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Claims for Patent: 4,703,038

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Claims for Patent: 4,703,038

Title: Combination of dihydropyridines with angiotensin converting enzymes-inhibitors
Abstract:The invention concerns a combination of dihydropyridine derivatives with compounds which inhibit the formation of enzymes which control the conversion of angiotensin I into angiotensin II and their use as antihypertensive agents.
Inventor(s): Garthoff; Bernward (Hilden, DE), Kazda; Stanislav (Wuppertal, DE), Knorr; Andreas (Wuppertal, DE)
Assignee: Bayer Aktiengesellschaft (Leverkusen, DE)
Application Number:06/785,182
Patent Claims: 1. A combination of compounds comprising a compound of the formula I ##STR7## wherein R and R.sup.6 are independently hydroxyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.2 -C.sub.4 -alkenoxy, di-C.sub.1 -C.sub.4 -alkylamino- C.sub.1 -C.sub.4 -alkoxy, acylamino-C.sub.1 -C.sub.4 -alkoxy, acylamino-C.sub.1 -C.sub.4 alkoxy, acyloxy-C.sub.1 -C.sub.4 -alkoxy, aryloxy, Ar-C.sub.1 -C.sub.4 -alkoxy, substituted aryloxy or substituted Ar-C.sub.1 -C.sub.4 -alkoxy, the substituent being methyl, halogen or methoxy, amino, C.sub.1 -C.sub.4 -alkylamino, di-C.sub.1 -C.sub.4 - alkylamino, aryl-C.sub.1 -C.sub.4 -alkylamino or hydroxylamino,

R.sup.1 denotes hydrogen, alkyl with 1 to 20 carbon atoms, which includes branched cyclic and unsaturated alkyl groups, substituted C.sub.1 -C.sub.4 alkyl, the substituent being halogen, hydroxyl, C.sub.1 -C.sub.4 -alkoxy, aryloxy, amino, C.sub.1 -C.sub.4 alkylamino, di-C.sub.1 -C.sub.4 -alkylamino, acylamino, arylamino, guanidino, imidazolyl, indolyl, mercapto, C.sub.1 -C.sub.4 -alkylthio, arylthio, carboxyl, carboxamido or carbo-C.sub.1 -C.sub.4 - alkoxy, phenyl, substituted phenyl, the substituent being C.sub.1 -C.sub.4 - alkyl, C.sub.1 -C.sub.4 -alkoxy or halogen, Ar-C.sub.1 -C.sub.4 -alkyl or heteroar-C.sub.1 -C.sub.4 - alkyl, Ar-C.sub.2 -C.sub.4 - alkenyl or heteroar-C.sub.2 -C.sub.4 alkenyl, substituted Ar-C.sub.1 -C.sub.4 -alkyl, substituted heteroar- C.sub.1 -C.sub.4 -alkyl, substituted Ar-C.sub.2 -C.sub.4 -alkenyl or substituted heteroar-C.sub.2 -C.sub.4 - alkneyl, the substituent being halogen or dihalogen, C.sub.1 -C.sub.4 -alkyl, hydroxyl, C.sub.1 -C.sub.4 - alkoxy, amino aminomethyl, acylamino, di-C.sub.1 -C.sub.4 -alkylamino, carboxyl, halogeno-C.sub.1 -C.sub.4 -alkyl, cyano or sulphoamido; or Ar-C.sub.1 -C.sub.4 -alkyl or heteroar C.sub.1 -C.sub.4 - alkyl, which is substituted on the alkyl part by amino or acylamino,

R.sub.2 and R.sub.7 denote hydrogen or C.sub.1 -C.sub.4 -alkyl,

R.sub.3 is hydrogen, C.sub.1 -C.sub.4 -alkyl, phenyl-C.sub.1 -C.sub.4 - alkyl, aminomethylphenyl- C.sub.1 -C.sub.4 -alkyl, hydroxyphenyl-C.sub.1 -C.sub.4 -alkyl, hydroxy-C.sub.1 -C.sub.4 - alkyl, acylamino-C.sub.1 -C.sub.4 -alkyl, amino-C.sub.1 -C.sub.6 -alkyl, dimethylamino-C.sub.1 -C.sub.6 alkyl, halogen-lower alkyl, guanidino-C.sub.1 -C.sub.4 -alkylm imidazolyl-C.sub.1 -C.sub.4 -alkyl, indolyl-C.sub.1 -C.sub.4 -alkyl, mercapto-C.sub.1 -C.sub.4 -alkyl or C.sub.1 -C.sub.4 -alkylthio-C.sub.1 -C.sub.4 -alkyl,

R.sup.4 is hydrogen or C.sub.1 -C.sub.4 - alkyl and

R.sup.5 is hydrogen, C.sub.1 -C.sub.4 -alkyl, phenyl, phenyl-C.sub.1 -C.sub.4 - alkyl, hydroxyphenyl-C.sub.1 -C.sub.4 alkyl, hydroxy-C.sub.1 -C.sub.4 -alkyl, amino-C.sub.1 -C.sub.4 -alkyl, amino-C.sub.1 -C.sub.4 -alkyl, guanidino-C.sub.1 -C.sub.4 - alkyl, imdazolyl-C.sub.1 -C.sub.4 - alkyl, indolyl- alkyl, mercapto, C.sub.1 -C.sub.4 -alkyl or C.sub.1 -C.sub.4 -alklyl or C.sub.1 -C.sub.4 -alkylthio-C.sub.1 -C.sub.4 -alkyl, or

R.sup.4 and R.sup.5 can be linked to one another to form an alkylene bridge with 2 to 4 carbon atoms, an alkylene bridge with 2 or 3 carbon atoms and one sulphur atom or an alkylene bridge which has 3 or 4 carbon atoms and contains a double bond or an alkylene bridge as above, substituted by hydroxyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.1 -C.sub.4 -alkyl or di-C.sub.1 -C.sub.4 -alkyl,

and the pharmaceutically acceptable salts thereof, with a dihyropyridine compound of the formula II ##STR8## in which R.sup.1 denotes C.sub.1 -C.sub.4 -alkyl, optionally substituted by C.sub.1 -C.sub.3 -alkoxy,

R.sup.2 denotes C.sub.1 -C.sub.10 -alkyl, optionally substituted by C.sub.1 -C.sub.3 -alkoxy, trifluoromethyl, trifluoroethyl or N-methyl-N-benzylamino,

R.sub.3 denotes C.sub.1 -C.sub.4 -alkyl, cyano or hydroxymethyl and X denotes 2- or 3-nitro, 2-chloro, 2,3-dichloro or a 2,3-ring member consisting of .dbd.N-O-N.dbd..

2. A combination according to claim 1, wherein the definitions of the formula I have the following meanings:

R denotes hydroxyl, C.sub.1 -C.sub.4 -alkoxy, C.sub.2 -C.sub.4 -alkenoxy, Ar-C.sub.1 -C.sub.4 -alkyloxy, di-C.sub.1 -C.sub.4 -alkylamino-C.sub.1 -C.sub.4 -alkoxy, acylamino-C.sub.1 -C.sub.4 -alkoxy or acyloxy-C.sub.1 -C.sub.4 -alkoxy,

R.sup.6 denotes alkyl with 1 to 8 carbon atoms, substituted C.sub.1 -C.sub.4 alkyl, the substituent being amino, arylthio, aryloxy or arylamino, aralkyl or heteroaralkyl, the alkyl section having 1 to 3 carbon atoms; or substituted aralkyl or heteroaralkyl, the alkyl groups having 1 to 3 carbon atoms and the substituent or substituents being halogen, dihalogen, amino, aminoalkyl, hydroxyl, C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.4 -alkyl,

R.sup.2 and R.sup.7 hydrogen,

R.sup.3 C.sub.1 -C.sub.6 -alkyl or amino-C.sub.1 -C.sub.6 -alkyl and

R.sup.4 and R.sup.5 can be linked together, via the carbon and nitrogen atoms to which they are bonded, to form a ring of the formula ##STR9## wherein Y, is CH.sub.2, S or CHOCH.sub.3,

and the pharmaceutically acceptable salts thereof.

3. A combination according to claim 1, wherein the definitions of the formula I have the following meanings:

R denotes hydroxyl or C.sub.1 -C.sub.4 - alkoxy

R.sup.6 denotes hydroxyl,

R.sup.2 and R.sup.7 denote hydrogen,

R.sup.3 and R.sup.7 denote hydrogen,

R.sup.3 denotes methyl or amino- C.sub.1 -C.sub.6 -alkyl,

R.sup.4 and R.sup.5 Are linked via the carbon and nitrogen atom to form proline, 4-thiaproline or 4-methoxy-proline and

R.sup.1 denotes alkyl with 1 to 8 carbon atoms, substituted C.sub.1 -C.sub.4 -alkyl, the substituent being amino, arylthio or aryloxy, arylkyl or heteroaralkyl, the alkyl section having 1 to 3 carbon atoms, or substituted aralkyl or substituted heteroaralkyl, the alkyl groups having 1 to 3 carbon atoms and the substituent or substituents being halogen, dihalogen, amino, aminoalkyl, hydroxyl, C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.4 -alkyl, and the pharmaceutically acceptable salts thereof.

4. A combination according to claim 1, wherein the compound formula I is selected from the group consisting of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline or its maleate salt and N-.alpha.-(1-(S -carboxy-3-phenylpropyl)-L-Lysyl-L-proline.

5. A combination according to claim 1, wherein the definition of the formula II have the following meanings:

X denotes 2-nitro, 3-nitro, 2-chloro, 2,3-dichloro or 2,3.dbd.N-O-N.dbd.,

R.sub.1 denotes methyl, ethyl, propyl or propyloxyethyl,

R.sub.2 denotes methyl, ethyl propyl, butyl and propyloxyethyl, methoxyethyl, decyl, trifluoromethylmethyl or 2-(N-benzyl-N-methyl)aminoethyl and

R.sub.3 denotes methyl, hydroxymethyl or cyano.

6. A combination according to claim 1, wherein the compound according to formula II is selected from the group consisting of nisoldipine, nicardipine and felodipine.

7. A combination according to claim 1, containing 1 part by weight of a compound according to formula I and 1-10 parts by weight of a dihydropyridine of the formula II.

8. A combination according to claim 1, containing 1 part by weight of a compound according to formula I and 1-3 parts by weight of a dihydropyridine of the formula II.

9. A combination according to claim 1, containing 1 part by weight of a compound according to formula I and 3 parts by weight of a dihydropyridine of the formula II.

10. A process for treating circulatory diseases by administering an effective amount of the combination of claim 1.

11. A process for treating hypertension by administering an effective amount of the combination of claim 1.

12. A medicament containing a combination according to claim 1.

13. A process for the preparation of the medicament, wherein the compounds according to formulae I and II of claim 1 are dissolved in inert solvents and, after the solvent has been evaporated off, the resulting combination is mixed, if appropriate with auxiliaries.

14. A combination of compounds comprising a mixture of a compound selected from the group consisting of N-(1-(S)pethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline and its maleate salt and N-.alpha.-(1-(s) - carboxy-3-phenylpropyl)-L-Lysyl-L-proline and a dihydropyridine compound selected from the group consisting of nitrendipine, nisoldipine, nicardipine and felodipine.

15. A combination of compounds comprising a mixture of N-(1-(S)-ethyoxycarbonyl-3-phenylpropyl)-L-alanyl-proline and nitrendipine.

16. A process for treating hypertension by administering an effective amount of the combination of a compound selected from the group consisting of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline or it maleate salt and N-.alpha.-(1-(S)-carboxy-3-phenylpropyl)-L-Lysyl-L-proline dihydropyridine compound selected from the group consisting of nitrendipine, nisoldipine, nicardipine, and felodipine.

17. A process for treating hypertension by administering an effective amount of the combination of N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline and nitrendipine.
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