Thiophene systems. 9. Thienopyrimidinedione derivatives as potential antihypertensive agents.
A series of thieno[3,4-d]-, thieno[3,2-d]-, and thieno[2,3-d]pyrimidine-2,4-diones with (phenylpiperazinyl)alkyl substitution at N-3 have been synthesized and evaluated for antihypertensive effects in spontaneously hypertensive rats (SHR). These 49 compounds were compared to the vasodilator standards prazosin and the isosteric quinazoline-2,4-dione SGB 1534. Substitution at the 2-, 3-, or 4-position of the phenyl ring was examined, with that at the 2-position more potent than 4-substitution while the isomeric 3-substituted compounds were least potent. Neither alkylation nor acylation at the N-1 position improved the antihypertensive effects as compared to hydrogen. The three thienopyrimidine-2,4-diones (3-5) that contain a [(2-methoxyphenyl)piperazinyl]ethyl moiety at N-3 and hydrogen at N-1 were found to be potent oral antihypertensive agents in the SHR with doses (mg/kg, po) for reducing systolic blood pressure (SBP) by 50 mmHg (ED-50SBP) of 0.21, 0.19, and 1.0, respectively. The compounds 1-5 were further evaluated for alpha blocking potency by measuring the iv doses necessary to antagonize the phenylephrine pressor response by 50% (ED50) in the SHR. The ED50 values (micrograms/kg) are 10.4, 3.3, 1.7, 2.1, and 15.4, respectively. These results clearly show that all three thiophene systems have potent activity as antihypertensive agents and that 3 and 4 are more potent than 1 or 2 as alpha 1-antagonists in vivo.
Russell
R K
RK
Research Laboratories, Ortho Pharmaceutical Corporation, Raritan, New Jersey 08869.
Press
J B
JB
Rampulla
R A
RA
McNally
J J
JJ
Falotico
R
R
Keiser
J A
JA
Bright
D A
DA
Tobia
A
A
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000188:drug therapy*; D007700:Kinetics; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*
D011743:Pyrimidines; D011942:Receptors, Adrenergic, alpha; D013876:Thiophenes; D010656:Phenylephrine; D011224:Prazosin