A compound having the structure (I) wherein R is selected from the group consisting of 1) and 2), or a pharmaceutically acceptable salt thereof, and methods of using the compounds for treating hypertension.
1. A compound of the formula I:
or a pharmaceutically acceptable salt thereof, wherein
R is selected from the group consisting of
R 2 , in each instance in which it occurs, is independently —C 1-6 alkyl;
R 3 is —C 1-6 alkyl or —C 1-6 alkylene-aryl;
X is selected from the group consisting of
R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, halogen, and —O—C 1-6 alkyl.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of
—CH 2 CH 2 CH 2 CH 2 —,
—CH 2 CH(CH 3 )CH 2 CH 2 —,
—CH(CH 3 )CH 2 CH 2 CH 2 —,
—CH 2 CH 2 CH(CH 3 )CH 2 —,
—CH 2 CH 2 CH 2 CH(CH 3 )—,
—CH(CH 3 )CH 2 CH 2 —,
—CH 2 CH 2 CH 2 CH 2 CH 2 —,
—CH 2 CH 2 CH(CH 3 )CH 2 CH 2 —
—CH(CH 3 )CH 2 CH 2 CH 2 CH 2 —
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , and —CH(CH 3 ) 2 .
4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH(CH 3 ) 2 and —CH 2 —C 6 H 5 .
5. A compound of claim 1 , selected from the group consisting of
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl-4-[({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)methyl]benzoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-[1-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)ethyl]benzoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-[({[(1Z)-2,2-diethyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)methyl]benzoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)cyclohexanecarboxylate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl cis-4-({[(1Z)-2-tert-butyl-2-methyl-1-oxidohydrazono]amino}oxy)cyclohexanecarboxylate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl trans-4-({[(1Z)-2-tert-butyl-2-methyl-1-oxidohydrazono]amino}oxy)cyclohexanecarboxylate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl trans-4-({[(1Z)-2,2-diethyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)cyclohexanecarboxylate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 5-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)pentanoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 5-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)-3-methylpentanoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl (3R)-5-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)-3-methylpentanoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl (3S)-5-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)-3-methylpentanoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 5-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)-2-methylpentanoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 5-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)-4-methylpentanoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 5-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)hexanoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 4-({[(1E)-2-tert-butyl-2-methyl-1-oxidohydrazono]amino}oxy)-2-methylbutanoate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 2-[2-({[(1Z)-2-tert-butyl-2-methyl-1-oxidohydrazono]amino}oxy)ethyl]-trans-cyclopropanecarboxylate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 2-[2-({[(1Z)-2-tert-butyl-2-methyl-1-oxidohydrazono]amino}oxy)ethyl]-cis-cyclopropanecarboxylate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 2-[({[2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)methyl]cyclopropanecarboxylate,
Ethyl 1-{(Z)-[(5-{[(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl]oxy}-5-oxopentyl)oxy]-NNO-azoxy}-L-prolinate,
(3S)-3-(4-Chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl 5-({[(1Z)-2-benzyl-2-isopropyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)pentanoate,
5-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)pentyl (3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl carbonate,
5-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)-3-methylpentyl (3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl carbonate,
(2S)-6-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-11 5 -diazan-1-ylidene]amino}oxy)hexan-2-yl (3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl carbonate, and
Methyl 1-[(Z)-({5-[({[(3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-7-yl]oxy}carbonyl)oxy]pentyl}oxy)-NNO-azoxy]-L-prolinate,
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
7. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising a compound of claim 1 , a diuretic, and a pharmaceutically acceptable carrier.
9. A method for treating hypertension in a patient which comprises administering to the patient a therapeutically effective amount of the composition of claim 6 .