WO1992012135A1 - (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile - Google Patents

(-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile Download PDF

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Publication number
WO1992012135A1
WO1992012135A1 PCT/FI1992/000003 FI9200003W WO9212135A1 WO 1992012135 A1 WO1992012135 A1 WO 1992012135A1 FI 9200003 W FI9200003 W FI 9200003W WO 9212135 A1 WO9212135 A1 WO 9212135A1
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Prior art keywords
methyl
tartaric acid
phenyl
pyridazinyl
oxo
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PCT/FI1992/000003
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Inventor
Pentti Nore
Erkki Honkanen
Reijo Bäckström
Tom Wikberg
Heimo Haikala
Jorma Haarala
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Orion Oyj
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Orion Yhtyma Oy
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Priority claimed from GB919100049A external-priority patent/GB9100049D0/en
Priority claimed from GB919118947A external-priority patent/GB9118947D0/en
Priority to RO93-00896A priority Critical patent/RO111847B1/en
Priority to KR1019930701800A priority patent/KR100207145B1/en
Priority to JP4501428A priority patent/JP2635445B2/en
Priority to EP92901317A priority patent/EP0565546B1/en
Priority to US08/081,360 priority patent/US5424428A/en
Priority to GEAP19922483A priority patent/GEP19991868B/en
Priority to CA002099262A priority patent/CA2099262C/en
Application filed by Orion Yhtyma Oy filed Critical Orion Yhtyma Oy
Priority to DE69201640T priority patent/DE69201640T2/en
Priority to HU9301911A priority patent/HU218659B/en
Publication of WO1992012135A1 publication Critical patent/WO1992012135A1/en
Priority to PL92310250A priority patent/PL169415B1/en
Priority to PL92299920A priority patent/PL169435B1/en
Priority to NO932367A priority patent/NO300682B1/en
Priority to BG97915A priority patent/BG62002B1/en
Anticipated expiration legal-status Critical
Priority to US08/454,856 priority patent/US5569657A/en
Priority to HK117395A priority patent/HK117395A/en
Priority to LVP-95-358A priority patent/LV11174B/en
Priority to CY187896A priority patent/CY1878A/en
Priority to FI972077A priority patent/FI109902B/en
Priority to NO2001021C priority patent/NO2001021I1/en
Priority to LU90920C priority patent/LU90920I2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the pure (-) enantiomer of [[4-(1 ,4,5,6- tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile of formula
  • 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 invention is useful as cardiotonic agent, anti hypertensive and vasodilator for the treatment of congestive heart failure.
  • (+) and (-) enantiomers of [[4-(1 ,4,5,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl)phenyl]hydrazono]propanedinitrile (I) can be separated by passage of the racemic compound over a chiral phase chromatography column.
  • the minor component in a partly enriched enantiomer mixture may be crystallized out as racemic compound (II) from dioxane leaving the rest of the major component in the solution.
  • the salts (Ilia) or (lllb) obtained in the crystallization mentioned above were filtered and the free base was liberated with potassium carbonate solution and the product were treated with dioxane.
  • Both enantiomers of (I) are thus obtained by this two phase crystallization procedure in high optical purity of over 99 %.
  • the yield in this process is also very good, because the rasemic compound (I) is obtained from dioxane in crystalline state and may be recycled.
  • Both resolving compounds L- or D-tartaric may be alternatively used in the above process, but the natural L-tartaric acid is preferable because it is much cheaper.
  • optically substantially pure (-) and (+) enantiomers of the compound (I) may then be prepared from the corresponding optically substantially pure (-) and (+) enantiomer of compound (II), respectively, by the usual process disclosed in applicant's patent application GB 2228004, in high optical purity and in nearly quantitative yields.
  • the process described in GB 2228004 for preparing the compound (I) comprises treating the compound of formula (II) with sodium nitrite and malononitrile in acidic conditions.
  • optically substantially pure means here optical purity over about 90 %, preferably over 95 % and more preferably over 99 %.
  • Salts of the enantiomers of compound (I) may be prepared by known methods. Pharmaceutically acceptable salts are useful as active medicaments, however, preferred are the salts with alkali or alkaline earth metals.
  • Cardiotonic action of the (-) and (+) enantiomers of [[4-(1 ,4,5,6-tetra- hydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile (I) was studied in isolated, electrically paced, right ventricular papillary muscle of guinea-pig. Experiments were carried out in normal Tyrode's bath solution as described by Otani et al., Japan. J. Pharmacol. 45, 425, 1987.
  • the pharmaceutically active compound according to this invention is formulated into dosage forms using the principles known in the art. It is given to mammalian organisms, i.e., humans, a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions.
  • the composition according to the invention contains an therapeuticaliy effective amount of the pharma ⁇ ceutically active compound of the invention.
  • the contents of the active compound is in the composition from about 0.5 to 100 % per weight.
  • the compound of the invention may be administered to man in oral doses as low as ranging from about 1 to 50 mg per day. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art.
  • compositions are formulated depending upon the purpose of the medicine, normal uncoated tablets being quite satisfactory. Sometimes it is advisable to use coated tablets, i.e. so-called enterotablets, to secure that the medicine reaches the desired part of the gastrointestinal tract. Dragees and capsules may be used too.
  • Example 5 508 mg (2.5 mmol) of pure (+)-6-(4-aminophenyl)-5-methylpyridazin- 3(2H)one obtained in Example 1 was dissolved in 100 ml of 2-propanol. 750 mg (5.0 mmol) of D-tartaric acid was added and the mixture was heated to boiling. On cooling 800 mg of crystalline (+)-6-(4-aminophenyl)5-methyl- pyridazin-3(2H)one D-tartrate mono 2-propanol solvate was obtained, mp. 97- 105°C.
  • Example 5 508 mg (2.5 mmol) of pure (+)-6-(4-aminophenyl)-5-methylpyridazin- 3(2H)one obtained in Example 1 was dissolved in 100 ml of 2-propanol. 750 mg (5.0 mmol) of D-tartaric acid was added and the mixture was heated to boiling. On cooling 800 mg of crystalline (+)-6-(4
  • the optical purities of the compounds were determined by the high performance liquid chromatography.
  • the instrument was a Waters 600 E gradient pump with a Waters 991 photodiode array detector and a Waters 700 Satellite Wisp injector (Millipore Co.) controlled by a NEC Powermate SX Plus computer.
  • the enantiomers of 6-(4-aminophenyl)-5-methylpyridazin-3(2H)one were separated by using a sellulose-type chiral column (Chiracel «OJ, 4.6x250 mm, Daicel Chemical Industries LTD.).
  • the mobile phase consisted of 97 % 2- propanol and 3 % hexane. The flow rate was 0.3 ml/min.

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Abstract

Optically substantially pure (-) enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile or pharmaceutically acceptable salt thereof, intermediates and a process for the preparation are described. The product is useful as a cardiotonic agent, antihypertensive and vasodilator for the treatment of congestive heart failure.

Description

(-)-[[4-(1 ,4,5,6-TETRAHYDRO-4-METHYL-6-OXO-3-PYRIDAZINYL)PHENYL]- HYDRAZONO]PROPANEDINITRILE
The present invention relates to the pure (-) enantiomer of [[4-(1 ,4,5,6- tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile of formula
Figure imgf000003_0001
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 invention is useful as cardiotonic agent, anti hypertensive 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]propanedinitrile (I) with melting point of 258- 263°C has been described earlier in applicant's patent application GB 2228004. It was shown that the compound (I) is potent in the treatment of congestive heart failure and has significant calcium dependent binding to troponin. Our further studies have 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 of [[4-(1 ,4,5,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl)phenyl]hydrazono]propanedinitrile (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 pure 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-amino- phenyl)-5-methyl-pyridazin-3(2H)one of formula (II)
Figure imgf000004_0001
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. This method is, however, not applicable for industrial scale. An enantio- selθctivθ 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 %.
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 (Ilib) or corresponding (+)-6-(4-aminophenyl)-5-methylpyridazin- 3(2H)one with D-tartaric acid 2-propanol solvate (Ilia) crystallize in good yield and in practical optical purity.
(+) x L-tartaric acid x 2-propanol solvate J Ula
(-) x L-tartaric acid x 2-prσpanol solvate J nib
Figure imgf000004_0002
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 major component in the solution. Thus the salts (Ilia) or (lllb) obtained in the crystallization mentioned above were filtered and the free base was liberated with potassium carbonate solution and the product were treated with dioxane. Both enantiomers of (I) are thus obtained by this two phase crystallization procedure in high optical purity of over 99 %. The yield in this process is also very good, because the rasemic compound (I) is obtained from dioxane in crystalline state and may be recycled. Both resolving compounds L- or D-tartaric may be alternatively used in the above process, but the natural L-tartaric acid is preferable because it is much cheaper.
The optically substantially pure (-) and (+) enantiomers of the compound (I) may then be prepared from the corresponding optically substantially pure (-) and (+) enantiomer of compound (II), respectively, by the usual process disclosed in applicant's patent application GB 2228004, in high optical purity and in nearly quantitative yields. The process described in GB 2228004 for preparing the compound (I) comprises treating the compound of formula (II) with sodium nitrite and malononitrile in acidic conditions. The term "optically substantially pure" means here optical purity over about 90 %, preferably over 95 % and more preferably over 99 %.
Salts of the enantiomers of compound (I) may be prepared by known methods. Pharmaceutically acceptable salts are useful as active medicaments, however, preferred are the salts with alkali or alkaline earth metals.
Solubility TABLE 1.
The water solubility of (-) enantiomer and racemic mixture of [[4-(1 ,4,5,6- tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedi- nitrile (I) in 67 mM phosphate buffer (pH 2).
Compound Solubility (mg/ml)
(-) enantiomer 0.029 racemic 0.0007 Cardiotonic action
Cardiotonic action of the (-) and (+) enantiomers of [[4-(1 ,4,5,6-tetra- hydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile (I) was studied in isolated, electrically paced, right ventricular papillary muscle of guinea-pig. Experiments were carried out in normal Tyrode's bath solution as described by Otani et al., Japan. J. Pharmacol. 45, 425, 1987.
The results are presented in Table 2. They show that the (-) enantiomer was 47 times more potent than the (+) enantiomer.
TABLE 2.
Cardiotonic effects of the (-) and (+) enantiomers of [[4-(1 ,4,5,6-tetra- hydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile in guinea-pig papillary muscle.
Enantiomer ECgn, mM
(-) 0.06 (+) 2.8
Bioavailability
Concentration of total [[4-(1 ,4,5,6-tetrahydro-4-methyl-6-oxo-3- pyridazinyl)phenyl]hydrazono]propanedinitrile in dog plasma after single dose oral administration of the racemate (1 mg/kg) and (-)-enantiomer (0.5 mg/kg) is shown in Figure 1. Curve A is for the (-)-enantiomer and curve B is for the racemic [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydra- zono]propanedinitrile. The figure shows that when (-)-enantiomer is used instead of the racemate less than half dose is needed to produce the same plasma concentration level of the total drug substance.
The pharmaceutically active compound according to this invention is formulated into dosage forms using the principles known in the art. It is given to mammalian organisms, i.e., humans, a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions. The composition according to the invention contains an therapeuticaliy effective amount of the pharma¬ ceutically active compound of the invention. The contents of the active compound is in the composition from about 0.5 to 100 % per weight. In general, the compound of the invention may be administered to man in oral doses as low as ranging from about 1 to 50 mg per day. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art. It is evident that suitable carriers, solvents, gel forming ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting compounds and other ingredients normally used in this field of technology may be also used. The LD50 value of the (-) enantiomer given intravenously to rats was 57 mg/kg.
The compositions are formulated depending upon the purpose of the medicine, normal uncoated tablets being quite satisfactory. Sometimes it is advisable to use coated tablets, i.e. so-called enterotablets, to secure that the medicine reaches the desired part of the gastrointestinal tract. Dragees and capsules may be used too.
Example 1
Resolution of racemic 6-(4-aminophenyl)-5-methylpyridazin-3(2H)one with L- tartaric acid.
(±)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)one (203 g, 1 mole) was dissolved in 2-propanol (40 dnrι3) on heating. To this solution (L)-tartaric acid (300 g, 2 mole) was gradually added. The mixture was stirred on heating until a clear solution was obtained. The solution was cooled slowly to room tempera¬ ture with stirring. After it has been stirred over night at 20°C the crystalline product (Illb) was filtered. The wet salt was dissolved in water (1.5 dm3) and potassium carbonate solution (190 g K2CO3 in 0.75 dm3 of water) was added with stirring. The free base was filtered, washed with water and dried. The product (104.6 g) was dissolved in dioxane (0.6 dm3) on heating and allowed to cool to room temperature. The racemic 6-(4-aminophenyl)-5-methyl- pyridazin-3(2H)one was filtered (74.6g) and the filtrate was evaporated to dryness in vacuo yielding (-)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)one as a crystalline solid (23.8 g) with optical purity of 99.5 %, m.p. 207 - 210°C, [afo25 = -383° (ethanol-water-conc. HCl 17:2:1 ). The 2-propanol solution containing the (+)-enantiomer together with the racemate of compound (I) was evaporated to dryness in vacuo. The residue was treated with potassium carbonate solution as described above to give a mixture of (+)-enantiomer and racemate (87.3 g) which was dissolved on heating in dioxane (0.48 drrι3). The racemate was filtrated after cooling (48.0 g) and the filtrate was evaporated to dryness in vacuo yielding (+)-6-(4-amino- phenyl)-5-methylpyridazin-3(2H)one as a crystalline solid (26.1 g) with optical purity of 99.5 %, mp. 206 - 209°C, [afo25 = +391° (ethanol-water-conc. HCl 17:2:1). In total 122.6 g of racemate was recovered. The yield of (-)-enantiomer of (I) was thus 59.2 % and the yield of (+)-enantiomer of (I) 64.9 %.
Example 2
(+)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono3- propanedinitriie
The title compound was prepared as described in patent application GB 2228004 from (+)-6-(4-amino-phenyl)-5-methylpyridazin-3(2H)one. Yield 98 %, mp 210-214°C , [afo25- 568° (tetrahydrofurane-methanol 1 :1).
Example 3.
(-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]- propanedinitrile
The title compound was obtained as described above from (-)-6-(4- aminophenyl)-5-methylpyridazin-3(2H)one. Yield 97 %, mp 210-214°C, [a]-?5-* -566° (tetrahydrofurane-methanol 1:1).
Example 4.
Preparation of pure diastereomeric salt (Ilia)
508 mg (2.5 mmol) of pure (+)-6-(4-aminophenyl)-5-methylpyridazin- 3(2H)one obtained in Example 1 was dissolved in 100 ml of 2-propanol. 750 mg (5.0 mmol) of D-tartaric acid was added and the mixture was heated to boiling. On cooling 800 mg of crystalline (+)-6-(4-aminophenyl)5-methyl- pyridazin-3(2H)one D-tartrate mono 2-propanol solvate was obtained, mp. 97- 105°C. Example 5
Preparation of pure diastereomeric salt (1Mb)
The above process was repeated by using (-)-6-(4-amino-phenyl)-5- methylpyridazin-3(2H)one and L-tartaric acid. Mp. 98-106°C.
Example 6
Preparation of (-)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)one by resolution of the corresponding racemate with L-tartaric acid.
(±)-6-(4-aminophenyl)-5-methylpyridazin-3(2H)one (203 g, 1 mole) was dissolved in 2-propanol (10 dm3) on heating. To this solution (L)-tartaric acid (300 g, 2 mole) was gradually added. The mixture was stirred on heating until a clear solution was obtained and cooled slowly during 3 h to 50°C and stirred further over night at 50°C. The crystalline product was filtered and the procedure described in Example 1 was repeated. The yield of (-)-6-(4-amino- phenyl)-5-methylpyridazin-3(2H)one was 30.3 g (97.4 % of the theoretical). The optical purity was 99.7 %. In total 140.8 g of the racemate was recovered.
The optical purities of the compounds were determined by the high performance liquid chromatography. The instrument was a Waters 600 E gradient pump with a Waters 991 photodiode array detector and a Waters 700 Satellite Wisp injector (Millipore Co.) controlled by a NEC Powermate SX Plus computer. The enantiomers of 6-(4-aminophenyl)-5-methylpyridazin-3(2H)one were separated by using a sellulose-type chiral column (Chiracel «OJ, 4.6x250 mm, Daicel Chemical Industries LTD.). The mobile phase consisted of 97 % 2- propanol and 3 % hexane. The flow rate was 0.3 ml/min. The enantiomers of [[4-(1 ,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]- propanedinitrile were separated by using a β-cyclodextrin column (Cyclobond lb, 4.6x250 mm, Advance Separation Technologies Inc.). The mobile phase consisted of 41 % methanol in water buffered to pH 4.0 with 1 % triethyl- ammonium acetate. The flow rate was 0.3 ml/min.

Claims

Claims
1. (-)-[[4-(1 ,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]- hydrazono]propanedinitrile and pharmaceutically acceptable salts thereof.
2. A pharmaceutical composition which comprises a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
3. A process for the optical resolution of (±)-6-(4-aminophenyl)-5-methyl- pyridazin-3(2H)one, which process comprises contacting the mixture of enantiomers with L- or D-tartaric acid in 2-propanol, recovering the resulting crystalline salt and optionally basifying the salt to form the corresponding free base.
4. A process as claimed in claim 3, wherein the free base is further dissolved in dioxane and the filtrate containing the optically active free base is recovered.
5. A process as claimed in claim 3 or 4, wherein the L- or D-tartaric acid is used in an amount of from about 2 to about 3 equivalents of acid per equivalent of enantiomers.
6. A process as claimed in claim 3, 4 or 5, wherein the crystalline salt comprises diastereomeric intermediate salt of formulae (Ilia) or (I I lb)
(+) L-tartaric acid x 2-propanol solvate J IQa
(-) x L-tartaric acid x 2-propanol solvate J nib
Figure imgf000010_0001
7. A process for preparing optically substantially pure (-)-[[4-(1 ,4,5,6- tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile or (+)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]- propanedinitrile which comprises treating optically substantially pure (-) or (+) enantiomer of 6-(4-aminophenyI)-5-methylpyridazin-3(2H)one prepared according to any of claims 3-6 with sodium nitrite and malononitrile.
8. Diastereomeric intermediate salts of formulae (Ilia) or (1Mb)
L-tartaric acid x 2-propanol solvate J IHa
L-tartaric acid x 2-propanol solvate J mb
Figure imgf000011_0001
9. A method for treating congestive heart failure in a mammalian organism, said method comprising administering an effective amount to treat congestive heart failure of a compound as claimed in claim 1 to a mammalian organism in need of such treatment.
PCT/FI1992/000003 1991-01-03 1992-01-03 (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile Ceased WO1992012135A1 (en)

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Application Number Priority Date Filing Date Title
HU9301911A HU218659B (en) 1991-01-03 1992-01-03 A process for the preparation of (-) - {4- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl] hydrazino} propanedinitrile and pharmaceutical compositions containing it.
DE69201640T DE69201640T2 (en) 1991-01-03 1992-01-03 (-) - [[4- (1,4,5,6-TETRAHYDRO-4-METHYL-6-OXO-3-PYRIDAZINYL) PHENYL] -HYDRAZONO] PROPANDINITRILE.
KR1019930701800A KR100207145B1 (en) 1991-01-03 1992-01-03 (-)-((4- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenylhydrazono) propanedinitrile
JP4501428A JP2635445B2 (en) 1991-01-03 1992-01-03 (-)-[[4- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl] hydrazono] propanedinitrile
EP92901317A EP0565546B1 (en) 1991-01-03 1992-01-03 (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile
RO93-00896A RO111847B1 (en) 1991-01-03 1992-01-03 OPTICAL AL [4- (1,4,5,6-TETRAHYDRO-4-METHYL-6-OXO-3-PYRIDAZINYL) PHENYL HYDRAZONE PROPANDINITRILE, PREPARATION AND INTERMEDIATE PROCESSING PROCEDURE
US08/081,360 US5424428A (en) 1991-01-03 1992-01-03 (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]pr
GEAP19922483A GEP19991868B (en) 1991-01-03 1992-01-03 (-)-[[4-(1,4,5,6-Tetrahydro-4-Methyl-6- oxo-3-Pyridazinyl)Phenyl]-Hydrazono¬]Propane¬di¬nit¬rile
CA002099262A CA2099262C (en) 1991-01-03 1992-01-03 (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl]hydrazono]propanedinitrile
PL92310250A PL169415B1 (en) 1991-01-03 1993-06-25 methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile PL PL PL PL PL PL PL EN
PL92299920A PL169435B1 (en) 1991-01-03 1993-06-25 Method for the preparation of pure enantiomers of 6-(4-aminophenyl)-5-methyl-pyridazin--3(2H)-one PL PL PL PL PL PL PL PL
NO932367A NO300682B1 (en) 1991-01-03 1993-06-28 (-) - ££ 4- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl | hydrazono | propanedinitrile
BG97915A BG62002B1 (en) 1991-01-03 1993-06-29 (-)-//4-(1,4,5,6-terrahydro-4-methyl-6-oxo-pyridazinile)phenyl/-hy drazone/propandinitryl
US08/454,856 US5569657A (en) 1991-01-03 1995-05-31 (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile
HK117395A HK117395A (en) 1991-01-03 1995-07-20 (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]propanedinitrile
LVP-95-358A LV11174B (en) 1991-01-03 1995-11-30 (-)-££4- (1,4,5,6- tetrahydro- 4- methyl- 6- oxo- 3- pyridazinyl ) phenyl-|- hydrazono| propanedinitrile
CY187896A CY1878A (en) 1991-01-03 1996-04-05 (-)-((4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)-hydrazono)propanedinitrile
FI972077A FI109902B (en) 1991-01-03 1997-05-15 New cardiotonic agent, hypotensive and vasodilator - is optically pure (-)enantiomer of ((4-(1,4,5,6-tetra:hydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono)propane:di:nitrile
NO2001021C NO2001021I1 (en) 1991-01-03 2001-11-20 Levosimendan
LU90920C LU90920I2 (en) 1991-01-03 2002-05-17 Levosimendan (simday)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9100049.7 1991-01-03
GB919100049A GB9100049D0 (en) 1991-01-03 1991-01-03 (-)-6-(4-(dicyanomethylidenehydrazino)phenyl)-4,5-dihydro-5-methylpyridazin-3(2h)one
GB9118947.2 1991-09-05
GB919118947A GB9118947D0 (en) 1991-09-05 1991-09-05 Method for the optical resolution of racemic 6-(4-amino-phenyl)-methyl-pyridazin-3(2h)one and preparation of optically active derivatives thereof

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US5512572A (en) * 1992-05-06 1996-04-30 Orion-Yhtyma Oy Anti-ischemic medicament
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US5856480A (en) * 1994-11-11 1999-01-05 Nippon Soda Co., Ltd. Optically active compound
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JP2635445B2 (en) 1997-07-30
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DE69201640T2 (en) 1995-08-10
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NO932367L (en) 1993-06-28
BG62002B1 (en) 1998-12-30
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IL100553A0 (en) 1992-09-06
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US5512571A (en) 1996-04-30
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LV11174A (en) 1996-04-20
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EP0565546B1 (en) 1995-03-08
NO2001021I1 (en) 2001-12-03
IL100553A (en) 1995-12-31
BR1100737A (en) 2000-03-21
US5569657A (en) 1996-10-29
EE02946B1 (en) 1996-12-16
ATE119525T1 (en) 1995-03-15
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