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Claims for Patent: 5,721,244

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Claims for Patent: 5,721,244

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; Hans Jorg (Kronberg/Taunus, DE)
Assignee: Hoechst Aktiengesellschaft (Frankfurt an Main, DE)
Application Number:08/483,961
Patent Claims: 1. A pharmaceutical composition comprising:

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

R=hydrogen,

an aliphatic radical with 1-8 carbon atoms,

an alicyclic radical with 3-9 carbon atoms, or

an aromatic radical with 6-12 carbon atoms,

an araliphatic radical with 7-14 carbon atoms,

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

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

R.sup.a represents an aliphatic radical with 1-4 carbon atoms or an aromatic radical with 6-12 carbon atoms,

R.sup.1 is hydrogen,

an aliphatic radical with 1-6 carbon atoms,

an alicyclic radical with 3-9 carbon atoms,

an alicyclic-aliphatic radical with 4-12 carbon atoms,

an aromatic radical with 6-12 carbon atoms,

an araliphatic radical with 7-16 carbon 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 aliphatic radical with 1-6 carbon atoms,

an alicyclic radical with 3-9 carbon atoms,

an aromatic radical with 6-12 carbon atoms,

an araliphatic radical with 7-16 carbon atoms and

R.sup.4 and R.sup.5 together with the atoms carrying them form a heterocyclic bicyclic or tricyclic ring system selected from tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azaspiro[4,5]decane, 2-azaspiro[4,4]nonane, spiro[(bicyclo[2,2,1]heptane)-2,3'-pyrrolidine], spiro [(bicyclo[2,2,2]octane)-2,3'-pyrrolidine], 2-azatricyclo[4,3,0,1.sup.6.9 ]decane, decahydrocyclophepta[b]pyrrole, octahydroisoindole, octahydrocyclocopenta[c]pyrrole, 2,2,3a,4,5,7a-hexahydroindole, 2-azabicyclo[3,1,0]-hexane, hexahydrocyclopenta[b]pyrrole,

or a physiologically acceptable salt thereof, and

(b) a calcium antagonist or a physiologically acceptable salt thereof;

wherein said ACE inhibitor and said calcium antagonist are present in said composition in amounts effective for treating hypertension;

and with the proviso that when said calcium antagonist is 4-(2,3-dichlorophenyl)-2,6-dimethyl-3-methoxycarbonyl-5-ethoxycarbonyl-1,4 -dihydropyridine (felodipine), said angiotensin-converting enzyme inhibitor is not 1-(2S,3aR,7aS)-octahydro[1H]indole-2-S-carboxylic acid (trandolapril).

2. A composition according to claim 1, wherein:

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, or (C.sub.6 -C.sub.12)-aryl,

R.sup.1 is hydrogen, (C.sub.1 -C.sub.6)-alkyl, (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,

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, or (C.sub.2 -C.sub.6)-alkenyl, and

R.sup.4 and R.sup.5 are as defined in claim 1.

3. A composition according to claim 1, wherein said ACE inhibitor is 1-[N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(2S,3aR,7aS)-octahydro[ 1H]indole-2-carboxylic acid (trandolapril) or a physiologically acceptable salt thereof, or 2-[N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-1,2,3,4-tetrahydroisoqu inoline-3-S-carboxylic acid (quinapril) or a physiologically acceptable salt thereof.

4. A composition according to claim 1, wherein the amounts of ACE inhibitor, or salt thereof, and calcium antagonist, or salt thereof, in combination are effective for simultaneous, separate or periodic regulated use in the treatment of high blood pressure.

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

6. A composition according to claim 1, wherein the amounts of ACE inhibitor, or salt thereof, and calcium antagonist, or salt thereof, in said composition are effective as a medicament in the treatment of coronary head disease.

7. A method for the treatment of high blood pressure, comprising administering to a host in recognized need thereof a pharmaceutical composition according to claim 1.

8. A method for the treatment of cardiac insufficiency, comprising administering to a host in recognized need thereof a pharmaceutical composition according to claim 1.

9. A method for the treatment of coronary head disease, comprising administering to a host in recognized need thereof a pharmaceutical composition according to claim 1.

10. A pharmaceutical composition according to claim 1, wherein said composition further comprises a physiologically acceptable carrier.

11. A pharmaceutical composition comprising:

(a) an angiotensin-converting enzyme inhibitor (ACE inhibitor) of the formula I ##STR15## in which n=1 or 2,

R=

hydrogen,

an aliphatic radical with 1-8 carbon atoms,

an alicyclic radical with 3-9 carbon atoms, or

an aromatic radical with 6-12 carbon atoms,

an araliphatic radical with 7-14 carbon atoms,

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

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

R.sup.a represents an aliphatic radical with 1-4 carbon atoms or an aromatic radical with 6-12 carbon atoms,

R.sup.1 is hydrogen,

an aliphatic radical with 1-6 carbon atoms,

an alicyclic radical with 3-9 carbon atoms,

an alicyclic-aliphatic radical with 4-12 carbon atoms,

an aromatic radical with 6-12 carbon atoms,

an araliphatic radical with 7-16 carbon 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 aliphatic radical with 1-6 carbon atoms,

an alicyclic radical with 3-9 carbon atoms,

an aromatic radical with 6-12 carbon atoms,

an araliphatic radical with 7-16 carbon atoms and

R.sup.4 and R.sup.5 together with the atoms carrying them form a heterocyclic bicyclic or tricyclic ring system selected from tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azaspiro[4,5]decane, 2-azaspiro[4,4]nonane, spiro[(bicyclo[2,2,1]heptane)-2,3'-pyrrolidine], spiro [(bicyclo[2,2,2]octane)-2,3'-pyrrolidine], 2-azatricyclo[4,3,0,1.sup.6.9 ]decane, decahydrocyclophepta[b]pyrrole, octahydroisoindole, octahydrocyclocopenta[c]pyrrole, 2,2,3a,4,5,7a-hexahydroindole, 2-azabicyclo[3,1,0]-hexane, hexahydrocyclopenta[b]pyrrole,

or a physiologically acceptable salt thereof, and

(b) a calcium antagonist or a physiologically acceptable salt thereof;

wherein said ACE inhibitor and said calcium antagonist are present in said composition in amounts effective for treating cardiac insufficiency;

and with the proviso that when said calcium antagonist is 4-(2,3-dichlorophenyl)-2,6-dimethyl-3-methoxycarbonyl-5-ethoxycarbonyl-1,4 -dihydropyridine (felodipine), said angiotensin-converting enzyme inhibitor is not 1-[N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(2S,3aR,7aS)-octahydro[ 1H]indole-2-S-carboxylic acid (trandolapril).

12. A pharmaceutical composition comprising:

(a) an angiotensin-converting enzyme inhibitor (ACE inhibitor) of the formula I ##STR16## in which n=1 or 2,

R=

hydrogen,

an aliphatic radical with 1-8 carbon atoms,

an alicyclic radical with 3-9 carbon atoms, or

an aromatic radical with 6-12 carbon atoms,

an araliphatic radical with 7-14 carbon atoms,

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

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

R.sup.a represents an aliphatic radical with 1-4 carbon atoms or an aromatic radical with 6-12 carbon atoms,

R.sup.1 is hydrogen,

an aliphatic radical with 1-6 carbon atoms,

an alicyclic radical with 3-9 carbon atoms,

an alicyclic-aliphatic radical with 4-12 carbon atoms,

an aromatic radical with 6-12 carbon atoms,

an araliphatic radical with 7-16 carbon 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 aliphatic radical with 1-6 carbon atoms,

an alicyclic radical with 3-9 carbon atoms,

an aromatic radical with 6-12 carbon atoms,

an araliphatic radical with 7-16 carbon atoms and

R.sup.4 and R.sup.5 together with the atoms carrying them form a heterocyclic bicyclic or tricyclic ring system selected from tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azaspiro[4,5]decane, 2-azaspiro[4,4]nonane, spiro[(bicyclo[2,2,1]heptane)-2,3'-pyrrolidine], spiro [(bicyclo[2,2,2]octane)-2,3'-pyrrolidine], 2-azatricyclo[4,3,0,1.sup.6.9 ]decane, decahydrocyclophepta[b]pyrrole, octahydroisoindole, octahydrocyclocopenta[c]pyrrole, 2,2,3a,4,5,7a-hexahydroindole, 2-azabicyclo[3,1,0]-hexane, hexahydrocyclopenta[b]pyrrole,

or a physiologically acceptable salt thereof, and

(b) a calcium antagonist or a physiologically acceptable salt thereof;

wherein said ACE inhibitor and said calcium antagonist are present in said composition in amounts effective for treating coronary heart disease;

and with the proviso that when said calcium antagonist is 4-(2,3-dichlorophenyl)-2,6-dimethyl-3-methoxycarbonyl-5-ethoxycarbonyl-1,4 -dihydropyridine (felodipine), said angiotensin-converting enzyme inhibitor is not 1-[N-(1-S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(2S,3aR,7aS)-octahydro[ 1H]indole-2-S-carboxylic acid (trandolapril).
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