Pyridazinone-substituted benzimidazoles and salts

• US 4,361,563 A
• Filed: 05/01/1981
• Issued: 11/30/1982
• Est. Priority Date: 08/25/1978
• Status: Expired due to Term

• Current Assignee: KARL Thomae Gesellschaft Mit Beschrankter Haftung
• Original Assignee: Dr. Karl Thomae GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Eberlein, Wolfgang, Heider, Joachim, Austel, Volkhard, Haarmann, Walter, Diederen, Willi
• Primary Examiner(s): Berch, Mark L.
• Application Number:
  US06/259,537
• Time in Patent Office: 578 Days
• Field of Search: 424/250, 544/238
• US Class Current: 514/247
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 237/04 having less than three double bonds between ring members or between ring members and non-ring members

Abstract

Compounds of the formula ##STR1## wherein R₁ is hydrogen; trifluoromethyl; alkyl of 1 to 11 carbon atoms; cycloalkyl of 3 to 7 carbon atoms; hydroxyl; alkoxy of 1 to 6 carbon atoms; mercapto; (alkyl of 1 to 6 carbon atoms)-mercapto; phenyl-(alkyl of 1 to 3 carbon atoms); phenyl; or mono-, di- or tri-substituted phenyl, where the substituents, which may be identical to or different from each other, are each halogen, alkyl of 1 to 4 carbon atoms, (alkyl of 1 to 6 carbon atoms)-sulfinyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, mercapto or (alkyl of 1 to 6 carbon atoms)-mercapto;

R₂ is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl-(alkyl of 1 to 3 carbon atoms); and

R₃ is alkyl of 1 to 6 carbon atoms; optically active antipodes thereof; and non-toxic, pharmaceutically acceptable acid addition salts of said compounds or of said optically active antiposed. The compounds are useful as cardiotonics and antithrombotics.

Claims

1. A compound of the formula ##STR7## wherein R₁ is hydrogen;

trifluoromethyl;

alkyl of 1 to 11 carbon atoms;

cycloalkyl of 3 to 7 carbon atoms;

hydroxyl;

alkoxy of 1 to 6 carbon atoms;

mercapto;

(alkyl of 1 to 6 carbon atoms)-mercapto;

phenyl(alkyl of 1 to 3 carbon atoms);

phenyl;

or mono-, di- or trisubstituted phenyl, where the substituents, which may be identical to or different from each other, are each halogen, alkyl of 1 to 4 carbon atoms, (alkyl of 1 to 6 carbon atoms)sulfinyl, hydroxyl, alkoxy of 1 to 6 carbon atoms, mercapto or (alkyl of 1 to 6 carbon atoms)-mercapto;

R₂ is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or phenyl-(alkyl of 1 to 3 carbon atoms); and

R₃ is alkyl of 1 to 6 carbon atoms;

an optically active antipode thereof;

or a non-toxic, pharmaceutically acceptable acid addition salt of said compound or of said optically active antipode.

2. A compound of claim 1 where

R₁ is hydrogen, trifluoromethyl;

alkyl of 1 to 11 carbon atoms;

cycloalkyl of 3 to 7 carbon atoms;

hydroxyl;

alkoxy of 1 to 6 carbon atoms;

mercapto;

(alkyl of 1 to 6 carbon atoms)-mercapto;

phenyl-(alkyl of 1 to 3 carbon atoms);

phenyl;

hydroxyphenyl;

halo-phenyl;

(alkyl of 1 to 4 carbon atoms)-phenyl;

(alkoxy of 1 to 6 carbon atoms)-phenyl;

methoxy-halo-phenyl;

methylmercaptophenyl;

methylsulfinyl-phenyl;

dimethoxy-phenyl;

methoxy-methylmercapto-phenyl;

methoxy-methylsulfinyl-phenyl;

or trimethoxy-phenyl;

R₂ is hydrogen, alkyl of 1 to 5 carbon atoms, cyclopropyl, cyclohexyl or benzyl; and

R₃ is alkyl of 1 to 4 carbon atoms;

an optically active antipode thereof;

or a non-toxic, pharmaceutically acceptable acid addition salt of said compound or of said optically active antipode.

3. A compound of claim 1, where

R₁ is hydrogen, methyl, isopropyl, n-pentyl, 2-pentyl, n-hexyl, n-undecyl, cyclopropyl, cyclohexyl, cycloheptyl, hydroxy, ethoxy, mercapto, methyl-mercapto, isopropyl-mercapto, n-hexylmercapto, trifluoromethyl, 1-phenyl-ethyl, 1-phenyl-2-propyl, phenyl, 2-fluorophenyl, 4-hydroxy-phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2,4-dimethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,4,5-trimethoxy-phenyl, 4-n-hexyloxy-phenyl, 4-methyl-phenyl, 4-tert. butyl-phenyl, 4-chloro-phenyl, 2-methoxy-4-methylmercapto-phenyl, 2-methoxy-4-methylsulfinyl-phenyl, or 2-bromo-5-methoxy-phenyl;

R₂ is hydrogen, methyl, 3-methyl-butyl, cyclopropyl, cyclohexyl, or benzyl; and

R₃ is methyl, ethyl, or n-butyl;

an optically active antipode thereof;

or a non-toxic, pharmaceutically acceptable acid addition salt of said compound or of said optically active antipode.

4. A compound of claim 1 where

R₁ is hydrogen, methyl, 2-pentyl, cyclopropyl, 1-phenyl-ethyl, ethoxy, methyl-mercapto, trifluoromethyl, phenyl, 4-methyl-phenyl, 2-fluorophenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 4-hexyloxy-phenyl, or 4-hydroxy-phenyl;

R₂ is hydrogen, 3-methyl-butyl, cyclopropyl or benzyl; and

R₃ is methyl;

an optically active antipode thereof;

or a non-toxic, pharmaceutically acceptable acid addition salt of said compound or of said optically active antipode.

5. A compound of claim 1, where p1 R₁ is methyl, trifluoromethyl, 4-methyl-phenyl, 1-phenyl-ethyl, 2-fluoro-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl or 4-hydroxy-phenyl;

R₂ is hydrogen; and

R₃ is methyl;

an optically active antipode thereof;

or a non-toxic, pharmaceutically acceptable acid addition salt of said compound or of said optically active antipode.

6. A compound of claim 1, which is 2-(4-methoxy-phenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole, an optically active antipode thereof, or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

7. A compound of claim 1, which is 1-(3-methyl-butyl)-2-methyl-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole, an optically active antipode thereof, or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

8. A compound of claim 1, which is 2-(4-methyl-phenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)-benzimidazole, an optically active antipode thereof, or a non-toxic, pharmaceutically acceptable acid addition salt thereof.

9. A cardiotonic or antithrombotic pharmaceutical composition consisting essentially of an inert pharmaceutical carrier and an effective cardiotonic or antithrombotic amount of a compound of claim 1.

10. The method of increasing the strength of myocardial contraction or preventing or relieving thrombosis in a warm-blooded animal in need thereof, which comprises perorally or parenterally administering to said animal a composition of claim 9.