Quinoline derivatives and pharmaceutical compositions and methods for treating cardiovascular disease with such compounds
First Claim
1. A compound of formula 1 or a pharmaceutically acceptable salt thereof. ##STR79## in which A--B is --CH2 --CH2 --, --CHOH--CH2 --, --CH2 --CHOH--, --C(O)--CH2 --, --CH2 --C(O)--, --C(NOR4)--CH2 -- or --CH2 --C(NOR4)--,R1 is hydrogen, hydroxy or lower alkoxy,R2 is ethyl or vinyl,R3 is C2-8 alkyl, C1-8 hydroxyalkyl, lower alkoxyalkyl or lower alkanoyloxyalkyl, C3-6 cycloalkyl, hydroxycycloalkyl, lower alkoxycycloalkyl or lower alkanoyloxycycloalkyl, cycloalkyl lower alkyl, hydroxy-, lower alkoxy- or lower alkanoyloxycycloalkyl lower alkyl, and each of said cycloalkyl moieties is C3-6 cycloalkyl;
- cyano, cyano lower alkyl, lower alkenyl, lower alkynyl, tetrahydrofuryl, mono- or di- lower alkylamino lower alkyl, mono- or di-lower alkylamino lower hydroxy alkyl;
unsubstituted or substituted phenyl, unsubstituted or substituted phenyl lower alkyl or unsubstituted or substituted phenyl hydroxy lower alkyl, unsubstituted or substituted diphenyl lower alkyl, unsubstituted or substituted phenyl lower alkenyl, unsubstituted or substituted benzoyl or unsubstituted or substituted benzoyl lower alkyl;
unsubstituted thienyl or thienoyl or substituted thienyl or thienoyl, wherein the substituents are one, two or three substituents selected from the group consisting of lower alkyl, lower alkoxy and halogen,R4 is lower alkyl, andZ is hydrogen, lower alkyl or unsubstituted or substituted phenyl, or Z and R3 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group, said substituted phenyl and said substituted benzoyl being substituted by one to three substituents selected from lower alkyl, lower alkoxy, halogen or hydroxy, with no more than two hydroxy;
whereby the configuration of the substituents at the 3- and 4- position of the depicted piperidine ring is cis, excluding N-(C2-6 alkyl, C2-6 hydroxyalkyl, NN-di-lower alkylamino lower alkyl, or optionally substituted C7-11 aralkyl) substituted derivatives of quinicine and cinchonicine.
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Accused Products
Abstract
The invention is concerned with novel quinicine and cinchonicine derivatives having cardiovascular activities of the formula or a salt thereof, ##STR1## in which A--B is --CH2 --CH2, --CHOH--CH2 --, --CH2 --CHOH--, --C(O)--CH2 --, --CH2 --C(O)--, --C(NOR4)--CH2 -- or --CH2 --C(NOR4)--; R1 is hydrogen, hydroxy or lower alkoxy; R2 is ethyl or vinyl; R3 is C2-8 alkyl, C1-8 hydroxyalkyl, lower alkoxy-alkyl or lower alkanoyloxyalkyl, C3-6 cycloalkyl, hydroxycycloalkyl, lower alkoxycycloalkyl or lower alkanoyloxycycloalkyl, cycloalkyl lower alkyl, hydroxy-, lower alkoxy- or lower alkanoyloxycycloalkyl lower alkyl; cyano, cyano lower alkyl, lower alkenyl, lower alkynyl, tetrahydrofuryl, mono- or di-lower alkylamino lower alkyl, mono- or di-lower alkylamino lower hydroxy alkyl; optionally substituted phenyl, phenyl lower alkyl or phenyl hydroxy lower alkyl, optionally substituted diphenyl lower alkyl, optionally substituted phenyl lower alkenyl, optionally substituted benzoyl or benzoyl lower alkyl, optionally substituted heteroaryl or heteroaryl lower alkyl, or optionally substituted heteroaroyl or heteroaroyl lower alkyl; R4 is lower alkyl, and Z is hydrogen, lower alkyl or optionally substituted phenyl, or Z and R3 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group, whereby the substituents at the 3- and 4-position of the piperidine ring are in the cis-position, excluding N-[C2-6 alkyl, C2-6 hydroxyalkyl, NN-di-lower alkylamino lower alkyl, optionally substituted C7-11 aralkyl] substituted derivatives of quinicine and cinchonicine.
The compounds of the formula may be in the form of their optically active enantiomers and/or their therapeutically acceptable salts.
Methods for the preparation of the compounds of the formula are also disclosed and form part of the invention.
34 Citations
22 Claims
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1. A compound of formula 1 or a pharmaceutically acceptable salt thereof. ##STR79## in which A--B is --CH2 --CH2 --, --CHOH--CH2 --, --CH2 --CHOH--, --C(O)--CH2 --, --CH2 --C(O)--, --C(NOR4)--CH2 -- or --CH2 --C(NOR4)--,
R1 is hydrogen, hydroxy or lower alkoxy, R2 is ethyl or vinyl, R3 is C2-8 alkyl, C1-8 hydroxyalkyl, lower alkoxyalkyl or lower alkanoyloxyalkyl, C3-6 cycloalkyl, hydroxycycloalkyl, lower alkoxycycloalkyl or lower alkanoyloxycycloalkyl, cycloalkyl lower alkyl, hydroxy-, lower alkoxy- or lower alkanoyloxycycloalkyl lower alkyl, and each of said cycloalkyl moieties is C3-6 cycloalkyl; - cyano, cyano lower alkyl, lower alkenyl, lower alkynyl, tetrahydrofuryl, mono- or di- lower alkylamino lower alkyl, mono- or di-lower alkylamino lower hydroxy alkyl;
unsubstituted or substituted phenyl, unsubstituted or substituted phenyl lower alkyl or unsubstituted or substituted phenyl hydroxy lower alkyl, unsubstituted or substituted diphenyl lower alkyl, unsubstituted or substituted phenyl lower alkenyl, unsubstituted or substituted benzoyl or unsubstituted or substituted benzoyl lower alkyl;
unsubstituted thienyl or thienoyl or substituted thienyl or thienoyl, wherein the substituents are one, two or three substituents selected from the group consisting of lower alkyl, lower alkoxy and halogen,R4 is lower alkyl, and Z is hydrogen, lower alkyl or unsubstituted or substituted phenyl, or Z and R3 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group, said substituted phenyl and said substituted benzoyl being substituted by one to three substituents selected from lower alkyl, lower alkoxy, halogen or hydroxy, with no more than two hydroxy;
whereby the configuration of the substituents at the 3- and 4- position of the depicted piperidine ring is cis, excluding N-(C2-6 alkyl, C2-6 hydroxyalkyl, NN-di-lower alkylamino lower alkyl, or optionally substituted C7-11 aralkyl) substituted derivatives of quinicine and cinchonicine. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 21, 22)
- cyano, cyano lower alkyl, lower alkenyl, lower alkynyl, tetrahydrofuryl, mono- or di- lower alkylamino lower alkyl, mono- or di-lower alkylamino lower hydroxy alkyl;
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13. N-(3-benzoylpropyl)-hydrocinchonicine.
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14. N-(3-benzoylpropyl)-hydrocinchonicinol-1.
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15. N-(3-benzoylpropyl)-desoxo-hydrocinchonicine.
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16. N-propyl-hydroquinicinol-1.
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17. N-butyl-hydroquinicinol-1.
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18. N-pentyl-hydroquinicinol-1.
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19. N-pentyl-hydrocinchonicinol-1.
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20. N-(4-methoxybutyl)-hydrocinchonicine.
Specification
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- Resources
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Current AssigneeACF Chemiefarma NV
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Original AssigneeACF Chemiefarma NV
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Inventorsde Bode, Ronus, Welle, Hendricus B. A., Trijzelaar, Hans B.
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Primary Examiner(s)Daus, Donald G.
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Assistant Examiner(s)RIVERS, DIANA
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Application NumberUS06/201,577Time in Patent Office1,421 DaysField of Search546/176, 546/177, 546/167, 546/168, 546/174, 424/258US Class Current514/314CPC Class CodesC07D 401/06 linked by a carbon chain co...
