Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1993-06-30
1995-06-13
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C07D 3714
Patent
active
054244285
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/Fi92/00003 filed Jan. 3, 1992.
The present invention relates to the pure (-) enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]prop anedinitrile of formula ##STR1##
The invention also relates to salts, compositions and a process for the preparation of this enantiomer as well as to new intermediates of this process.
The compound according to the inventor, is useful as cardiotonic agent, antihypertensive and vasodilator for the treatment of congestive heart failure.
The racemic mixture of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]prop anedinitrile (i) with melting point of 258.degree.-263.degree. C. has been described earlier in applicant's patent application GB 2228004, which corresponds to U.S. Pat. No. 5,151,420. It was shown that the compound (I) is potent in the treatment of congestive heart failure and bas significant calcium dependent binding to troponin. Our further studies nave now unexpectedly revealed that the cardiotonic potency is predominantly due to the optically active (-) enantiomer of this compound. Furthermore it was found that the water solubility of the (-) enantiomer is over 30 fold compared to the racemate. The bioavailability of the (-) enantiomer was also found to be superior compared to racemate. Therefore the pure (-) enantiomer is especially suitable over the racemic compound to be used as a medicament for treating congestive heart failure.
The (+) and (-) enantiomers [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]prop anedinitrile (I) can be separated by passage of the racemic compound over a chiral phase chromatography column. However, this method is tedious if larger amounts of material is needed.
Another possibility to obtain the pule enantiomers of compound (I) is the use of corresponding optically active enantiomers of 6-(4-aminophenyl)-5-methylpyridazin-3(2H)one as an intermediate. The racemic 6-(4-aminophenyl)-5-methyl-pyridazin-3(2H)one of formula (II) ##STR2## can be synthesized by methods known in the literature (J. Med. Chem., 17, 273-281 (1974)). The resolution of the racemic compound (II) has, however, been proved very difficult because the 4-amino group in the molecule is weakly basic. The salts of 6-(4-amino-phenyl)-5-methylpyridazin-3(2H)one with optically active acids hydrolyse on crystallization readily back to the compound (II) and to the resolving compound which interfere the resolution procedure or make it totally impossible.
The separation of the pure enantiomers of compound (II) on a chiral HPLC-column has been described in European patent application EP 208518, which corresponds to U.S. Pat. No. 4,946,842. This method is, however, not applicable for industrial scale. An enantioselective seven step synthesis of (-)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)one starting from (+)-2-chloropropionic acid has also been described in the literature (J. Org. Chem., 56, 1963 (1991)). The total yield in this method is only 12% giving (-)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)one with an optical purity of 97.2%.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a graph depicting the concentration of total [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]prop anedinitrile in dog plasma over time after single dose oral administration of the racemate and the (-) enantiomer.
It was now found that good enantiomeric separation of compound (II) could be obtained by using L- or D-tartaric acid in excess, preferably about 2 to about 3 equivalents, to the compound (II) in 2-propanol. The acid salts of (-)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)one with L-tartaric acid 2-propanol solvate (IIIb) or corresponding (+)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)one with D-tartaric acid 2-propanol solvate (IIIa) crystallize in good yield and in practical optical purity. ##STR3##
It was further found that the minor component in a partly enriched enantiomer mixture may be crystallized out as racemic compound (II) from dioxane leaving the rest of the m
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Howson et al. Jour. Med. (Chem, vol. 31 pp. 352-356 (1988).
J. Org. Chem. 1991, 56, 1963-1966, An Enantioselective Synthesis of SK&F 93505, A Key Intermediate For Preparing Cardiotonic Agents by Franklin F. Owings, Margaret Fox, Conrad J. Kowalski, and Neil H. Baine.
Journal of Medicinal Chemistry, 1974, vol. 17, No. 3, pp. 273-281, 6-Phenyl-4,5-Dihydro-3(2H)-Pyridazinones. A Series of Hypotensive Agents by William V. Curran and Adma Ross.
Backstrom Reijo
Haarala Jorma
Haikala Heimo
Honkanen Erkki
Nore Pentti
Daus Donald G.
Orion-yhtyma Oy
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