Angiotensin II receptor blocking 2,3,6 substituted quinazolinones

• US 5,281,603 A
• Filed: 04/23/1993
• Issued: 01/25/1994
• Est. Priority Date: 04/23/1993
• Status: Expired due to Term

• Current Assignee: American Colloid Company (Minerals Technologies Incorporated)
• Original Assignee: American Colloid Company (Minerals Technologies Incorporated)
• Inventors: Venkatesan, Aranapakam M., Levin, Jeremy I.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Grumbling, Matthew V.
• Application Number:
  US08/052,934
• Time in Patent Office: 277 Days
• Field of Search: 514/259, 544/284, 544/287
• US Class Current: 514/266.23
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The invention provides novel 2,3,6-substituted quinazolinones having the formula ##STR1## wherein R⁶ is ##STR2## and X, R, R¹, R², R³, R⁴ and R⁸ are described in the specification which have activity as angiotensin II (AII) antagonists.

Claims

1. A quinazolinone compound having the formula:

##STR14## wherein;

R is ##STR15## X is straight or branched alkyl of 3 to 5 carbon atoms;

R⁶ is ##STR16## R¹ is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), 2-pyridinyl, 4-pyridinyl, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms);

R² is H, or straight chain lower alkyl of 1 to 4 carbon atoms;

R³ is H, triphenylmethyl, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), straight chain lower alkyl of 1 to 4 carbon atoms;

R⁴ is H, straight chain lower alkyl of 1 to 4 carbon atoms, ##STR17## R¹¹ is lower alkyl of 1 to 3 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), --OR⁷, benzyloxy, --NH , --NHR⁷, --NR⁷ R⁷ ;

R⁷ is lower alkyl of 1 to 3 carbon atoms;

R⁸ is lower alkyl of 1 to 3 carbon atoms, phenyl; and

pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 wherein said salts are selected from potassium, sodium, calcium, magnesium or ammonium.

3. The compound according to claim 1 wherein

X is a straight chain alkyl of 3 or 4 carbon atoms;

R⁶ is ##STR18##

6. A pharmaceutical composition useful for treating angiotensin induced hypertension or congestive heart failure in a mammal comprising a suitable pharmaceutical carrier and an effective amount of a compound of claim 1.

7. A method of treating angiotensin induced hypertension in a mammal comprising administering a compound of claim 1 to said mammal in an amount effective to lower angiotensin induced hypertension.

8. The compound according to claim 1, CIS-3-[2-Butyl-3,4-dihydro-4-oxo-3-[[2'"'"'-(1H-tetrazol-5-yl)[1,1'"'"'-biphenyl]-4yl]methyl]6-quinazolinyl]-3a,6a-dihydro-5-methyl-pyrrolo[3,4-c]pyrazole-4,6-(1H,5H)-dione.

9. The compound according to claim 1, (3alpha,3aalpha,6aalpha)-3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'"'"'-(1H-tetrazol-5-yl)-[1,1'"'"'-biphenyl]-4-yl]methyl]-6quinaolinyl]-2,3,3a,6a-tetrahydro-3,5-dimethyl-pyrrolo[3,4-c]pyrazole-4,6(1H,5H)-dione.

14. A method of treating congestive heart failure in a mammal comprising administering a compound of claim 1 to said mammal in an amount effective to treat congestive heart failure.

15. A method of antagonizing the effects of Angiotensin II in a mammal comprising administering a compound of claim 1 to said mammal in an amount effective to treat the effects of Angiotensin II.

4. A quinazolinone compound having the formula:

##STR19## wherein;

R¹⁸ is ##STR20## X is straight or branched alkyl of 3 to 5 carbon atoms;

R⁶ is ##STR21## R¹ is H, straight chain lower alkyl of 1 to 4 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), 2-pyridinyl, 4-pyridinyl, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms);

R² is H, or straight chain lower alkyl of 1 to 4 carbon atoms;

R³ is H, triphenylmethyl, benzyl, substituted benzyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), straight chain lower alkyl of 1 to 4 carbon atoms;

R⁴ is H, straight chain lower alkyl of 1 to 4 carbon atoms, ##STR22## R¹¹ is lower alkyl of 1 to 3 carbon atoms, phenyl, substituted phenyl (substitution selected from mono-lower alkyl of 1 to 3 carbon atoms, trifluoromethyl, nitro, O-alkyl of 1 to 3 carbon atoms), --OR⁷, benzyloxy, --NH², --NHR⁷, --NR⁷ R⁷ ;

R⁷ is lower alkyl of 1 to 3 carbon atoms;

R⁸ is lower alkyl of 1 to 3 carbon atoms, phenyl.

5. The compound according to claim 4 wherein

X is a straight chain alkyl of 3 or 4 carbon atoms;

R⁶ is ##STR23##

10. The compound according to claim 4, Cis-3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'"'"'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'"'"'-biphenyl]-4-yl]methyl]-6-quinazolinyl]-3a,6a-dihydro-5-methyl-1-(triphenylmethyl)-pyrrolo[3,4-c]pyrazole-4,6-(1H,5H)-dione.

11. The compound according to claim 4, (3alpha,3aalpha,6aalpha)-3-(2-butyl-1,3-dihydro-4-oxo-6-quinazolinyl)tetrahydro-3,5-dimethyl-1-(triphenylmethyl)-pyrrolo[3,4-c]pyrazole-4,6-(1,5H)-dione.

12. The compound according to claim 4, (3alpha,3aalpha,6aalpha)-3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'"'"'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'"'"'-biphenyl]-4-yl]methyl]-6-quinazolinyl]tetrahydro-3,5-dimetyl-1-(triphenylmethyl)-pyrrolo[3,4-c]pyrazole-4,6-(1H,5H)-dione.

13. The compound according to claim 4, Cis-3-(2-butyl-1,4-dihydro-4-oxo-6-quinazolinyl)3a,6a-dihydro-5-methyl-1-(triphenylmethyl)-pyrrolo[3,-c]pyrazole-4,6(1H,5H)-dione.