R.sup.3 are the same or different and are hydrogen, (C.sub.1 -C.sub.4)-alkyl or benzyl.

20. A pharmaceutical composition, as claimed in claim 1, comprising:

a) a compound of the formula I in which

n=1 or 2,

R is methyl, ethyl, cyclohexyl, tert.-butoxycarbonylamino-(C.sub.1 -C.sub.4)-alkyl, benzoyloxycarbonyl-amino-(C.sub.1 -C.sub.4)-alkyl or phenyl, which can be mono- or disubstituted or, in the case of methoxy, trisubstituted by phenyl, (C.sub.1 -C.sub.2)-alkyl, (C.sub.1 or C.sub.2)-alkoxy, hydroxy, fluoro, chloro, bromo, amino, (C.sub.1 -C.sub.4)-alkylamino, di-(C.sub.1 -C.sub.4)-alkylamino, nitro and/or methylenedioxy,

R.sup.1 is hydrogen, (C.sub.1 -C.sub.3)-alkyl, (C.sub.2 or C.sub.3)-alkenyl, the optionally protected side chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyl or benzoylmethyl,

R.sup.2 and R.sup.3 are the same or different and are hydrogen, (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.6 -C.sub.12)-aryl-(C.sub.1 -C.sub.4)-alkyl, and

R.sup.4 and R.sup.5 together with the atoms carrying them form an octahydrocyclopenta[b]pyrrole ring system, or a physiologically acceptable salt thereof; and

b) a compound of the formula II ##STR17## in which R.sup.6 is methyl, ethyl or isopropyl and

R.sup.7 is methoxycarbonyl, ethoxycarbonyl or 1,2,4-oxadiazol-3-yl,

or a physiologically acceptable salt thereof.

21. A pharmaceutical composition as claimed in claim 1, wherein said composition comprises a physiologically acceptable carrier.

22. A pharmaceutical composition, comprising a) 1-[N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-3aS,6aS)-octahydrocyclo penta[b]pyrol-2-S-carboxylic acid or a physiologically tolerated salt thereof in combination with b) 4-(2,3-dichlorophenyl)-2,6-dimethyl-3-methoxycarbonyl-5-ethoxycarbonyl-1,4 -dihydropyridine or a physiologically acceptable salt thereof, wherein a) and b) are present in a pharmaceutically synergistically effective amount.

23. A method for the treatment of high blood pressure, which comprises administering a pharmaceutical composition as claimed in claim 22.

24. A method for the treatment of cardiac insufficiency, which comprises administering a pharmaceutical composition as claimed in claim 22.

25. A method for the treatment of coronary heart disease, which comprises administering a pharmaceutical composition as claimed in claim 22.

26. A pharmaceutical composition as claimed in claim 22, wherein said composition comprises a physiologically acceptable carrier.
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